Schedule M of Drugs Rules, 1945

7986 GI/2023 (1) REGD. No. D. L.-33004/99 The Gazette of India EXTRAORDINARY PART II—Section 3—Sub-section (i) PUBLISHED BY AUTHORITY No. 738] NEW DELHI, THURSDAY, DECEMBER 28, 2023/PAUSHA 7, 1945 CG-DL-E-05012024-251166 7986 GI/2023 (148) MINISTRY OF HEALTH AND FAMILY WELFARE (Department of Health and Family Welfare) NOTIFICATION New Delhi, the 28th December, 2023 G.S.R. 922(E).—Whereas, a draft of certain rules further to amend the Drugs Rules, 1945 was published as required under sub-section (1) of section 12 and sub-section (1) of section 33 of the Drugs and Cosmetics Act, 1940 (23 of 1940) (thereafter referred to as the said Act) vide notification of the Government of India in the Ministry of Health and Family Welfare (Department of Health and Family Welfare), number G.S.R. 999(E), dated the 5th October, 2018, published in the Gazette of India, Extraordinary, Part II, Section 3, Sub-section (i), inviting objections and suggestions from persons likely to be affected thereby, before the expiry of a period of thirty days from the date on which the copies of the said Official Gazette containing the said notification were made available to the public; And, whereas, copies of the said Gazette were made available to the public on 9th October, 2018; And, whereas, objections or suggestions received from the public on the said rules were considered by the Central Government; Now, therefore, in exercise of the powers conferred by sections 12 and 33 of the Drugs and Cosmetics Act, 1940 (23 of 1940), the Central Government, after consultation with the Drugs Technical Advisory Board constituted under section 5 of the said Act, hereby makes the following rules further to amend the Drugs Rules, 1945, namely:- 1. Short title and commencement.- (1) These rules may be called the Drugs (….. Amendment) Rules, 2023. (2) They shall come into force from the date of their publication in the Official Gazette. 2. In the Drugs Rules, 1945 (hereinafter referred to as the principal rules), in rule 74, in clause (o), for the words “Good Manufacturing Practices”, the words “Good Manufacturing Practices and Requirements of Premises, Plant and Equipment for Pharmaceutical Products” shall be substituted. 3. In the principal rules, in rule 76, in clause (8), for the words “Good Manufacturing Practices”, the words “Good Manufacturing Practices and Requirements of Premises, Plant and Equipment for Pharmaceutical Products” shall be substituted. 4. In the principal rules, in rule 78, in clause (p), for the words “Good Manufacturing Practices”, the words “Good Manufacturing Practices and Requirements of Premises, Plant and Equipment for Pharmaceutical Products” shall be substituted. 5. In the principal rules, for Schedule M, the following Schedule shall be substituted, namely:- SCHEDULE M [See rules 71, 74, 76 and 78] GOOD MANUFACTURING PRACTICES AND REQUIREMENTS OF PREMISES, PLANT AND EQUIPMENT FOR PHARMACEUTICAL PRODUCTS Note.—To achieve the objectives listed below, each licensee shall evolve appropriate methodology, systems and procedures which shall be documented and maintained for inspection and reference; and the manufacturing premises shall be used exclusively for production of drugs and no other manufacturing activity shall be undertaken therein. PART I GOOD MANUFACTURING PRACTICES FOR PHARMACEUTICAL PRODUCTS: MAIN PRINCIPLES 1. Pharmaceutical Quality System (PQS): 1.1. The manufacturer must assume responsibility for the quality of the pharmaceutical products to ensure that they are fit for their intended use, comply with the requirements of the licence and do not place patients at risk due to inadequate safety, quality or efficacy. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment of staff in different departments and at all levels within the company, the company’s suppliers and the distributors. To achieve this quality objective reliably there must be a comprehensively designed and correctly implemented pharmaceutical quality system incorporating Good Manufacturing Practices (GMP) and Quality Risk Management (QRM). 1.2. Senior management has the ultimate responsibility to ensure that an effective pharmaceutical quality system is in place, is adequately resourced, and that roles, responsibilities, and authorities are defined, communicated and implemented throughout the organisation. Senior management’s leadership and active participation in the pharmaceutical quality system is essential. This shall ensure the support and commitment of staff at all levels and sites within the organisation to the pharmaceutical quality system. 1.3. Quality management is a wide-ranging concept covering all matters that individually or collectively influence the quality of a product. It is the totality of the arrangements made with the object of ensuring that pharmaceutical products are of the quality required for their intended use. Quality management, therefore, incorporates Good Manufacturing Practices and other factors, including those outside the scope of this Part, such as product design and development. 1.4. Good Manufacturing Practices applies to the life-cycle stages from the manufacture of investigational medicinal products, technology transfer, and commercial manufacturing, until the product discontinuation. The product quality system can extend to the pharmaceutical development life-cycle stages and shall facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and manufacturing activities. All parts of the product quality system shall be adequately resourced and maintained, including being provided with sufficient competent personnel, suitable premises, equipment and facilities. 1.5. The product quality system appropriate to the manufacture of pharmaceutical products shall ensure that— (a) product realisation is achieved by designing, qualifying, planning, implementing, maintaining and continuously improving a system that allows the consistent delivery of products with appropriate quality attributes; (b) product and process knowledge is managed throughout all lifecycle stages; (c) pharmaceutical products are designed and developed in a way that takes into account, the requirements of GMP and other GXPs such as those of Good Laboratory Practices (GLP) and Good Clinical Practices (GCP); (d) production and quality control operations shall be clearly specified in a written form and GMP requirements are adopted; (e) managerial responsibilities are clearly specified in the job descriptions; (f) arrangements are made for the manufacture, supply and use of the correct starting and packaging materials, the selection and monitoring of suppliers and for verifying that each delivery is the correct material from the approved supply chain; (g) all necessary controls on starting materials, intermediate products, and bulk products and other in process controls, calibrations and validations are carried out; (h) the finished product is correctly processed and checked, according to the defined procedures; (i) pharmaceutical products are not sold or supplied before the authorised persons have certified that each production batch has been produced and controlled in accordance with the requirements of the licence and other applicable regulations relevant to the production, control and release of pharmaceutical products; (j) processes are in place to ensure the management of outsourced activities; (k) satisfactory arrangements exist to ensure, as far as possible, that the pharmaceutical products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf-life; (l) there is a procedure for self-inspection or quality audit that regularly appraises the effectiveness and applicability of the product quality system; (m) product and processes are monitored and the results taken into account in batch release, in the investigation of deviations and, with a view to taking preventive action to avoid potential deviations occurring in the future; (n) arrangements are in place for the prospective evaluation and approval of planned changes and their approval prior to their implementation, taking into account regulatory notification and approval where required. After implementation of any change, an evaluation is undertaken to confirm that the quality objectives were achieved and that there was no unintended adverse impact on product quality; (o) regular reviews of the quality of pharmaceutical products are conducted with the objective of verifying the consistency of the process and identifying where there is a need for improvement; (p) a state of control is established and maintained by developing and using effective monitoring and control systems for process performance and product quality; (q) continual improvement is facilitated through the implementation of quality improvements appropriate to the current level of process and product knowledge; (r) there is a system for QRM; and (s) deviations, suspected product defects and other problems are reported, investigated and recorded. An appropriate level of root cause analysis is applied during such investigations. The most likely root causes shall be identified and appropriate corrective and preventive actions shall be identified and taken. The effectiveness of corrective and preventive actions shall be monitored. 1.6. There shall be periodic management reviews, with the involvement of senior management, of the operation of the product quality system to identify opportunities for continual improvement of products, processes and the system itself. Unless otherwise justified, such reviews shall be conducted at least annually. 1.7. The product quality system shall be defined and documented. A quality manual or an equivalent documentation shall be established and shall contain a description of the quality management system including management responsibilities. 2. Quality Risk Management (QRM): 2.1. Quality Risk Management is a systematic process for the assessment, control, communication and review of risks to the quality of the medicinal product. It can be applied both proactively and retrospectively. 2.2. Quality Risk Management shall ensure that the- (a) evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient; (b) level of effort, formality and documentation of the QRM process is commensurate with the level of risk. 2.3. Product quality review 2.3.1. Regular, periodic or rolling quality reviews of all pharmaceutical products, including products for export only, shall be conducted with the objective of verifying the consistency of the existing process and the appropriateness of current specifications for both starting materials and finished product, to highlight any trends and to identify product and process improvements. 2.3.2. Such reviews shall normally be conducted and documented annually, taking into account previous reviews, and shall include at least,- (a) review of starting materials and packaging materials used for the product, especially those from new sources and in particular the review of supply chain traceability of active substances; (b) a review of critical in-process controls, and finished product results; (c) a review of all batches that failed to meet established specifications and their investigation; (d) a review of all significant deviations or non-conformity, the related investigations and the effectiveness of resultant corrective and preventive actions taken; (e) a review of all changes made to the processes or analytical methods; (f) a review of dossier variations submitted, granted or refused; (g) a review of the results of the stability monitoring programme and any adverse trends; (h) a review of all quality related returns, complaints and recalls and the investigations performed at the time; (i) a review of adequacy of any other previous corrective actions on product processes or equipment; (j) post marketing commitments for new dossiers and variations to the dossiers; (k) the qualification status of relevant equipment and utilities, e.g., heating, ventilation and air conditioning, water or compressed gases and a review of the results of monitoring the output of such equipment and utilities; and (l) a review of technical agreements to ensure that they are up to date. 2.3.3. The manufacturer shall evaluate the results of the review and an assessment shall be made as to whether corrective and preventive actions or any revalidation shall be undertaken, under the product quality system. Corrective and preventive actions shall be completed in a timely and effective manner, according to documented procedures. There shall be procedures for the on-going management and review of these actions, and the effectiveness of these procedures shall be verified during self-inspection. Quality reviews may be grouped by product type e.g., solid dosage forms, liquid dosage forms, or sterile products, where scientifically justified. There shall be a technical agreement in place between the various parties that defines their respective responsibilities in producing the quality review. The authorised person responsible for final batch certification shall ensure that the quality review is performed in a timely manner and is accurate. 3. Good manufacturing practices for pharmaceutical products: 3.1. Good manufacturing practices is that part of quality management which ensures that products are consistently produced and controlled according to the quality standards appropriate to their intended use as required by the conditions of licence, clinical trial permission or product specifications. Good manufacturing practices are concerned with both production and quality control. Good manufacturing practices are aimed primarily at managing and minimising the risks inherent in pharmaceutical manufacture to ensure the quality, safety and efficacy of products. Under Good manufacturing practices— (1) all manufacturing processes are clearly defined, systematically reviewed for associated risks in the light of scientific knowledge and experience and shown to be capable of consistently manufacturing pharmaceutical products of the required quality that comply with their specifications; (2) qualification and validation are performed; (3) all necessary resources are provided, including the following, namely- (a) sufficient and appropriately qualified and trained personnel; (b) adequate premises and space; (c) suitable equipment and services; (d) appropriate materials, containers and labels; (e) approved procedures and instructions; (f) suitable storage and transport; (g) adequate personnel, laboratories and equipment are in process controls; and (h) books necessary for ensuring compliance with the requirements relating to product development, manufacturing and quality control testing such as the Drugs and Cosmetics Act, 1940, the Drugs Rules, 1945, the Indian Pharmacopoeia (Current Edition) and other relevant books and guidance documents officially issued by the Ministry of Health and Family Welfare, Government of India; (4) instructions and procedures are written in clear and unambiguous language, specifically applicable to the facilities provided; (5) procedures are carried out correctly and personnel are trained to do so; (6) records are made (manually or by recording instruments or by both) during manufacture to show that all the steps required by the defined procedures and instructions have in fact been taken and that the quantity and quality of the product are as expected. Any significant deviations are fully recorded and investigated with the objective of determining the root cause and appropriate corrective and preventive action is implemented; (7) records covering manufacture and distribution, which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form; (8) the proper storage and distribution of the products which minimises any risk to their quality; (9) a system is available to recall any batch of product from sale or supply; and (10) complaints about marketed products are examined, the causes of quality defects investigated and appropriate measures are taken in respect of the defective products to prevent recurrence. 4. Sanitation and hygiene: A high level of sanitation and hygiene shall be practiced in every aspect of the manufacture of drugs. The scope of sanitation and hygiene covers personnel, premises, equipment and apparatus, production materials and containers, products for cleaning and disinfection and anything that could become a source of contamination to the product. Potential sources of contamination shall be eliminated through an integrated comprehensive programme of sanitation and hygiene. 5. Qualification and validation: 5.1. In accordance with GMP, each pharmaceutical company shall identify what qualification and validation work is required to prove that the critical aspects of their particular operation is controlled. 5.2. The key elements of a qualification and validation programme of a company shall be clearly defined and documented in a validation master plan. 5.3. Qualification and validation shall establish and provide documentary evidence that— (a) the premises, supporting utilities, equipment and processes have been designed in accordance with the requirements for good manufacturing practices [design qualification (DQ)]; (b) the premises, supporting utilities and equipment have been built and installed in compliance with their design specifications [installation qualification (IQ)]; (c) the premises, supporting utilities and equipment operate in accordance with their design specifications [operational qualification (OQ)]; (d) a specific process shall consistently produce a product meeting its predetermined specifications and quality attributes [process validation (PV), also called performance qualification (PQ)]. 5.4. Any aspect of operation, including significant changes to the premises, facilities, equipment or processes, which may affect the quality of the product, directly or indirectly, shall be qualified and validated. 5.5. Qualification and validation shall not be considered as one-off exercises. An on-going programme shall follow their first implementation and shall be based on a periodic review. 5.6. The commitment to maintain continued validation status shall be stated in the relevant company documentation, such as the quality manual or validation master plan. 5.7. The responsibility for performing validation shall be clearly defined. 5.8. Validation studies are an essential part of good manufacturing practices and shall be conducted in accordance with predefined and approved protocols. 5.9. A written report summarising the results recorded and the conclusions reached shall be prepared and stored. 5.10. Processes and procedures shall be established on the basis of the results of the validation performed. 5.11. Particular attention shall be paid to the validation of analytical test methods, automated systems and cleaning procedures. 5.12. The premises, equipment or process system, facility qualification and validation shall be carried out. 6. Complaints and adverse reaction: 6.1. All complaints and other information concerning potentially defective products shall be carefully reviewed according to the written procedures and corrective action shall be taken. 6.2. A person responsible for handling the complaints and deciding the measures to be taken shall be designated, together with sufficient supporting staff to assist him or her. If this person is different from the authorised person, the latter shall be made aware of any complaint, investigation or recall. 6.3. There shall be written procedures describing the action to be taken, including the need to consider a recall, in the case of a complaint concerning a possible product defect. 6.4. Special attention shall be given to establishing that the product that gave rise to a complaint was defective. 6.5. Any complaint concerning a product defect shall be recorded with all the original details and thoroughly investigated. The person responsible for Quality Control (QC) shall normally be involved in the review of such investigations. 6.6. If a product defect is identified or suspected in a batch, consideration shall be given as to whether other batches shall be checked in order to determine whether they are also affected. In particular, other batches that may contain reprocessed product from the defective batch shall be investigated. 6.7. Where necessary, appropriate follow-up action, possibly including product recall, shall be taken after investigation and evaluation of the complaint. 6.8. All decisions made and measures taken as a result of a complaint shall be recorded and referenced to the corresponding batch records. 6.9. Complaint records shall be regularly reviewed for any indication of specific or recurring problems that require attention and might justify the recall of marketed products. 6.10. The licensing authorities shall be informed if a manufacturer is considering action following the faulty manufacture, product deterioration, a suspect product or any other serious quality problems with a product. 6.11. The licensee shall have a pharmacovigilance system in place for collecting, processing and forwarding the reports to the licensing authorities for information on the adverse drug reactions emerging from the use of drugs manufactured or marketed by the licensee. 7. Product recalls: 7.1. There shall be a system to recall from the market, products known or suspected to be defective. 7.2. The authorised person shall be responsible for the execution and coordination of recalls. He or she shall have sufficient staff to handle all aspects of the recalls with the appropriate degree of urgency. 7.3. There shall be established written procedures, which are regularly reviewed and updated, for the organisation of any recall activity. Recall operations shall be capable of being initiated at the required level in the distribution chain. 7.4. An instruction shall be included in the written procedures to store recalled products in a secure segregated area. 7.5. The licensing authorities shall be informed of any intention to recall the product because it is, or is suspected of being, defective. 7.6. The distribution records shall be readily available to the authorised person, and they shall contain sufficient information on wholesalers and directly supplied customers to permit an effective recall. 7.7. The progress of the recall process shall be monitored and recorded. Records shall include the disposition of the product. A final report shall be issued, including reconciliation between the delivered and recovered quantities of the products. 7.8. The effectiveness of the arrangements for recall shall be tested and evaluated from time to time. 7.9. A prompt and effective product recall system of defective products shall be devised for timely information of all concerned stockists, wholesalers, suppliers, up to the retail level within the shortest period. The licensee may make use of both print and electronic media in this regard. 7.10. There shall be an established written procedure in the form of Standard Operating Procedure for effective recall of products distributed by the licensee. Recall operations shall be capable of being initiated, so as to effectively reach at the level of each distribution channel. 7.11. The distribution records shall be readily made available to the persons designated for recall. 7.12. The designated person shall record a final report issued, including reconciliation between the delivered and the recovered quantities of the products. 7.13. The effectiveness of the arrangements for recall shall be evaluated from time to time. 7.14. The recalled products shall be stored separately in a secured segregated area pending final decision on them. 8. Change control: 8.1. A formal change control system shall be established to evaluate all changes that may affect the production and control of the product. 8.2. Written procedures shall cover the identification, documentation, appropriate review, and approval of changes in raw materials, specifications, analytical methods, facilities, support systems, equipment (including computer hardware), processing steps, labelling and packaging materials and computer software. 8.3. Any proposals for relevant changes to GMP shall be drafted, reviewed and approved by the appropriate organisational units and reviewed and approved by the quality units. 8.4. The potential impact of the proposed change on the quality of the intermediate or Active Pharmaceutical Ingredient (API) or finished product shall be evaluated. A classification procedure may help in determining the level of testing, validation and documentation needed to justify changes to a validated process. Changes can be classified (e.g., as minor or major) depending on their nature and extent and the effect of these changes may have on the process. Scientific judgement shall be used to determine what additional testing and validation studies are appropriate to justify a change in a validated process. 8.5. When implementing the approved changes, measures shall be taken to ensure that all the documents are affected by the changes as revised. 8.6. After the change has been implemented there shall be an evaluation of the first batch produced or tested under the change. 8.7. The potential for critical changes to affect established retest or expiry dates shall be evaluated. If necessary, samples of the intermediate or API or finished product produced by the modified process can be placed on an accelerated stability programme or can be added to the stability monitoring programme or both. 9. Production under loan licence or contract and contract analysis and other activities: 9.1. Principle- Production under loan licence or contract and contract analysis and any other activity covered by good manufacturing practices must be correctly defined, agreed and controlled in order to avoid misunderstandings that could result in a product, or work or analysis, of unsatisfactory quality. 9.2. General 9.2.1. All arrangements for production under loan licence or contract and analysis, including technology transfer and any proposed changes in technical or other arrangements, shall be in accordance with the licence for the product concerned. 9.2.2. The contract shall permit the loan licensee or contract giver to audit the facilities and activities of the manufacturing facility provider or contract acceptor or mutually agreed sub-contractors. 9.2.3. In the case of contract analysis, the final approval for release must be given by the authorised person in accordance with good manufacturing practices and the licence as specified in the contract. 9.3. Loan licensee or contract giver 9.3.1. The product quality system of the loan licensee or contract giver shall include the control and review of any outsourced activities. The contract giver is responsible for assessing the legality, suitability and competence of the manufacturing facility provider or contract acceptor to successfully carry out the work or tests required, for approval for contract activities, and for ensuring by means of the contract that the principles of good manufacturing practices incorporating quality risk management principles are followed. 9.3.2. The loan licensee or contract giver shall provide the manufacturing facility provider or contract acceptor with all the information necessary to carry out the contracted operations correctly in accordance with the licence and any other legal requirements. The loan licensee or contract giver shall ensure that the manufacturing facility provider or contract acceptor is fully aware of any hazards associated with the product, work or tests that might pose a risk to premises, equipment, personnel, other materials or other products. 9.3.3. The loan licensee or contract giver shall review and assess the records and results related to the outsourced activities. The contract giver shall ensure that all the products and materials delivered by the manufacturing facility provider or contract acceptor have been processed in accordance with good manufacturing practices and the licence; comply with their specifications and that the product has been released by the authorised person in accordance with good manufacturing practices and the licence. 9.3.4. The loan licensee or contract giver shall monitor and review the performance of the manufacturing facility provider or contract acceptor including the implementation of any needed improvements and their effectiveness. 9.3.5. The loan licensee or contract giver is responsible for ensuring that the manufacturing facility provider or contract acceptor understands that his or her activities may be subject to inspection by the competent authorities. 9.4. Manufacturing facility provider or contract acceptor 9.4.1. The manufacturing facility provider or contract acceptor must have adequate premises, equipment, knowledge, experience and competent personnel to satisfactorily carry out the work ordered by the loan licensee or contract giver. Contract manufacture shall be undertaken only by a manufacturer who holds a valid manufacturing licence. 9.4.2. The manufacturing facility provider or contract acceptor shall not pass to a third party any of the work entrusted to him or her under the contract without the loan licensee or contract giver’s prior evaluation and approval of the arrangements. Arrangements made between the manufacturing facility provider or contract acceptor and any third party shall ensure that information and knowledge, including that from assessments of the suitability of the third party, are made available in the same way as between the original loan licensee or contract giver and contract acceptor. 9.4.3. The manufacturing facility provider or contract acceptor shall refrain from any activity (including unauthorised changes outside the terms of the contract) that may adversely affect the quality of the product manufactured oranalysed or both for the loan licensee or contract giver. 9.5. Contract 9.5.1. There must be a written contract between the loan licensee or contract giver and the manufacturing facility provider or contract acceptor which clearly establishes the responsibilities of each party, covering the outsourced activities, the products or operations to which they are related, communication processes relating to the outsourced activities and any technical arrangements made in connection with it. 9.5.2. The contract must clearly state the way in which the authorised person, in releasing each batch of product for sale or issuing the certificate of analysis, exercises his or her full responsibility and ensures that each batch has been manufactured in, and checked for, compliance with the requirements of the licence. 9.5.3. Technical aspects of the contract shall be drawn up by competent persons with suitable knowledge of pharmaceutical technology, analysis and good manufacturing practices. 9.5.4. All arrangements for production and analysis must be in accordance with the licence and agreed by both parties. 9.5.5. The contract shall clearly describe who is responsible for contracted activities e.g., knowledge management, technology transfer, supply chain, sub-contracting, testing and releasing materials and undertaking production and quality control, including in-process controls, and who has responsibility for sampling and analysis. In the case of contract analysis, the contract shall state whether or not the manufacturing facility provider or contract acceptor shall take samples at the premises of the manufacturer. 9.5.6. Manufacturing, analytical and distribution records, and reference samples, shall be kept by, or be available to, the loan licensee or contract giver. Any records relevant to assessing the quality of a product in the event of complaints or a suspected defect, or to investigating a suspected product or laboratory fraud, must be accessible and specified in the procedures of the loan licensee or contract giver. 9.5.7. The contract shall describe the handling of starting materials, intermediate, bulk and finished products, if they are rejected. It shall also describe the procedure to be followed if the contract analysis shows that the tested product must be rejected. 10. Self-inspection, quality audits and suppliers’ audits and approval: 10.1. The purpose of self-inspection is to evaluate the manufacturer’s compliance with good manufacturing practices in all aspects of production and QC. The self-inspection programme shall be designed to detect any shortcomings in the implementation of good manufacturing practices and to recommend the necessary corrective actions. Self-inspections shall be performed routinely, and may be, in addition, performed on special occasions e.g., in the case of product recall or repeated rejections, or when an inspection by the regulatory authorities is announced. The team responsible for self-inspection shall consist of personnel who can evaluate the implementation of good manufacturing practices objectively. All recommendations for corrective action shall be implemented. The procedure for self-inspection shall be documented and there shall be an effective follow-up programme. 10.2. Items for self-inspection-Written instructions for self-inspection shall be established to provide a minimum and uniform standard of requirements. These may include questionnaires on good manufacturing practices requirements covering at least the following items, namely:- (a) personnel; (b) premises including personnel facilities; (c) maintenance of buildings and equipment; (d) storage of starting materials and finished products; (e) equipment; (f) production and in-process controls; (g) quality control (QC); (h) documentation; (i) sanitation and hygiene; (j) validation and revalidation programmes; (k) calibration of instruments or measurement systems; (l) recall procedures; (m) complaints management; (n) labels control; and (o) results of previous self-inspections and any corrective steps taken. 10.3. Self-inspection team- Management shall appoint a self-inspection team consisting of experts in their respective fields who are familiar with GMP. The members of the team may be appointed from inside or outside the company. 10.4. Frequency of self-inspection- The frequency with which self-inspections are conducted may depend on company requirements but shall be at least once in a year. The frequency shall be stated in the procedure. 10.5. Self-inspection report- A report shall be made at the completion of a self-inspection. The report shall include the following, namely:- (a) self-inspection results; (b) evaluation and conclusions; and (c) recommended corrective actions. 10.6. Follow-up action- There shall be an effective follow-up programme. The company management shall evaluate both the self-inspection report and the corrective actions as necessary. 10.7. Quality audit- It may be useful to supplement self-inspections with a quality audit. A quality audit consists of an examination and assessment of all or part of a quality system with the specific purpose of improving it. A quality audit is usually conducted by outside or independent specialists or a team designated by the management for this purpose. Such audits may also be extended to suppliers and contractors. 10.8. Suppliers’ audits and approval 10.8.1. The person responsible for quality control shall have responsibility, together with other relevant departments, for approving suppliers who can reliably supply starting and packaging materials that meet established specifications. 10.8.2. Before suppliers are approved and included in the approved suppliers’ list or specifications, they shall be evaluated. The evaluation shall take into account a supplier’s history and the nature of the materials to be supplied. If an audit is required, it shall determine the supplier’s ability to conform with good manufacturing practices standards. 11. Personnel: 11.1. Principle-The establishment and maintenance of a satisfactory system of Quality Assurance (QA) and the correct manufacture and control of pharmaceutical products and active ingredients rely upon people. For this reason there must be sufficient qualified personnel to carry out all the tasks for which the manufacturer is responsible. Individual responsibilities shall be clearly defined and understood by the persons concerned and recorded as written descriptions. 11.2. General 11.2.1. The manufacturer shall have an adequate number of personnel with the necessary qualifications and practical experience. The responsibilities placed on any one individual shall not be so extensive as to present any risk to quality. 11.2.2. Responsible staff shall have its specific duties recorded in written descriptions and adequate authority to carry out its responsibilities. Its duties may be delegated to designated deputies with a satisfactory level of qualifications. There shall be no gaps or unexplained overlaps in the responsibilities of personnel concerned with the application of good manufacturing practices. The manufacturer shall have an organisation chart. 11.2.3. All personnel shall be aware of the principles of good manufacturing practices that affect them and receive initial and continuing training, including hygiene instruction, relevant to their needs. All personnel shall be motivated to support the establishment and maintenance of high quality standards. 11.2.4. Steps shall be taken to prevent unauthorised people from entering production, storage and QC areas. Personnel who do not work in these areas shall not use them as a passageway. 11.3. Key personnel 11.3.1. Key personnel include the heads of production, the heads of quality units and the authorised person. The quality units typically comprise the QA and QC functions. In some cases, these could be combined in one department. The authorised person may also be responsible for one or more of these quality units. Normally, key posts shall be occupied by full-time personnel. The heads of production and quality units shall be independent of each other. In large organisations, it may be necessary to delegate some of the functions; however, the responsibility cannot be delegated. 11.3.2. Key personnel responsible for supervising the production and quality units for pharmaceutical products shall possess the qualifications and experience as specified under the rules. Their education shall include the study of an appropriate combination of the following, namely:- (a) chemistry (analytical or organic) or biochemistry; (b) chemical engineering; (c) microbiology; (d) pharmaceutical sciences and technology; (e) pharmacology and toxicology; (f) physiology; or (g) other related sciences. They shall also have adequate practical experience in the manufacture and QA of pharmaceutical products. In order to gain such experience, a preparatory period may be required, during which they shall perform their duties under professional guidance. The scientific education and practical experience of experts shall be such, so as to enable them to exercise independent professional judgement, based on the application of scientific principles and understanding to the practical problems encountered in the manufacture and QC of pharmaceutical products. 11.3.3. The heads of the production and the quality units shall have shared, or jointly exercised, responsibilities relating to quality. They may include the following, namely:- (a) authorisation of written procedures and other documents, including amendments; (b) monitoring and control of the manufacturing environment; (c) plant hygiene; (d) process validation and calibration of analytical apparatus; (e) training, including the application and principles of QA; (f) approval and monitoring of suppliers of materials; (g) approval and monitoring of contract manufacturers; (h) designation and monitoring of storage conditions for materials and products; (i) performance and evaluation of in-process controls; (j) retention of records; (k) monitoring of compliance with good manufacturing practices requirements; and (l) inspection, investigation and taking of samples in order to monitor factors that may affect product quality. 11.3.4. The head of production has the following responsibilities, namely:- (a) to ensure that products are produced and stored in accordance with the appropriate documentation in order to obtain the required quality; (b) to approve the instructions relating to production operations, including the in-process controls and to ensure their strict implementation; (c) to ensure that the production records are evaluated and signed by a designated person; (d) to check the maintenance of the department, premises and equipment; (e) to ensure that the appropriate process validations and calibrations of control equipment are performed and recorded and the reports are made available; and (f) to ensure that the required initial and continuing training of production personnel is carried out and adapted according to need. 11.3.5. The heads of the quality units generally have the following responsibilities, namely:- (a) to approve or reject starting materials, packaging materials and intermediate, bulk and finished products in relation to their specifications; (b) to evaluate batch records; (c) to ensure that all necessary testing is carried out; (d) to approve sampling instructions, specifications, test methods and other QC procedures; (e) to approve and monitor analysis carried out under contract; (f) to check the maintenance of the department, premises and equipment; (g) to ensure that the appropriate validations, including those of analytical procedures and calibrations of control equipment are carried out; (h) to ensure that the required initial and continuing training of quality unit personnel is carried out and adapted according to need; (i) establishment, implementation and maintenance of the quality system; (j) supervision of the regular internal audits or self-inspections; (k) participation in external audit (vendor audit); and (l) participation in validation programmes. 11.3.6. The authorised person is responsible for compliance with technical or regulatory requirements related to the quality of finished products and the approval for the release of finished product for sale or supply. 11.3.7. Assessment of finished products shall embrace all relevant factors, including the production conditions, the results of in-process testing, the manufacturing (including packaging) documentation, compliance with the specification for the finished product and an examination of the finished pack. 11.3.8. No batch of product is to be released for sale or supply prior to certification by the authorised persons. 11.3.9. The authorised person responsible for approving a batch for release shall always ensure that the following requirements have been met:- (a) the licence and the approval requirements for the product have been met for the batch concerned; (b) the principles and guidelines of GMP, as laid down in this Part, have been followed; (c) the principal manufacturing and testing processes have been validated; (d) all the necessary checks and tests have been performed and account taken of the production conditions and manufacturing records; (e) any planned changes or deviations in manufacturing or QC have been notified in accordance with a well-defined reporting system before any product is released. Such changes may need notification and approval by the licensing authority; (f) any additional sampling, inspection, tests and checks have been carried out or initiated, as appropriate, to cover planned changes and deviations; (g) all necessary production and QC documentation has been completed and endorsed by supervisors trained in appropriate disciplines; (h) appropriate audits, self-inspections and spot-checks are carried out by experienced and trained staff; (i) approval has been given by the head of quality control; and (j) all relevant factors have been considered, including the factor associated with the output batch directly under review (e.g., sub-division of output batches from a common input, factors associated with continuous production runs). 11.3.10. The function of the approval of the release of a finished batch or a product can be delegated to a designated person with appropriate qualifications and experience who will release the product in accordance with an approved procedure. This is normally done by quality assurance by means of batch review. 11.4. Training 11.4.1. The manufacturer shall provide training in accordance with a written programme for all personnel whose duties take them into manufacturing areas or into the control laboratories (including the technical, maintenance and cleaning personnel) and for other personnel as required. 11.4.2. Besides basic training on the theory and practice of good manufacturing practices, newly recruited personnel shall receive training appropriate to the duties assigned to them. Continuous training shall also be given, and its practical effectiveness be assessed periodically. Approved training programmes shall be available. Training records shall be kept. 11.4.3. Personnel working in areas where contamination is a hazard e.g., clean areas or areas where highly active, toxic, infectious or sensitising materials are handled, shall be given specific training. 11.4.4. The concept of quality assurance and all the measures which aid its understanding and implementation shall be fully discussed during the training sessions. 11.4.5. Visitors or untrained personnel shall preferably not be taken into the production and quality control areas. If this is unavoidable, they shall be given relevant information in advance (particularly about personal hygiene) and the prescribed protective clothing. They shall be closely supervised. 11.4.6. Consultant and contract staff shall be qualified for the services they provide. Evidence of this shall be included in the training records. 11.5. Personal hygiene 11.5.1. All personnel, prior to and during employment, as appropriate, shall undergo health checkups. Personnel conducting visual inspections shall also undergo periodic eye checkups. 11.5.2. All personnel shall be trained in the practices of personal hygiene. A high level of personal hygiene shall be observed by all those concerned with manufacturing processes. In particular, personnel shall be instructed to wash and sanitise their hands before entering production areas. Signs to this effect shall be posted and instructions are complied with. 11.5.3. Any person shown at any time to have an apparent illness or open lesions that may adversely affect the quality of products shall not be allowed to handle starting materials, packaging materials, in-process materials or drugs until his or her health condition is no longer judged to be a risk. 11.5.4. All employees shall be instructed and encouraged to report to their immediate supervisor any conditions (relating to plant, equipment or personnel) that they consider may adversely affect the products. 11.5.5. Direct contact shall be avoided between the operator’s hands and starting materials, primary packaging materials and intermediate or bulk products. 11.5.6. To ensure protection of the product from contamination, personnel shall wear clean body coverings appropriate to the duties they perform, including appropriate hair covering. Used clothes, if reusable, shall be stored in a separate closed containers until properly laundered and, if necessary, disinfected or sterilised. 11.5.7. Smoking, eating, drinking, chewing, and keeping plants, food, drink, smoking material and personal medicines shall not be permitted in production, laboratory and storage areas, or in any other areas where they might adversely influence product quality. 11.5.8. Personal hygiene procedures, including the wearing of protective clothing, shall apply to all persons entering production areas, whether they are temporary or full-time employees or non employees, e.g., contractors’ employees, visitors, senior managers and inspectors. 12. Premises: 12.1. Principle- Premises must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. They shall conform to the conditions as laid down in the Factories Act, 1948 (63 of 1948). 12.2. General 12.2.1. The layout and design of premises must aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross contamination, build-up of dust or dirt, and in general, any adverse effect on the quality of products. 12.2.2. Where dust is generated (e.g., during sampling, weighing, mixing and processing operations or packaging of powder), measures shall be taken to avoid cross-contamination and facilitate cleaning. 12.2.3. Premises shall be situated in an environment that, when considered together with measures to protect the manufacturing process, presents minimum risk of causing any contamination of materials or products. 12.2.4. Premises used for the manufacture of finished products shall be suitably designed and constructed to facilitate good sanitation. 12.2.5. Premises shall be carefully maintained, and it shall be ensured that repair and maintenance operations do not present any hazard to the quality of products. 12.2.6. Premises shall be cleaned and, where applicable, disinfected according to detailed written procedures and records shall be maintained. 12.2.7. Electrical supply, lighting, temperature, humidity and ventilation shall be appropriate and they do not adversely affect, directly or indirectly, either the pharmaceutical products during their manufacture and storage or the accurate functioning of equipment. 12.2.8. The design, installation, qualification and maintenance of the Heating, Ventilation, Air Conditioning (HVAC) systems of the manufacturing plant shall be carried out. 12.2.9. Premises shall be designed and equipped so as to afford maximum protection against the entry of insects, birds or other animals. There shall be a procedure for rodent and pest control. 12.2.10. Premises shall be designed to ensure the logical flow of materials and personnel. 12.3. Ancillary areas 12.3.1. Rest and refreshment rooms shall be separate from manufacturing and control areas. 12.3.2. Facilities for changing and storing clothes and for washing and toilet purposes shall be easily accessible and appropriate for the number of users. Toilets shall not communicate directly with production or storage areas. 12.3.3. Maintenance workshops shall, if possible be separated from production areas. Whenever parts and tools are stored in the production area, they shall be kept in rooms or lockers reserved for that use. 12.3.4. Animal houses shall be well isolated from other areas, with separate entrance (animal access) and air-handling facilities. 12.4. Storage areas 12.4.1. Storage areas shall be of sufficient capacity to allow orderly storage of the various categories of materials and products with proper separation and segregation; starting and packaging materials, intermediates, bulk and finished products, products in quarantine and released, rejected, returned or recalled products. 12.4.2. Storage areas shall be designed or adapted to ensure good storage conditions. In particular, they shall be clean, dry, sufficiently lit and maintained within acceptable temperature limits. Where special storage conditions are required (e.g., temperature, humidity) they shall be provided, controlled, monitored and recorded, where appropriate. 12.4.3. Receiving and dispatch bays shall be separated and shall protect the materials and products from the weather. Receiving areas shall be designed and equipped to allow containers of incoming materials to be cleaned, if necessary, before storage. 12.4.4. Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorised personnel. Any system replacing the physical quarantine shall give equivalent security. 12.4.5. Segregation shall be provided for the storage of rejected, recalled or returned materials or products. 12.4.6. Highly active and radioactive materials, narcotics, other dangerous drugs, and substances presenting special risks of abuse, fire or explosion shall be stored in safe and secure areas. 12.4.7. Printed packaging materials are considered critical to the conformity of the pharmaceutical product to its labelling and special attention shall be paid to sampling and the safe and secure storage of these materials. 12.4.8. There shall normally be a separate sampling area for starting materials. If sampling is performed in the storage area, it shall be conducted in such a way so as to prevent contamination or cross-contamination. 12.5. Weighing areas-The weighing of starting materials and the estimation of yield by weighing shall be carried out in separate weighing areas designed for that use, for example, with provisions for dust control. Such areas may be part of either storage or production areas. 12.6. Production areas 12.6.1. In order to minimise the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities must be available for the production of particular pharmaceutical products, such as highly sensitising materials (e.g., penicillins) or biological preparations (e.g., live microorganisms). The production of certain other highly active products, such as some antibiotics, hormones, cytotoxic substances and non-pharmaceutical products, shall not be conducted in the same facilities. In exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations (including cleaning validation) are made. The manufacture of technical poisons, such as pesticides and herbicides, shall not be allowed in premises used for the manufacture of pharmaceutical products. 12.6.2. Premises shall preferably be laid out in such a way so as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels. 12.6.3. The adequacy of the working and in-process storage space shall permit the orderly and logical positioning of equipment and materials so as to minimise the risk of confusion between different pharmaceutical products or their components, to avoid cross-contamination and to minimise the risk of omission or wrong application of any of the manufacturing or control steps. 12.6.4. Where starting and primary packaging materials and intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) shall be smooth and free from cracks and open joints, shall not shed particulate matter and shall permit easy and effective cleaning and, if necessary, disinfection. 12.6.5. Pipework, light fittings, ventilation points and other services shall be designed and sited to avoid the creation of recesses that are difficult to clean. As far as possible, for maintenance purposes, they shall be accessible from outside the manufacturing areas. 12.6.6. Drains shall be of adequate size and designed and equipped to prevent back-flow. Open channels shall be avoided where possible, but if they are necessary they shall be shallow to facilitate cleaning and disinfection. 12.6.7. Production areas shall be effectively ventilated, with air-control facilities (including filtration of air to a sufficient level to prevent contamination and cross-contamination, as well as control of temperature and, where necessary, humidity) appropriate to the products handled, to the operations undertaken and to the external environment. These areas shall be regularly monitored during both production and non-production periods so as to ensure compliance with their design specifications. 12.6.8. Premises for the packaging of pharmaceutical products shall be specifically designed and laid out so as to avoid mix ups, contamination or cross-contamination. 12.6.9. Production areas shall be well lit, particularly where visual online controls are carried out. 12.7. Quality Control (QC) areas 12.7.1. QC laboratories shall be separated from production areas. Areas where biological, microbiological or radioisotope test methods are employed shall be separated from each other. 12.7.2. QC laboratories shall be designed to suit the operations to be carried out in them. Sufficient space shall be given to avoid mix ups and cross-contamination. There shall be adequate suitable storage space for samples, reference standards (if necessary, with cooling), solvents, reagents and records. 12.7.3. The design of the laboratories shall take into account the suitability of construction materials, prevention of fumes, and ventilation. There shall be separate air supply to laboratories and production areas. Separate air-handling units and other provisions are needed for biological, microbiological and radioisotope laboratories. 12.7.4. A separate room may be needed for instruments to protect them against electrical interference, vibration, contact with excessive moisture and other external factors or where it is necessary to isolate the instruments. 13. Equipment: 13.1. Equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. The layout and design of equipment must aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt, and, in general, any adverse effect on the quality of products. 13.2. Equipment shall be installed in such a way so as to minimise any risk of error or of contamination. 13.3. Fixed pipework shall be clearly labelled to indicate the contents and, where applicable, the direction of flow. 13.4. All service pipework and devices shall be adequately marked and special attention paid to the provision of non-interchangeable connections or adaptors for dangerous gases and liquids. 13.5. Balances and other measuring equipment of an appropriate range and precision shall be available for production and control operations and shall be calibrated according to a fixed schedule. 13.6. Production equipment shall be thoroughly cleaned according to a fixed schedule. 13.7. Laboratory equipment and instruments shall be suited to the testing procedures undertaken. 13.8. Washing, cleaning and drying equipment shall be chosen and used so as not to be a source of contamination. 13.9. Production equipment shall not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be reactive, additive or absorptive to an extent that would affect the quality of the product. 13.10. Defective equipment shall be removed from production and QC areas. If this is not possible, it shall be clearly labelled as defective to prevent use. 13.11. Closed equipment shall be used whenever appropriate. Where open equipment is used or equipment is opened, precautions shall be taken to minimize the contamination. 13.12. Non-dedicated equipment shall be cleaned according to validated cleaning procedures between being used for production of different pharmaceutical products to prevent cross-contamination. 13.13. Current drawings of critical equipment and support systems shall be maintained. 14. Materials: 14.1. The main objective of a pharmaceutical plant is to produce finished products for patients’ use from a combination of materials (starting and packaging). 14.2. Materials include starting materials, packaging materials, gases, solvents, process aids, reagents and labelling materials. 14.3. No materials used for operations such as cleaning, lubrication of equipment and pest control shall come into direct contact with the product. Where possible, such materials shall be of a suitable grade (e.g., food grade) to minimise health risks. 14.4. All incoming materials and finished products shall be quarantined immediately after receipt or processing, until they are released for use or distribution. 14.5. All materials and products shall be stored under the appropriate conditions established by the manufacturer, and in an orderly fashion, to permit batch segregation and stock rotation by a first-expire, first-out rule. 14.6. Water used in the manufacture of pharmaceutical products shall be suitable for its intended use. There shall be validated system for treatment of water drawn from own or any other source to render it potable in accordance with the standards specified by the Bureau of Indian Standards or Local Municipality, as the case may be, so as to produce purified water conforming to Pharmacopoeial specification. Purified Water so produced shall only be used for all the operations except washing and cleaning operations where potable water may be used. Water shall be stored in tanks, which do not adversely affect quality of water and ensure freedom from microbiological growth. The tank shall be cleaned periodically and records maintained by the licensee in this behalf. Good manufacturing practices regarding the design, installation and operation of pharmaceutical water systems including guidance about which quality of water to use for specific applications, such as the manufacture of active pharmaceutical ingredients and dosage forms, shall be ensured. 14.7. The purchase of starting materials is an important operation that shall involve staff who has a particular and thorough knowledge of the products and suppliers. 14.8. Starting materials shall be purchased only from the approved suppliers and, where possible, directly from the producer. It is also recommended that the specifications established by the manufacturer for the starting materials be discussed with the suppliers. It is beneficial for all critical aspects of the production and control of the starting material in question, including handling, labelling and packaging requirements as well as complaints and rejection procedures, to be contractually agreed between the manufacturer and the supplier. 14.9. For each consignment, at a minimum, the containers shall be checked at least for integrity of package and seal and for correspondence between the order, the delivery note, and the supplier’s labels. 14.10. All incoming materials shall be checked to ensure that the consignment corresponds to the order. Containers shall be cleaned where necessary and labelled, if required, with the prescribed information. Where additional labels are attached to containers, the original information shall not be lost. 14.11. Damage to containers and any other problem that might adversely affect the quality of a material shall be recorded and reported to the QC Department and investigated. 14.12. If one delivery of material is made up of different batches, each batch must be considered as separate for sampling, testing and release. 14.13. Starting materials in the storage area shall be appropriately labelled. Labels shall bear at least the following information, namely:— (a) the designated name of the product and the internal code reference where applicable; (b) the batch number given by the supplier and, on receipt, the control or batch number given by the manufacturer, if any, documented so as to ensure traceability; (c) the status of the contents (e.g., in quarantine, on test, released, rejected, returned or recalled); and (d) where appropriate, an expiry date or a date beyond which retesting is necessary. When fully validated computerised storage systems are used, not all of the above information need be in a legible form on the label. 14.14. Only raw materials which have been released by the QC Department and which are within their shelf life shall be used. 14.15. The raw materials other than APIs, if released by QC Department without specific batch testing, for use in manufacturing, it shall be based on vendor approval and statistical data analysis of earlier test results of such material for release. 14.16. There shall be appropriate procedures or measures to ensure the identity of the contents of each container of starting material. Bulk containers from which samples have been drawn shall be identified. 14.17. Only starting materials released by the QC Department and within their shelf-life shall be used. 14.18. Starting materials shall be dispensed only by designated persons, following a written procedure, to ensure that the correct materials are accurately weighed or measured into clean and properly labelled containers. 14.19. Each dispensed material and its weight or volume shall be independently checked and recorded. 14.20. Materials dispensed for each batch of the final product shall be kept together and conspicuously labelled as such. 14.21. The purchase, handling and control of primary and printed packaging materials shall as for starting materials. 14.22. Particular attention shall be paid to printed packaging materials. They shall be stored in secure conditions so as to exclude the possibility of unauthorised access. Roll feed labels shall be used wherever possible. Cut labels and other loose printed materials shall be stored and transported in separate closed containers so as to avoid mix ups. Packaging materials shall be issued for use only by designated personnel following an approved and documented procedure. 14.23. Each delivery or batch of printed or primary packaging material shall be given a specific reference number or identification mark. 14.24. Out-dated or obsolete primary packaging material or printed packaging material shall be destroyed and its disposal shall be recorded. 14.25. All products and packaging materials to be used shall be checked on delivery to the packaging department for quantity, identity and conformity with the packaging instructions. 14.26. All containers and closures intended for use shall comply with the pharmacopoeial requirements. Suitable validated test methods, sample sizes, specifications, cleaning procedure and sterilisation procedure, wherever indicated, shall be strictly followed to ensure that these are not reactive, additive, absorptive, or leach to an extent that significantly affects the quality or purity of the drug. No second hand or used containers and closures shall be used. 14.26.1. Whenever bottles are being used, the written schedule of cleaning shall be laid down and followed. Where bottles are not dried after washing, they shall be rinsed with purified water or water for injection, as the case may be. 14.26.2. The requirements mentioned in this Part do not include requirements of machinery, equipment and premises required for preparation of containers and closures for different dosage forms and categories of drugs. The suitability and adequacy of the machinery, equipment and premises shall be examined taking into consideration the requirements of each licensee in this respect. 14.26.3. Packaging material to be used for pharmaceutical products shall be in accordance with the requirements prescribed in Indian Pharmacopoeia (IP). 14.27. Intermediate and bulk products shall be kept under appropriate conditions. 14.28. Intermediate and bulk products purchased shall be handled on receipt as they were starting materials. 14.29. Finished products shall be held in quarantine until their final release, after which they shall be stored as usable stock under conditions established by the manufacturer. 14.30. The evaluation of finished products and the documentation necessary for release of a product for sale are described in paragraph 19. 14.31. Rejected materials and products shall be clearly marked and stored separately in restricted areas. They shall either be returned to the suppliers or, where appropriate, reprocessed or destroyed in a timely manner. Whatever action is taken shall be approved by the authorised personnel and recorded. 14.32. The reworking or recovery of rejected products shall be exceptional. It is permitted only if the quality of the final product is not affected, if the specifications are met, and if it is done in accordance with a defined and authorised procedure after evaluation of the risks involved. A record shall be kept of the reworking or recovery. A reworked batch shall be given a new batch number. 14.33. The introduction of all or part of earlier batches, conforming to the required quality standards, into a batch of the same product at a defined stage of manufacture shall be authorised beforehand. This recovery shall be carried out in accordance with a defined procedure after evaluation of the risks involved, including any possible effect on shelf-life. The recovery shall be recorded. 14.34. The need for additional testing of any finished product that has been reprocessed, reworked or into which a recovered product has been incorporated, shall be considered by the QC Department. 14.35. Recalled products shall be identified and stored separately in a secure area until a decision is taken and the decision shall be made as soon as possible. 14.36. Products returned from the market shall be destroyed unless it is certain that their quality is satisfactory; in such cases they may be considered for resale or relabelling, or alternative action taken only after they have been critically assessed by the QC function in accordance with a written procedure. The nature of the product, any special storage conditions it requires, its condition and history, and the time elapsed since it was issued shall be taken into account in the assessment. Where any doubt arises over the quality of the product, it shall not be considered suitable for reissue or reuse. Any action taken shall be appropriately recorded. 14.37. There shall be records for the receipt and preparation of reagents and culture media. 14.38. Reagents made up in the laboratory shall be prepared according to the written procedures and appropriately labelled. The label shall indicate the concentration, standardisation factor, shelf-life, the date when re-standardisation is due and the storage conditions. The label shall be signed and dated by the person preparing the reagent. 14.39. Both positive and negative controls shall be applied to verify the suitability of culture media each time they are prepared and used. The size of the inoculum used in positive controls shall be appropriate to the sensitivity required. 15. Reference Standards: 15.1. Whenever official reference standards exist, they shall be used. 15.2. Indian Pharmacopoeia reference standards shall be procured from Indian Pharmacopoeia Commission. 15.3. Official reference standards shall only be used for the purpose described in the appropriate monograph. 15.4. Reference standards prepared by the manufacturer shall be tested, released and stored in the same way as official standards. They shall be kept under the responsibility of a designated person in a secure area. 15.5. Secondary or working standards may be established by the application of appropriate tests and checks at regular intervals to ensure standardisation. 15.6. Reference standards shall be properly labelled with at least the following information, namely- (a) name of the material; (b) batch or lot number and control number; (c) date of preparation; (d) shelf-life; (e) potency; and (f) storage conditions. 15.7. All in-house working standards or secondary standards shall be standardised against an official reference standard, when available, initially and at regular intervals thereafter. 15.8. All reference standards shall be stored and used in a manner that will not adversely affect their quality. 16. Waste materials: 16.1. Provision shall be made for the proper and safe storage of waste materials waiting disposal. Toxic substances and flammable materials shall be stored in suitably designed, separate, enclosed cupboards. 16.2. Waste material shall not be allowed to accumulate. It shall be collected in suitable receptacles for removal to collection points outside the buildings and disposed of safely and in a sanitary manner at regular and frequent intervals. 16.3. The disposal of sewage and effluents (solid, liquid and gas) from the manufacturing area shall be in conformity with the requirements of the guidelines issued by the Environmental Pollution Control Board. 16.4. All bio-medical waste shall be destroyed as per the provisions of the Bio-Medical Waste (Management and Handling) Rules, 2016. 16.5. Rodenticides, insecticides, fumigating agents and sanitising materials shall not be permitted to contaminate equipment, starting materials, packaging materials, in-process materials or finished products. 17. Documentation: 17.1. Principle-Good documentation is an essential part of the quality assurance system and, as such, shall exist for all aspects of good manufacturing practices. Its aims are to define the specifications and procedures for all materials and methods of manufacture and control; to ensure that all personnel concerned with manufacture know what to do and when to do it; to ensure that authorised persons have all the information necessary to decide whether or not to release a batch of a drug for sale; to ensure the existence of documented evidence, traceability and to provide records and an audit trial that will permit investigation. It ensures the availability of the data needed for validation, review and statistical analysis. The design and use of documents depend upon the manufacturer. In some cases, some or all of the documents described in this paragraph may be brought together, but they will usually be separate. 17.2. General 17.2.1. Documents shall be designed, prepared, reviewed and distributed with care. They shall comply with the relevant Parts of the manufacturing and licences. 17.2.2. Documents shall be approved, signed and dated by the responsible persons. No document shall be changed without authorisation and approval. 17.2.3. Documents shall have unambiguous contents; the title, nature and purpose shall be clearly stated. They shall be laid out in an orderly manner and be easy to check. Reproduced documents shall be clear and legible. The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process. 17.2.4. Documents shall be regularly reviewed and kept up to date. When a document has been revised, a system shall exist to prevent inadvertent use of the superseded version. Superseded documents shall be retained for a specific period of time. 17.2.5. Where documents require the entry of data, these entries shall be clear, legible and indelible. Sufficient space shall be provided for such entries. 17.2.6. Any alteration made to a document shall be signed and dated; the alteration shall be done in such a way so as to permit the reading of the original information. Where appropriate, the reason for the alteration shall be recorded. 17.2.7. Records shall be made or completed when any action is taken and in such a way that all significant activities concerning the manufacture of pharmaceutical products are traceable. Records shall be retained for at least one year after the expiry date of the finished product. 17.2.8. Data (and records for storage) may be recorded by electronic data-processing systems or by photographic or other reliable means. Master formulae and detailed SOPs relating to the system in use shall be available and the accuracy of the records shall be checked. If documentation is handled by electronic data-processing methods, only authorised persons shall be able to enter or modify data in the computer system, and there shall be a record of changes and deletions; access shall be restricted by passwords or other means and the entry of critical data shall be independently checked. Batch records stored electronically shall be protected by back-up transfer on magnetic tape, microfilm, electronic discs, paper printouts or other means. It is particularly important that, during the period of retention, the data are readily available. 17.2.9 The site master file shall be prepared and maintained up to date as per the Appendix-I this Part. 17.3. Documents Required: 17.3.1. Labels 17.3.1.1. Labels applied to containers, equipment or premises shall be clear, unambiguous and in the company’s agreed format. It is often helpful in addition to the wording on the labels to use colours to indicate status (e.g., quarantined, accepted, reject0ed and clean). 17.3.1.2. All finished drugs shall be identified by labelling bearing at least the following information, namely:- (a) the name of the drugs; (b) a list of the active ingredients [if applicable, with the International Nonproprietary Names (INN)], showing the amount of each present and a statement of the net contents (e.g., number of dosage units, weight and volume); (c) the batch number assigned by the manufacturer; (d) the expiry date and date of manufacture in an uncoded form; (e) any special storage conditions or handling precautions that may be necessary; (f) directions for use, and warnings and precautions that may be necessary; and (g) the name and address of the manufacturer or the company and the person responsible for placing the product on the market. 17.3.1.3. For reference standards, the label or accompanying document or both shall indicate potency or concentration, date of manufacture, expiry date, date the closure if it is first opened, storage conditions and control number, as appropriate. 17.3.2. Specifications and testing procedures 17.3.2.1. Testing procedures described in documents shall be validated in the context of available facilities and equipment before they are adopted for routine testing. 17.3.2.2. There shall be appropriately authorised and dated specifications, including tests on identity, content, purity and quality for starting and packaging materials and for finished products; where appropriate, they shall also be available for intermediate or bulk products. Specifications for water, solvents and reagents (e.g., acids and bases) used in production shall be included. 17.3.2.3. Each specification shall be approved, signed and dated, and maintained by the QC or QA units. Specifications for starting materials, intermediates, bulk, finished products and packaging materials. 17.3.2.4. Periodic revisions of the specifications may be necessary to comply with new editions of the Indian pharmacopoeia or other official pharmacopoeia. 17.3.2.5. Pharmacopoeias, reference standards, reference spectra and other reference materials shall be available in the QC laboratory. 17.3.3. Specifications for starting and packaging materials 17.3.3.1. Specifications for starting, primary and printed packaging materials shall provide, if applicable, a description of the materials, including— (a) the designated name (if applicable, the INN) and internal code reference; (b) the reference, if any, to a pharmacopoeial monograph; and (c) qualitative and quantitative requirements with acceptance limits. 17.3.3.2. Depending on the company’s practice other data may be added to the specification, namely:- (a) the supplier and the original producer of the materials; (b) a specimen of printed materials; (c) directions for sampling and testing, or a reference to procedures; (d) storage conditions and precautions; and (e) the maximum period of storage before re-examination. 17.3.3.3. Packaging material shall conform to the specifications and shall be compatible with the material or with the drugs or both it contains. The material shall be examined for compliance with the specification, and for defects as well as for the correctness of identity markings. 17.3.3.4. Documents describing testing procedures shall state the required frequency for re assaying each starting material, as determined by its stability. 17.3.4. Specifications for intermediate and bulk products- Specifications for intermediate and bulk products shall be available. The specifications shall be similar to specifications for starting materials or for finished products, as appropriate. 17.3.5. Specifications for finished products- Specifications for finished products shall include the following, namely:— (a) the designated name of the product and the code reference, where applicable; (b) the designated names of the active ingredients (if applicable, with the INNs); (c) the formula or a reference to the formula if provided in any pharmacopoeia; (d) a description of the dosage form and package details; (e) directions for sampling and testing or a reference to procedures; (f) the qualitative and quantitative requirements, with acceptance limits; (g) the storage conditions and precautions, where applicable; and (h) the shelf-life. 17.3.6. Master formula records 17.3.6.1. A formally authorised master formula shall exist for each product and batch size to be manufactured. 17.3.6.2. The master formula records shall include the following, namely:- (a) the name of the product, with a product reference code relating to its specification; (b) a description of the dosage form, strength of the product and batch size; (c) a list of all starting materials to be used (if applicable with the INNs), with the amount of each, described using the designated name and a reference that is unique to that material (mention shall be made of any substance that may disappear in the course of processing); (d) a statement of the expected final yield with the acceptable limits and of relevant intermediate yields, where applicable; (e) a statement of the processing location and the principal equipment to be used; (f) the methods or reference to the methods to be used for preparing and operating the critical equipment, e.g., cleaning (especially after a change in product), assembling, calibrating, sterilising, use; (g) detailed step-wise processing instructions (e.g., checks on materials, pre treatments, sequence for adding materials, mixing times and temperatures); (h) the instructions for any in-process controls with their limits; (i) where necessary, the requirements for storage of the products, including the container, the labelling and any special storage conditions; (j) any special precautions to be observed; and (k) the hold time permitted for intermediate and in process material. 17.3.7. Packaging instructions- Formally authorised packaging instructions shall exist for each product, pack size and type. These shall normally include or make reference to the following, namely:— (a) the name of the product; (b) a description of its pharmaceutical form, strength and, where applicable, method of application; (c) the pack size expressed in terms of the number, weight or volume of the product in the final container; (d) a complete list of all the packaging materials required for a standard batch size, including quantities, sizes and types, with the code or reference number relating to the specifications for each packaging material; (e) where appropriate, an example or reproduction of the relevant printed packaging materials and specimens, indicating where the batch number and expiry date of the product have been marked; (f) special precautions to be observed, including a careful examination of the packaging area and equipment in order to ascertain the line clearance before and after packaging operations; (g) a description of the packaging operation, including any significant subsidiary operations, and equipment to be used; and (h) details of in-process controls with instructions for sampling and acceptance limits. 17.3.8. Batch processing records 17.3.8.1. A batch processing record shall be kept for each batch processed. It shall be based on the relevant Parts of the currently approved specifications on the record. The method of preparation of such records shall be designed to avoid errors. (copying or validated computer programmes are recommended. Transcribing from approved documents shall be avoided.) 17.3.8.2. Before any processing begins a check shall be made that the equipment and work station are clear of previous products, documents, or materials not required for the planned process, and that the equipment is clean and suitable for use. This check shall be recorded. 17.3.8.3. During processing, the following information shall be recorded at the time each action is taken, and after completion of the record shall be dated and signed by the person responsible for the processing operations, namely:- (a) the name of the product; (b) the number of the batch being manufactured; (c) dates and time of commencement of significant intermediate stages and of completion of production; (d) the name of the person responsible for each stage of production; (e) the initials of the operators of different significant steps of production and, where appropriate, of the persons who checked each of these operations (e.g., weighing); (f) the batch number or analytical control number or both and the quantity of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added); (g) any relevant processing operation or event and the major equipment used; (h) the hold time permitted for intermediate and in process material; (i) the in-process controls performed, the initials of the persons carrying them out, and the results obtained; (j) the amount of product obtained at different and pertinent stages of manufacture (yield), together with comments or explanations for significant deviations from the expected yield; and (k) notes on special problems including details, with signed authorisation for any deviation from the master formula. 17.3.9. Batch packaging records 17.3.9.1. A batch packaging record shall be kept for each batch or part batch processed. It shall be based on the relevant Parts of the approved packaging instructions and the method of preparing such records shall be designed to avoid errors. (copying or validated computer programmes are recommended. Transcribing from approved documents shall be avoided.) 17.3.9.2. Before any packaging operation begins, checks shall be made that the equipment and work station are clear of previous products, documents or materials not required for the planned packaging operations and that equipment is clean and suitable for its use. These checks shall be recorded. 17.3.9.3. The following information shall be recorded at the time each action is taken, and the date and the person responsible shall be clearly identified by signature or electronic password, namely:- (a) the name of the product, the batch number and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained, the quantity actually obtained and the reconciliation; (b) the date and time of packaging operations; (c) the name of the responsible person carrying out the packaging operation; (d) (d) the initials of the operators of the different significant steps; (e) the checks made for identity and conformity with the packaging instructions, including the results of in-process controls; (f) details of the packaging operations carried out, including references to equipment and the packaging lines used, and, when necessary, the instructions for keeping the product if it is unpacked or a record of returning product that has not been packaged to the storage area; (g) whenever possible, samples of the printed packaging materials used, including specimens bearing the approval for the printing and regular check (where appropriate) of the batch number, expiry date, and any additional overprinting; (h) notes on any special problems, including the details of any deviation from the packaging instructions, with written authorisation by an appropriate person; and (i) the quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of product obtained to permit an adequate reconciliation. 17.3.10. Standard operating procedures and records: 17.3.10.1. Standard Operating Procedures (hereinafter to be referred as SOPs) and associated records of actions taken or, where appropriate, conclusions reached shall be available for the following, namely- (a) equipment assembly and validation; (b) analytical apparatus and calibration; (c) maintenance, cleaning and sanitisation; (d) personnel matters including qualifications, training, clothing and hygiene; (e) environmental monitoring; (f) pest control; (g) complaints; (h) recalls; and (i) returns. 17.3.10.2. There shall be SOPs and records for the receipt of each delivery of starting material and primary and printed packaging material. 17.3.10.3. The records of the receipts shall include the following, namely- (a) the name of the material on the delivery note and the containers; (b) the “in-house” name or code or both of material, if different from clause (a); (c) the date of receipt; (d) the supplier’s name and, if possible, manufacturer’s name; (e) the manufacturer’s batch or reference number; (f) the total quantity and number of containers received; (g) the batch number assigned after receipt; and (h) any relevant comment (e.g. state of the containers). 17.3.10.4. There shall be SOPs for the internal labelling, quarantine and storage of starting materials, packaging materials and other materials, as appropriate. 17.3.10.5. SOPs shall be available for each instrument and piece of equipment (e.g., use, calibration, cleaning and maintenance) and placed in close proximity to the equipment. 17.3.10.6. There shall be SOPs for sampling, which specify the persons authorised to take samples. 17.3.10.7. The sampling instructions shall include- (a) the method of sampling and the sampling plan; (b) the equipment to be used; (c) any precautions to be observed to avoid contamination of the material or any deterioration in its quality; (d) the amount of samples to be taken; (e) instructions for any required sub-division of the sample; (f) the type of sample containers to be used, and whether they are for aseptic sampling or for normal sampling and labelling; and (g) any specific precautions to be observed, especially in regard to the sampling of sterile or noxious material. 17.3.10.8. There shall be an SOPs describing the details of the batch (lot) numbering system, with the objective of ensuring that each batch of intermediate, bulk or finished product is identified with a specific batch number. 17.3.10.9. The SOPs for batch numbering that are applied to the processing stage and to the respective packaging stage shall be related to each other. 17.3.10.10. The SOPs for batch numbering shall ensure that the same batch numbers will not be used repeatedly; this applies also to reprocessing. 17.3.10.11. Batch-number allocation shall be immediately recorded, e.g. in a logbook. The record shall include at least the date of allocation, product identity and size of batch. 17.3.10.12. There shall be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to be used. The tests performed shall be recorded. 17.3.10.13. Analysis records shall include at least the following data, namely- (a) the name of the material or product and, where applicable, dosage form; (b) the batch number and, where appropriate, the manufacturer and supplier; (c) references to the relevant specifications and testing procedures; (d) test results, including observations and calculations, and reference to any specifications (limits); (e) date and reference number of testing; (f) the initials of the persons who performed the testing; (g) the date and initials of the persons who verified the testing and the calculations, where appropriate; and (h) a clear statement of release or rejection (or other status decision) and the dated signature of the designated person. 17.3.10.14. Written release and rejection procedures shall be available for materials and products and in particular for the release for sale of the finished product by an authorised person. 17.3.10.15. Records shall be maintained regarding the distribution of each batch of a product in order, for example, to facilitate the recall of the batch, if necessary. 17.3.10.16. Records shall be kept for major and critical equipment, as appropriate, of any validations, calibrations, maintenance, cleaning or repair operations, including dates and the identity of the people who carried out these operations. 17.3.10.17. The use of major and critical equipment and the areas where products have been processed shall be appropriately recorded in chronological order. 17.3.10.18. There shall be written procedures assigning responsibility for cleaning and sanitation and describing in sufficient detail the cleaning schedules, methods, equipment and materials to be used and facilities and equipment to be cleaned and such written procedures shall be followed. 18. Good practices in production: 18.1. Principle- Production operations must follow clearly defined procedures in accordance with manufacturing and licences, with the objective of obtaining products of the requisite quality. 18.2. General 18.2.1. All handling of materials and products, such as receipt and cleaning, quarantine, sampling, storage, labelling, dispensing, processing, packaging and distribution shall be done in accordance with written procedures or instructions and, where necessary, recorded. 18.2.2. Deviation from instructions or procedures shall be avoided as far as possible. If deviations occur, they shall be in accordance with an approved procedure. The authorisation of the deviation shall be approved in writing by a designated person, with the involvement of the QC Department, when appropriate. 18.2.3. Checks on yields and reconciliation of quantities shall be carried out as necessary to ensure that there are no discrepancies outside acceptable limits. 18.2.4. Operations on different products shall not be carried out simultaneously or consecutively in the same room or area unless there is no risk of mix up or cross-contamination. 18.2.5. At all times during processing, all materials, bulk containers, major items of equipment, and, where appropriate, the rooms and packaging lines being used, shall be labelled or otherwise identified with an indication of the product or material being processed, its strength (where applicable) and the batch number. Where applicable, this indication shall also mention the stage of production. In some cases, it may be useful to also record the name of the previous product that has been processed. 18.2.6. Access to production premises shall be restricted to authorised personnel. 18.2.7. Non-medicinal products shall not be produced in areas or with equipment destined for the production of pharmaceutical products. 18.2.8. In-process controls are usually performed within the production area. The performance of such in-process controls shall not have any negative effect on the quality of the product or another product (e.g., cross-contamination or mix up). 18.3. Prevention of cross-contamination and bacterial contamination during production 18.3.1. When dry materials and products are used in production, special precautions shall be taken to prevent the generation and dissemination of dust. Provision shall be made for proper air control (e.g., supply and extraction of air of suitable quality). 18.3.2. Contamination of a starting material or of a product by another material or product must be avoided. This risk of accidental cross-contamination arises from the uncontrolled release of dust, gases, particles, vapours, sprays or organisms from materials and products in process, from residues on equipment, from intruding insects, and from operators’ clothing, skin, etc. The significance of this risk varies with the type of contaminant and of the product being contaminated. Among the most hazardous contaminants are highly sensitising materials, biological preparations such as living organisms, certain hormones, cytotoxic substances and other highly active materials. Products in which contamination is likely to be most significant are those administered by injection or applied to open wounds and those given in large doses or over a long time or both. Highly hazardous, poisonous and explosive materials such as narcotics, psychotropic drugs and substances presenting potential risks of abuse, fire or explosion shall be stored in safe and secure areas. Adequate fire protection measures shall be provided in conformity with the rules of the concerned civic authorities. 18.3.3. Cross-contamination shall be avoided by taking appropriate technical or organisational measures, namely:- (a) carrying out production in dedicated and self-contained areas (which may be required for products such as penicillins, cytotoxic, sex hormones, spore forming, live vaccines, live bacterial preparations and certain other biologicals); (b) conducting campaign production (separation in time) followed by appropriate cleaning in accordance with a validated cleaning procedure; (c) providing appropriately designed airlocks, pressure differentials and air supply and extraction systems; (d) minimising the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air; (e) wearing protective clothing where products or materials are handled; (f) using cleaning and decontamination procedures of known effectiveness; (g) using a closed system in production; (h) testing for residues; and (i) using cleanliness status labels on equipment. 18.3.4. Measures to prevent cross-contamination and their effectiveness shall be checked periodically according to SOPs. 18.3.5. Production areas where susceptible products are processed shall undergo periodic environmental monitoring (e.g., for microbiological and particulate matter, where appropriate). 18.4. Processing operations 18.4.1. Before any processing operation is started, steps shall be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues, labels or documents not required for the current operation. 18.4.2. Any necessary in-process controls and environmental controls shall be carried out and recorded. 18.4.3. Means shall be instituted of indicating failures of equipment or of services (e.g., water and gas) to equipment. Defective equipment shall be withdrawn from use until the defect has been rectified. After use, production equipment shall be cleaned without delay according to detailed written procedures and stored under clean and dry conditions in a separate area or in a manner that will prevent contamination. 18.4.4. Time limits for storage of process materials and equipment, after cleaning and before use, shall be stated and based on relevant data. 18.4.5. Containers for filling shall be cleaned before filling. Attention shall be given for avoiding and removing any contaminants such as glass fragments and metal particles. 18.4.6. Any significant deviation from the expected yield shall be recorded and investigated. 18.4.7. Checks shall be carried out to ensure that pipelines and other pieces of equipment used for the transportation of products from one area to another area are connected in the correct manner. 18.4.8. Pipes used for conveying distilled or deionized water and, where appropriate, other water pipes shall be sanitised and stored according to written procedures that detail the action limits for microbiological contamination and the measures to be taken. 18.4.9. Measuring, weighing, recording and control equipment and instruments shall be serviced and calibrated at pre-specified intervals and records maintained. To ensure satisfactory functioning, instruments shall be checked daily or prior to use for performing analytical tests. The date of calibration and servicing and the date when recalibration is due shall be clearly indicated on a label attached to the instrument. 18.4.10. Repair and maintenance operations shall not present any hazard to the quality of the products. 18.5. Packaging operations: 18.5.1. When the programme for packaging operations is being set up, particular attention shall be given to minimising the risk of cross-contamination, mix ups or substitutions. Different products shall not be packaged in close proximity unless there is physical segregation or an alternative system that will provide equal assurance. 18.5.2. Before packaging operations are begun, steps shall be taken to ensure that the work area, packaging lines, printing machines and other equipment are clean and free from any products, materials or documents used previously and which are not required for the current operation. The line clearance shall be performed according to an appropriate procedure and checklist and shall be recorded. 18.5.3. The name and batch number of the product being handled shall be displayed at each packaging station or line. 18.5.4. Normally, filling and sealing shall be followed as quickly as possible by labelling. If labelling is delayed, appropriate procedures shall be applied to ensure that no mix ups or mislabelling can occur. 18.5.5. The correct performance of any printing (e.g., of code numbers or expiry dates) done separately or in the course of the packaging shall be checked and recorded. Attention shall be paid to printing by hand, which shall be rechecked at regular intervals. 18.5.6. Special care shall be taken when cut labels are used and when overprinting is carried out off line and in hand-packaging operations. Roll-feed labels are normally preferable to cut labels in helping to avoid mix ups. Online verification of all labels by automated electronic means can be helpful in preventing mix ups, but checks shall be made to ensure that any electronic code readers, label counters or similar devices are operating correctly. When labels are attached manually, in-process control checks shall be performed more frequently. 18.5.7. Printed and embossed information on packaging materials shall be distinct and resistant to fading or erasing. 18.5.8.1. Regular online control of the product during packaging shall include at a minimum checks on— (a) the general appearance of the packages; (b) whether the packages are complete; (c) whether the correct products and packaging materials are used; (d) whether any overprinting is correct; and (e) the correct functioning of line monitors. 18.5.8.2. Samples taken away from the packaging line shall not be returned. 18.5.9. Products that have been involved in an unusual event during packaging shall be reintroduced into the process only after special inspection, investigation and approval by the authorised personnel. A detailed record shall be kept of this operation. 18.5.10. Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units produced shall be investigated, satisfactorily accounted for and recorded before release. 18.5.11. Upon completion of a packaging operation, any unused batch-coded packaging materials shall be destroyed and the destruction shall be recorded. A documented procedure requiring checks to be performed before returning unused materials shall be followed, if uncoded printed materials are returned back to the stock. 18.5.12. Production records shall be reviewed as part of the approval process of batch release before transfer to the authorised person. Any divergence or failure of a batch to meet production specifications shall be thoroughly investigated. The investigation shall, if necessary, extend to other batches of the same product and other products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusion and follow-up action. 19. Good practices in quality control: 19.1. Quality control is the part of good manufacturing practices concerned with sampling, specifications and testing and with the organisation and documentation which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be compliant with the requirements. QC is not confined to laboratory operations, but may be involved in many decisions concerning the quality of the product. 19.2. The independence of QC from production is considered fundamental. 19.3. Each manufacturer shall have a QC function. The QC function shall be independent of other Departments and under the authority of a person with appropriate qualifications and experience. Adequate resources must be available to ensure that all the QC arrangements are effectively and reliably carried out. The basic requirements for QC are as follows— (a) adequate facilities, trained personnel and approved procedures must be available for sampling, inspecting, and testing starting materials, packaging materials and intermediate, bulk and finished products and where appropriate for monitoring environmental conditions for good manufacturing practices purposes; (b) samples of starting materials, packaging materials, intermediate products, bulk products and finished products must be taken by methods and personnel approved by the QC Department; (c) qualification and validation; (d) records must be made (manually or by recording instruments or both) demonstrating that all the required sampling, inspecting and testing procedures have actually been carried out and that any deviations have been fully recorded and investigated; (e) the finished products must contain ingredients complying with the qualitative and quantitative composition of the product described in the licence; the ingredients must be of the required purity, in their proper container and correctly labelled; (f) records must be made of the results of inspecting and testing the materials and intermediate, bulk and finished products against specifications; product assessment must include a review and evaluation of the relevant production documentation and an assessment of deviations from specified procedures; (g) sufficient samples of starting materials and products must be retained to permit future examination of the product, if necessary; the retained product must be kept for the appropriate time in its final pack unless the pack is exceptionally large, in which case one that is equivalent to the marketed packaging system may be used. 19.4.1. Other QC responsibilities include the following, namely:- (a) establishing, validating and implementing all QC procedures; (b) evaluating, maintaining and storing reference standards for substances; (c) ensuring the correct labelling of containers of materials and products; (d) ensuring that the stability of the active pharmaceutical ingredients and products are monitored; (e) participating in the investigation of complaints related to the quality of the product; (f) participating in environmental monitoring; and (g) participation in quality risk management programme. 19.4.2. These activities shall be carried out in accordance with written procedures and, where necessary, recorded. 19.5. Quality control personnel shall have access to the production areas for sampling and investigation as appropriate. 19.6. Control of starting materials and intermediate, bulk and finished products 19.6.1. All tests shall follow the instructions given in the relevant written test procedure for each material or product. The result shall be checked by the supervisor before the material or product is released or rejected. 19.6.2. Samples shall be representative of the batches of material from which they are taken in accordance with the approved written procedure. 19.6.3. Sampling shall be carried out so as to avoid contamination or other adverse effects on quality. The containers that have been sampled shall be marked accordingly and carefully resealed after sampling. 19.6.4. Care shall be taken during sampling to guard against contamination or mix up of, or by, the material being sampled. All sampling equipment that comes into contact with the material shall be clean. Hazardous or potent materials may require special precautions. 19.6.5. Sampling equipment shall be cleaned and, if necessary, sterilised before and after each use and stored separately from other laboratory equipment. 19.6.6. Each sample container shall bear a label indicating- (a) the name of the sampled material; (b) the batch or lot number; (c) the number of the container from which the sample has been taken; (d) the number of the sample; (e) the signature of the person who has taken the sample; and (f) the date of sampling. 19.6.7. Out-of-specification results obtained during testing of materials or products shall be investigated in accordance with an approved procedure and record shall be maintained. 19.7. Test requirements 19.7.1. Before releasing a starting or packaging material for use, the QC in-charge shall ensure that the materials have been tested for conformity with specifications for identity, strength, purity and other quality parameters. 19.7.2. An identity test shall be conducted on a sample from each container of starting material. It is permissible to sample only a proportion of the containers where a validated procedure has been established to ensure that no single container of starting material has been incorrectly labelled. 19.7.2.1. The above validation shall take account of at least the following aspects, namely:- (a) the nature and status of the manufacturer and of the supplier and their understanding of the good manufacturing practices requirements; (b) the QA system of the manufacturer of the starting material; (c) the manufacturing conditions under which the starting material is produced and controlled; and (d) the nature of the starting material and the medicinal products in which it will be used. 19.7.2.2. Under such a system it is possible that a validated procedure for exemption from the requirement for identity testing of each incoming container of starting material could be accepted for the following, namely- (a) starting materials coming from a single product manufacturer or plant; or (b) starting materials coming directly from a manufacturer, or in the manufacturer’s sealed container where there is a history of reliability and regular audits of the manufacturer’s QA system are conducted by the purchaser (the manufacturer of the medicinal product) or by an officially accredited body. 19.7.2.3. It is improbable that such a procedure could be satisfactorily validated for either- (a) starting materials supplied by intermediaries, such as brokers, where the source of manufacture is unknown or not audited; or (b) starting materials for use in parenteral products. 19.7.3. Each batch (lot) of printed packaging materials shall be examined following its receipt. 19.7.4. In lieu of full testing by the manufacturer, a certificate of analysis may be accepted from the supplier, provided that the manufacturer establishes the reliability of the supplier’s analysis through appropriate periodic validation of the supplier’s test results and through on-site audits of the supplier’s capabilities. Certificates must be originals and not photocopies or otherwise have their authenticity assured. Certificates must contain at least the following information, namely:— (a) identification (name and address) of the issuing supplier; (b) signature of the competent official and statement of his or her qualifications; (c) the name of the material tested; (d) the batch number of the material tested; (e) the specifications and methods used; (f) the test results obtained; and (g) the date of testing. 19.7.5. In-process control records shall be maintained and form part of the batch records. 19.7.6. For each batch of drugs, there shall be an appropriate laboratory determination of satisfactory conformity to its finished product specification prior to its release. 19.7.7. Products failing to meet the established specifications or any other relevant quality criteria shall be rejected. 19.8. Batch record review: 19.8.1. Quality control records shall be reviewed as part of the approval process of batch release before transfer to the authorised person. Any divergence or failure of a batch to meet its specifications shall be thoroughly investigated. The investigation shall, if necessary, extend to other batches of the same product and other products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusion and follow-up action. 19.8.2. Retention samples from each batch of finished product shall be kept for at least one year after the expiry date. Finished products shall usually be kept in their final packaging and stored under the recommended conditions. If exceptionally large packages are produced, smaller samples might be stored in appropriate containers. Samples of active starting materials shall be retained for at least one year beyond the expiry date of the corresponding finished product. Other starting materials (other than solvents, gases and water) shall be retained for a minimum of two years, if their stability allows. Retention samples of materials and products shall be of a size sufficient to permit at least two full re examinations. 19.9. Stability studies 19.9.1. QC shall evaluate quality and stability of finished pharmaceutical products and, when necessary, of starting materials and intermediate products. 19.9.2. QC shall establish expiry dates and shelf-life specifications on the basis of stability tests related to storage conditions. 19.9.3. A written programme for on-going stability determination shall be developed and implemented to include elements such as — (a) a complete description of the drug involved in the study; (b) the complete set of testing parameters and methods, describing all tests for potency, purity, and physical characteristics and documented evidence that these tests indicate stability; (c) provision for the inclusion of a sufficient number of batches; (d) the testing schedule for each drug; (e) provision for special storage conditions; (f) provision for adequate sample retention; and (g) a summary of all the data generated, including the evaluation and the conclusion of the study. 19.9.4. Stability shall be determined prior to marketing and following any significant changes, for example, in processes, equipment or packaging materials. 20. Computerised systems: 20.1. GMP-related computerised systems shall be validated. The depth and scope of validation depends on the diversity, complexity and criticality of the computerised application. 20.2. Appropriate installation qualification and operational qualification shall demonstrate the suitability of computer hardware and software to perform assigned tasks. 20.3. Commercially available software that has been qualified does not require the same level of testing. If an existing system was not validated at the time of installation, a retrospective validation could be conducted, if appropriate documentation is available. 20.4. Computerised systems shall have sufficient controls to prevent unauthorised access or changes to data. There shall be controls to prevent omissions in data (e.g., the system being turned off and data not captured). There shall be a record of any data change made, the previous entry, the person who made the change and when the change was made. 20.5. Written procedures shall be available for the operation and maintenance of computerised systems. 20.6. Where critical data are being entered manually, there shall be an additional check on the accuracy of the data entered. This can be done by a second operator or by the system itself. 20.7. Incidents related to computerised systems that could affect the quality of products or the reliability of records or test results shall be recorded and investigated. 20.8. Changes to the computerised system shall be made according to a change procedure and shall be formally authorised, documented and tested. Records shall be kept of all changes, including modifications and enhancements made to the hardware, software and any other critical component of the system. These records shall demonstrate that the system is maintained in a validated state. 20.9. A back-up system shall be provided so that there is no permanent loss of records due to system breakdown or failure. Means of ensuring data protection shall be established for all computerised systems. 20.10. Data may be recorded by other means in addition to the computer system. Appendix-I Site Master File The licensee shall prepare a succinct document in the form of ‘Site Master File’ containing specific and factual Good Manufacturing Practices about the production or control or both of pharmaceutical manufacturing preparations carried out at the licensed premises. It shall contain the following, namely 1. General information:- (a) brief information of the firm; (b) pharmaceutical manufacturing activities as permitted by the licensing authority; (c) other manufacturing activities, if any, carried out in the premises; (d) type of products licensed for manufacture with flow charts mentioning procedure and process flow; (e) number of employees engaged in the production, quality control, storage and distribution; (f) use of outside scientific, analytical or other technical assistance in relation to manufacture and analysis; (g) products details registered with foreign countries. (h) short description of the Quality Management System of the firm; (i) pharmaceutical Quality System; and (j) quality risk assessment. 2. Personnel:- (a) organisational chart showing the arrangement for quality assurance including production and quality control; (b) qualifications, experience and responsibilities of key personnel; (c) outline for arrangements for basic and in-service training and how the records are maintained; (d) health requirements for personnel engaged in production; and (e) personnel hygiene requirements, including clothing. 3. Premises:- (a) simple plan or description of manufacturing areas drawn to scale; (b) nature of construction and fixtures or fittings; (c) brief description of ventilation systems. More details shall be given for critical areas with potential risk of airborne contamination (schematic drawing of systems). Classification of the rooms used for the manufacture of sterile products shall be mentioned; (d) special areas for the handling of the highly toxic, hazardous and sensitising materials; (e) brief description of water system (schematic drawings of systems), including sanitation; and (f) description of planned preventive maintenance programmes for premises and of the recording system. 4. Equipment:- (a) brief description of major equipment used in production and Quality Control Laboratories (a list of equipment required); (b) description of planned preventive maintenance programmes for equipment and of the recording system; and (c) qualification and calibration including the recording systems and arrangements for computerised systems validation. 5. Sanitation:-availability of written specifications and procedures for cleaning manufacturing areas and equipment. 6. Documentation:- (a) arrangements for the preparation, revision and distribution of; (b) necessary documentation for the manufacture; and (c) any other documentation related to product quality that is not mentioned elsewhere (e.g., microbiological controls about air and water). 7. Production:- (a) brief description of production operations using, wherever possible, flow sheets and charts specifying important parameters; (b) arrangements for the handling of starting materials, packaging materials, bulk and finished products, including sampling, quarantine, release and storage; (c) arrangements for the handling of rejected materials and products; and (d) brief description of general policy for process validation. 8. Quality Assurance and Control:- (a) documentation system; (b) change control; (c) master validation plan and validation policy; (d) product quality review; and (e) description of the quality control system and of the activities of the QC Department. Procedures for the release of the finished products. 9. Manufacture under loan licence and licensee:- description of the way in which compliance of GMP by the loan licensee shall be assessed. 10. Distribution, complaints and product recall:- (a) arrangements and recording system for distribution; and (b) arrangements for the handling of complaints and product recalls. 11. Self-inspection:- short description of the self-inspection system indicating whether an outside, independent and experienced external expert was involved in evaluating the manufacturer’s compliance with GMP in all aspects of production. 12. Export of drugs:- (a) products exported to different countries; and (b) complaints and product recall, if any. Note.-The guidelines published by the World Health Organization (WHO) on following aspects relating to GMP through their Technical Report Series from time to time may be considered for general guidance purposes:- (1) Guidelines on the principles of airflow directions, air filtration standards, temperature, humidity and related parameters. (2) GMP guidelines regarding the design, installation and operation of pharmaceutical water systems including guidance about which quality of water to use for specific applications, such as the manufacture of APIs and dosage forms. (3) Guidelines on design, installation, qualification and maintenance of the HVAC systems of the manufacturing plant. (4) GMP guidelines for validation. (5) Guidelines on packaging of pharmaceutical products. PART II SPECIFIC REQUIREMENTS FOR MANUFACTURE OF STERILE PRODUCTS, PARENTERAL PREPARATIONS (SMALL VOLUME INJECTABLES AND LARGE VOLUME PARENTERALS) AND STERILE OPHTHALMIC PREPARATIONS Note.-Good Manufacturing Practices for pharmaceutical products:- Main principles as given in Part I shall be complied with, mutatis mutandis, for the manufacture of sterile products, parenteral preparations (small volume injectables and large volume parenterals) and sterile ophthalmic preparations. In addition to these requirements, the following specific requirements shall also be followed, namely:— 1. General considerations:- 1.1. The production of sterile preparations shall be carried out in clean areas, entry shall be through airlocks for personnel or for equipment and materials or both. Clean areas shall be maintained to an appropriate standard of cleanliness and supplied with air that has passed through filters of the required efficiency. 1.2. The various operations of component preparation (such as those involving containers and closures), product preparation, filling and sterilisation shall be carried out in separate areas within the clean area. These areas are classified into four grades as described in paragraph of this Part. 1.3. Manufacturing operations are divided here into two categories, namely:- (I) those, where the product is terminally sterilised; and (II) those, which are conducted aseptically at some or all stages. 2. Quality control:- 2.1. The sterility test applied to the finished product shall only be regarded as the last in a series of control measures by which sterility is assured. The test shall be validated for the product concerned. 2.2. Samples taken for sterility testing shall be representative of the whole of the batch but shall, in particular, include samples taken from parts of the batch considered to be most at risk of contamination, for example- (i) for products that have been filled aseptically, samples shall include containers filled at the beginning and end of the batch and after any significant interruption of work; (ii) for products that have been heat sterilised in their final containers, consideration shall be given to taking samples from that part of the load that is potentially the coolest. 2.3. The sterility of the finished product is assured by validation of the sterilisation cycle in the case of terminally sterilised products, and by “media simulation” or “media fill” runs for aseptically processed products. Batch processing records and, in the case of aseptic processing, environmental quality records, shall be examined in conjunction with the results of the sterility tests. The sterility test procedure shall be validated for a given product. Pharmacopoeial methods shall be used for the validation and performance of the sterility test. In those cases where parametric release has been authorised in place of sterility testing, special attention shall be paid to the validation and the monitoring of the entire manufacturing process. 2.4. For injectable products, the water for injection and the intermediate, if appropriate and finished products shall be monitored for endotoxins, using an established pharmacopoeial method that has been validated for each type of product. For large-volume parenterals, such monitoring of water or intermediates shall always be done, in addition to any tests required by an approved monograph for the finished product. When a sample fails a test, the cause of the failure shall be investigated and necessary action shall be taken. 2.5. The use of rapid microbiological methods to replace the traditional microbiological methods, and to obtain earlier results on the microbiological quality of, for example, water, the environment or bio burden, could be considered if appropriately validated and a comparative assessment of the proposed rapid method is performed against the pharmacopoeial method. 3. Sanitation:- 3.1. The sanitation of clean areas is particularly important. They shall be cleaned frequently and thoroughly in accordance with an approved written programme. Where disinfectants are used, more than one type shall be employed. Monitoring shall be regularly undertaken to detect contamination or the presence of an organism against which the cleaning procedure is ineffective. Interactions between different cleaning materials shall be validated. Appropriate cleaning validation shall be carried out to ensure disinfectant residuals can be detected and are removed by the cleaning process. 3.2. Disinfectants and detergents shall be monitored for microbial contamination; dilutions shall be kept in previously cleaned containers and shall only be stored for defined periods unless sterilised. Disinfectants and detergents used in Grade A and B areas shall be sterile before use. 3.3. A disinfectant programme shall also include a sporicidal agent since many common disinfectants are ineffective against spores. The effectiveness of cleaning and disinfectant procedures shall be demonstrated. 3.4. Fumigation of clean areas may be useful for reducing microbial contamination in inaccessible places. 4. Manufacture of sterile preparations:- 4.1. Clean areas for the manufacture of sterile products are classified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate level of environmental cleanliness in the operational state to minimise the risk of particulate or microbial contamination of the product or materials being handled. 4.2. Detailed information on methods for determining the microbiological and particulate cleanliness of air, surfaces, etc., is not given in this Part. International Organization for Standardisation (ISO) standards shall be used for classification of cleanliness according to concentration of airborne particles (determination of number of sample locations, calculation of sample size and evaluation of classification from the data obtained). Table 1 shall also be used to define the levels to be used as the basis for monitoring clean areas for airborne particles. 4.3. For the manufacture of sterile pharmaceutical preparations, four grades of clean areas are distinguished as follows:- Grade A: The local zone for high-risk operations, e.g., filling and making aseptic connections. Normally such conditions are achieved by using a unidirectional airflow workstation. Unidirectional airflow systems shall provide a homogeneous air speed of 0.36–0.54 m/s (guidance value) at a defined test position 15–30 cm below the terminal filter or air distributor system. The velocity at working level shall not be less than 0.36 m/s. The uniformity and effectiveness of the unidirectional airflow shall be demonstrated by undertaking airflow visualisation tests. Grade B: In aseptic preparation and filling, this is the background environment for the Grade A zone. Grades C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products or carrying out activities during which the product is not directly exposed (i.e., aseptic connection with aseptic connectors and operations in a closed system). A unidirectional airflow and lower velocities may be used in closed isolators and glove boxes. Explanation.- For the purpose of classification of grade C and grade D clean areas, the parameters provided in paragraph 4.6, 4.7, 4.9, and 4.11of this Part shall be applied. 4.4. In order to reach the B, C and D air grades the number of air changes shall be appropriate for the size of the room and the equipment and personnel present in it. 4.5. High-efficiency particulate air (hereinafter to be referred as HEPA) filters shall be subjected to an installed filter leakage test in accordance with ISO standards at a recommended interval of every six months, but not exceeding twelve months. The purpose of performing regular leak tests is to ensure the filter media, filter frame and filter seal are free from leaks. The aerosol selected for HEPA leak testing shall not support microbial growth and shall be composed of a sufficient number or mass of particles. HEPA filter patching is allowed at the filter manufacturer and in situ operation provided that the patch sizes and procedures follow the recommendations of ISO standards. 4.6. Clean rooms and clean-air devices shall be classified in accordance with ISO standards. 4.6.1. Classification shall be clearly differentiated from operational process environmental monitoring. The maximum permitted airborne particle concentration for each Grade is given in Table 1 below. Table 1 Maximum permitted airborne particle concentrate +-------+----------------------------+----------------------------+ | Grade | At rest | In operation | | +------------+------------+----+------------+------------+ | | 0.5 μm | 5.0 μm | | 0.5 μm | 5.0 μm | +=======+============+============+====+============+============+ | A | 3520 | 20 | | 3520 | 20 | +-------+------------+------------+----+------------+------------+ | B | 3520 | 29 | | 352000 | 2900 | +-------+------------+------------+----+------------+------------+ | C | 352000 | 2900 | | 3520000 | 29000 | +-------+------------+------------+----+------------+------------+ | D | 3520000 | 29000 | | Not defined| Not defined| +-------+------------+------------+----+------------+------------+ The “at rest” state is the condition where the installation is complete with equipment installed and operating in a manner agreed upon by the customer and supplier, but with no personnel present. The “in operation” state is the condition where the installation is functioning in the defined operating mode and the specified number of personnel is present. The areas and their associated environmental control systems shall be designed to achieve both the “at rest” and “in operation” states. 4.6.2. For classification purposes in Grade A zones, a minimum sample volume of 1 m³ shall be taken per sample location. Referring to Table 1, for Grade A the airborne particle classification is ISO 4.8 dictated by the limit for particles ≥ 5.0 μm. For Grade B (at rest) the airborne particle classification is ISO 5 for both particle sizes considered. For Grade C (at rest and in operation) the airborne particle classification is ISO 7 and ISO 8, respectively. For Grade D (at rest) the airborne particle classification is ISO 8. For classification purposes ISO standards methodology defines both the minimum number of sample locations and the sample size based on the class limit of the largest particle size considered and the method of evaluation of the data collected. The sample volume shall be determined according to ISO standards. However, for lower grades (Grade C in operation and Grade D at rest) the sample volume per location shall be at least two litres and the sample time per location shall be not less than one minute. 4.6.3. Portable particle counters with a short length of sample tubing shall be used for classification purposes to avoid the loss of particles ≥ 5.0 μm. Isokinetic sample heads shall be used in unidirectional airflow systems. 4.6.4. “In operation” classification may be demonstrated during normal operations, simulated operations or during media fills as worst-case simulation is required for this. ISO standards provide information on testing to demonstrate continued compliance with the assigned cleanliness classification. 4.7. Clean rooms and clean-air devices shall be routinely monitored while in operation and the monitoring locations based on a formal risk analysis study and the results obtained during the classification of rooms or clean-air devices or both. 4.7.1. For Grade A zones, particle monitoring shall be undertaken for the full duration of critical processing, including equipment assembly, except where justified by contaminants in the process that would damage the particle counter or present a hazard, for example, live organisms and radiological hazards. In such cases monitoring during routine equipment set-up operations shall be undertaken before exposure to the risk. Monitoring during simulated operations shall also be performed. The Grade A zone shall be monitored at a frequency and sample size such that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded. It is accepted that it may not always be possible to demonstrate low levels of ≥5.0 μm particles at the point of fill when filling is in progress, due to the generation of particles or droplets from the product itself. 4.7.2. It is recommended that a similar system be used for Grade B zones, although the sample frequency may be decreased. The importance of the particle monitoring system shall be determined by the effectiveness of the segregation between the adjacent Grade A and B zones. The Grade B zone shall be monitored at a frequency and with a sample size such that changes in levels of contamination and any deterioration of the system would be captured and alarms triggered if alert limits are exceeded. 4.7.3. Airborne particle monitoring systems may consist of independent particle counters; a network of sequentially accessed sampling points connected by manifold to a single particle counter; or multiple small particle counters located near monitoring points and networked to a data acquisition system. Combination of systems can also be used. The system selected shall be appropriate for the particle size considered. Where remote sampling systems are used, the length of tubing and the radii of any bends in the tubing shall be considered in the context of particle losses in the tubing. The selection of the monitoring system shall take account of any risk presented by the materials used in the manufacturing operation, for example, those involving live organisms or radiopharmaceuticals. 4.7.4. The sizes of samples taken for monitoring purposes using automated systems will usually be a function of the sampling rate of the system used. It is not necessary for the sample volume to be the same as that used for formal classification of clean rooms and clean-air devices. 4.7.5. The airborne particle conditions given in Table 1 for the “at rest” state shall be achieved in the absence of the operating personnel after a short “clean-up” or “recovery” period of about 15–20 minutes (guidance value), after completion of the operations. The particulate conditions given in Table 1 for Grade A “in operation” shall be maintained in the zone immediately surrounding the product whenever the product or open container is exposed to the environment. The “clean-up” or “recovery” test shall demonstrate a change in particle concentration by a factor of 100 within the prescribed time as per the ISO standards. 4.7.6. In order to demonstrate control of the cleanliness of the various clean areas during operation, they shall be monitored for airborne particles and microbial contamination. In addition to “at rest” and “in operation” classification, airborne particles shall be monitored periodically “in operation” at critical locations. The sampling plan need not be the same as that used for classification. Locations and sample sizes shall be determined based on an assessment of the process and contamination risk. 4.7.7. The monitoring of Grade C and D areas in operation shall be performed in accordance with the principles of QRM. The requirements and alert or action limits will depend on the nature of the operations carried out, but the recommended “clean-up period” shall be attained. 4.7.8. Other characteristics such as temperature and relative humidity depend on the product and nature of the operations carried out. These parameters shall not interfere with the defined cleanliness standard. 4.7.9. Examples of operations to be carried out in the various Grades are given in the Table 2 below: Table 2 Examples of operations to be carried out in the various Grades +-------+--------------------------------------------------------------------------------------------------+ | Grade | Examples of operations for terminally sterilised products | +=======+==================================================================================================+ | A | Filling of products, which are unusually at risk | +-------+--------------------------------------------------------------------------------------------------+ | C | Placement of filling and sealing machines, preparation of solutions, when (usually at risk). | | | Filling of product when usually at risk. | +-------+--------------------------------------------------------------------------------------------------+ | D | Moulding, blowing (pre forming) operations of solutions and components for subsequent filling. | +-------+--------------------------------------------------------------------------------------------------+ +-------+--------------------------------------------------------------------------------------------------+ | Grade | Examples of operations for aseptic preparations | +=======+==================================================================================================+ | A | Aseptic preparation and filling | +-------+--------------------------------------------------------------------------------------------------+ | B | Background room conditions for activities requiring Grade A | +-------+--------------------------------------------------------------------------------------------------+ | C | Preparation of solutions to be filtered | +-------+--------------------------------------------------------------------------------------------------+ | D | Handling of components after washing | +-------+--------------------------------------------------------------------------------------------------+ 4.8. To control the microbiological cleanliness of Grades A to D in-operation, the clean areas shall be monitored. Where aseptic operations are performed, monitoring shall be frequent using methods such as settle plates, volumetric air and surface sampling (e.g., swabs and contact plates). Sampling methods used in operation shall not interfere with zone protection. Results from monitoring shall be considered when reviewing batch documentation for finished product release. Surfaces and personnel shall be monitored after critical operations. Additional microbiological monitoring is also required outside production operations, e.g., after validation of systems, cleaning and sanitisation. 4.9. Levels of detection of microbial contamination shall be established for the purpose of setting alert and action limits and for monitoring the trends in environmental cleanliness in the facility. Limits expressed in Colony Forming Units(CFU) for the microbiological monitoring of clean areas in operation are given in Table 3 below. The sampling methods and numerical values included in the said Table are not intended to represent specifications, but are for information only. Table Recommended limits for microbial contamination +-------------+-----------------------+---------------------------------+---------------------------------+---------------------------------+ | Grade | Air sample (CFU/m3) | Settle plates (diameter 90 mm) (CFU/4 hours) | Contact plates (diameter 55 mm) (CFU/plate) | Glove print (5 fingers) (CFU/glove) | +=============+=======================+=================================+=================================+=================================+ | A | < 1 | < 1 | < 1 | < 1 | +-------------+-----------------------+---------------------------------+---------------------------------+---------------------------------+ | B | 10 | 5 | 5 | 5 | +-------------+-----------------------+---------------------------------+---------------------------------+---------------------------------+ | C | 100 | 50 | 25 | – | +-------------+-----------------------+---------------------------------+---------------------------------+---------------------------------+ | D | 200 | 100 | 50 | – | +-------------+-----------------------+---------------------------------+---------------------------------+---------------------------------+ These are average values. Individual settle plates may be exposed for less than four hours. 4.10. Appropriate alert and action limits shall be set for the results of particulate and microbiological monitoring. If the action limits are exceeded or a trend is identified in the alert limits, investigation shall be initiated and the appropriate corrective actions shall be taken, as prescribed in the operating procedures. 4.11. The area Grades specified in this Part shall be selected by the manufacturer on the basis of the nature of the process operations being performed and validation runs (e.g., aseptic media fills or others types of process simulations) are used to establish processing hold times and a maximum fill duration. The determination of an appropriate process area environment and a time limit shall be based on the microbial contamination (bio burden) found. 4.11.1. Terminally sterilised products 4.11.1.1. Components and products shall be prepared in at least a Grade D zone to ensure low microbial bio burden and particulate counts prior to filtration and sterilisation. Where the product is at unusual risk of microbial contamination (e.g., because it actively supports microbial growth, must be held for a long period before sterilisation, or is necessarily processed mainly in open vessels), the preparation shall generally be done in a Grade C zone. 4.11.1.2. The filling of products for terminal sterilisation shall generally be done in at least a Grade C environment. 4.11.1.3. Where the product is at unusual risk of contamination from the environment (e.g., because the filling operation is slow, the containers are wide-necked or are necessarily exposed for more than a few seconds before sealing), the filling shall be done in a Grade A zone with at least a Grade C background. 4.11.1.4. The preparation and filling of ointments, creams, suspensions and emulsions shall generally be done in a Grade C zone before terminal sterilisation. 4.11.2. Aseptic preparation 4.11.2.1. Components after washing shall be handled in at least Grade D zone. The handling of sterile starting materials and components, unless subjected to sterilisation or filtration through a microorganism-retaining filter later in the process, shall be undertaken in a Grade A zone with Grade B background. 4.11.2.2. The preparation of solutions which are to be sterile-filtered during the process shall be undertaken in Grade C zone (unless a closed system is used, in which Grade D zone may be justifiable). If not sterile-filtered (therefore an aseptic manipulation) the preparation of materials and products shall be undertaken in Grade A zone with Grade B background. 4.11.2.3. The handling and filling of aseptically prepared products, as well as the handling of exposed sterile equipment, shall be undertaken in Grade A zone with Grade B background. 4.11.2.4. The transfer of partially closed containers, as used in freeze-drying, before stoppering is completed, shall be undertaken either in Grade A zone with Grade B background or in sealed transfer trays in Grade B zone. 4.11.2.5. The preparation and filling of sterile ointments, creams, suspensions and emulsions shall be undertaken in Grade A zone with Grade B background when the product is exposed and is not subsequently filtered. 5. Processing: 5.1. Precautions to minimise contamination shall be taken during all processing stages, including the stages before sterilisation. 5.2. In general, preparations containing live micro-organisms shall not be made, nor shall containers be filled in areas used for the processing of other pharmaceutical products. However, if the manufacturer can demonstrate and validate effective containment and decontamination of the live micro-organisms, the use of multi-product facilities may be justifiable. Vaccines consisting of dead organisms or of bacterial extracts may be dispensed into containers in the same premises as other sterile pharmaceutical products, provided that the inactivation procedure has been properly validated. When multi-product facilities are used to manufacture sterile preparations containing live microorganisms and other sterile pharmaceutical products, the manufacturer shall demonstrate and validate the effective decontamination of the live micro-organisms, in addition to precautions taken to minimise contamination. 5.3. Validation of aseptic processing shall include a process simulation test using a nutrient medium (media fill). Selection of the nutrient medium shall be based on dosage form of the product and selectivity, clarity, concentration and suitability for sterilisation of the nutrient medium. 5.4. The process simulation test shall imitate as closely as possible the routine aseptic manufacturing steps except where the activity may lead to any potential microbial contamination. 5.5. Process simulation tests shall be performed as part of validation by running three consecutive satisfactory simulation tests. These tests shall be repeated at defined intervals and after any significant modification to the HVAC system, equipment or process. Process simulation tests shall incorporate activities and interventions known to occur during normal production as well as in the worst-case situations. The process simulation tests shall be representative of each shift and shift changeover to address any time-related and operational features. 5.6. The number of containers used for media fills shall be sufficient to enable a valid evaluation. For small batches the number of containers for media fills shall at least equal to the size of the product batch. The target shall be zero growth and the following shall apply: (a) when filling fewer than 5000 units, no contaminated units shall be detected; (b) when filling 5000–10000 units - (i) one contaminated unit shall result in an investigation, including consideration of a repeat media fill; (ii) two contaminated units are considered cause for revalidation following investigation. (c) when filling more than 10000 units - (i) one contaminated unit shall result in an investigation; (ii) two contaminated units are considered cause for revalidation following investigation. 5.7. For any run size, intermittent incidents of microbial contamination may be indicative of low-level contamination that shall be investigated. Investigation of gross failures shall include the potential impact on the sterility assurance of batches manufactured since the last successful media fill. 5.8. Care shall be taken to ensure that any validation does not compromise the processes. 5.9. Water sources, water-treatment equipment and treated water shall be monitored regularly for chemicals, biological contamination and contamination with endotoxins to ensure that the water complies with the specifications appropriate to its use. Records shall be maintained of the results of the monitoring and of any action taken. 5.10. Activities in clean areas, especially when aseptic operations are in progress, shall be kept to a minimum and the movement of personnel shall be controlled and methodical, so as to avoid excessive shedding of particles and organisms due to over-vigorous activity. As far as possible, personnel shall be excluded from Grade A zones. The ambient temperature and humidity shall not be uncomfortably high because of the nature of the garments worn and to reduce the risk of contamination liberated from the personnel. 5.11. The presence of containers and materials liable to generate fibres shall be minimised in clean areas and avoided completely when aseptic work is in progress. 5.12. Components, bulk-product containers and equipment shall be handled after the final cleaning process in such a way so as to ensure that they are not re-contaminated. The stage of processing of components as well as the bulk-product containers and equipment shall be properly identified. 5.13. The interval between the washing and drying and the sterilisation of components, bulk-product containers and equipment, as well as between sterilisation and use, shall be as short as possible and subject to a time limit appropriate to the validated storage conditions. 5.14. The time between the start of the preparation of a solution and its sterilisation or filtration through a bacteria-retaining filter shall be as short as possible. A maximum permissible time shall be set for each product that takes into account its composition and the prescribed method of storage. 5.15. Any gas that is used to purge a solution or blanket a product shall be passed through a sterilising filter. 5.16. The bio burden shall be monitored before sterilisation. There shall be working limits on contamination immediately before sterilisation, which are related to the efficiency of the method to be used. Bio burden assay shall be performed on each batch for both aseptically filled products and terminally sterilised products. Where overkill sterilisation parameters are set for terminally sterilised products, bio burden might be monitored only at suitable scheduled intervals. For parametric release systems, bio burden assay shall be performed on each batch and considered as an in-process test. Where appropriate, the level of endotoxins shall be monitored. All solutions, in particular large-volume infusion fluids, shall be passed through a microorganism-retaining filter, if possible sited immediately before filling. 5.17. Components, bulk-product containers, equipment and any other articles required in a clean area where aseptic work is in progress, shall be sterilised and wherever possible passed into the area through double ended sterilisers sealed into the wall. Other procedures that prevent the introduction of contamination may be acceptable in some circumstances. 5.18. The efficacy of any new processing procedure shall be validated and the validation shall be repeated at regular intervals thereafter or when any significant change is made in the process or equipment. 6. Sterilisation: 6.1. Whenever possible products intended to be sterile shall be terminally sterilised by heat in their final container. Where it is not possible to carry out terminal sterilisation by heating due to the instability of a formulation or incompatibility of a pack type (necessary to the administration of the product, e.g., plastic eye dropper bottles), a decision shall be taken to use an alternative method of terminal sterilisation following filtration or aseptic processing or both. 6.2. Sterilisation can be achieved by the use of moist or dry heat, by irradiation with ionizing radiation (noting that ultraviolet irradiation is not normally an acceptable method of sterilisation), by ethylene oxide (or other suitable gaseous sterilising agents), or by filtration with subsequent aseptic filling of sterile final containers. Each method has its advantages and disadvantages. Where possible and practicable, heat sterilisation is the method of choice. In any case the sterilisation process shall be in accordance with the marketing and manufacturing authorisations. 6.3. The microbial contamination of starting materials shall be minimal and their bio burden shall be monitored before sterilisation. Specifications shall include requirements for microbiological quality when the need for this has been indicated by monitoring. 6.4. All sterilisation processes shall be validated. Particular attention shall be paid when the adopted sterilisation method is used for a preparation that is not a simple aqueous or oily solution, for example, colloidal suspensions. 6.5. Before any sterilisation process is adopted, its suitability for the product and its efficacy in achieving the desired sterilising conditions in all parts of each type of load to be processed shall be demonstrated by physical measurements and by biological indicators, where appropriate. The validity of the process shall be verified at scheduled intervals, at least annually, and whenever significant modifications have been made to the equipment. Records shall be kept of the results. 6.6. For effective sterilisation the whole of the material shall be subjected to the required treatment and the process shall be designed to ensure that it is achieved. 6.7. Biological indicators shall be considered only as an additional method of monitoring the sterilisation process. They shall be stored and used according to the manufacturer’s instructions and their quality checked by positive controls. If they are used, strict precautions shall be taken to avoid any transfer of microbial contamination from them. 6.8. There shall be a clear means of differentiating products that have not been sterilised from those which have. Each basket, tray, or other carrier of products or components shall be clearly labelled with the name of the material, its batch number and an indication of whether or not it has been sterilised. Indicators such as autoclave tape may be used where appropriate to indicate whether or not a batch (or sub-batch) has passed through a sterilisation process, but they do not give a reliable indication that the batch is in fact sterile. 6.9. Validated loading patterns shall be established for all sterilisation processes. 6.10. Sterilisation records shall be available for each sterilisation run. They shall be approved as part of the batch-release procedure. 6.11.1. Terminal sterilisation 6.11.1.1. Each heat-sterilisation cycle shall be recorded by means of appropriate equipment of suitable accuracy and precision, e.g., on a time or temperature chart with a suitably large scale. The temperature shall be recorded by a probe situated at the coolest part of the load or loaded chamber, this point having been determined during the validation; the temperature shall preferably be checked against a second independent temperature probe located at the same position. Sterilisation records shall be available for each sterilisation run and shall be approved as part of the batch release procedure. Chemical or biological indicators may also be used but shall not take the place of physical controls. 6.11.1.2. Sufficient time shall be allowed for the whole of the load to reach the required temperature before measurement of the sterilising time is started. This time shall be determined for each type of load to be processed. 6.11.1.3. After the high-temperature phase of a heat sterilisation cycle, precautions shall be taken against contamination of a sterilised load during cooling. Any cooling fluid or gas in contact with the product shall be sterilised. 6.11.1.4. Both temperature and pressure shall be used to monitor the process. Control instrumentation shall normally be independent of monitoring instrumentation and recording charts. Where automated control and monitoring systems are used for these applications they shall be validated to ensure that critical process requirements are met. System and cycle faults shall be registered by the system and observed by the operator. The reading of the independent temperature indicator shall be routinely checked against the reading on the chart recorder during the sterilisation period. For sterilisers fitted with a drain at the bottom of the chamber, it may also be necessary to record the temperature at this position throughout the sterilisation period. There shall be regular leak tests on the chamber when a vacuum phase is part of the cycle. 6.11.1.5. The items to be sterilised, other than products in sealed containers, shall be wrapped in a material that allows the removal of air and the penetration of steam but prevents recontamination after sterilisation. Specially designed autoclavable stainless steel containers, that allow steam to enter and air to leave, can also be used. All parts of the load shall be in contact with water or saturated steam at the required temperature for the required time. 6.11.1.6. Care shall be taken to ensure that the steam used for sterilisation is of suitable quality chemical, microbiological and endotoxin analysis of condensate and physical examination of steam (such as dryness, superheat and non-condensable gases) and does not contain additives at a level that could cause contamination of the product or equipment. Steam used for sterilisation shall be tested regularly. 6.11.1.7. Sterilisation by dry heat may be suitable for non-aqueous liquids or dry-powder products. The process used shall include air circulation within the chamber and the maintenance of a positive pressure to prevent the entry of non-sterile air. If air is supplied it shall be passed through a microorganism-retaining filter (e.g., a HEPA filter). Where sterilization by dry heat is also intended to remove pyrogens, challenge tests using endotoxins are required as part of the validation. 6.11.1.8. Sterilisation by radiation is used mainly for heat-sensitive materials and products. Many pharmaceutical products and some packaging materials are radiation-sensitive, so this method is permissible only when the absence of deleterious effects on the product has been confirmed experimentally. Ultraviolet irradiation is not an acceptable method for terminal sterilisation. 6.11.1.9. If sterilisation by radiation is done by an outside contractor, the manufacturer is responsible for ensuring that the requirements of paragraph 6.8 are met and that the sterilisation process is validated. 6.11.1.10. During the sterilisation procedure the radiation dose shall be measured. The dosimeters used for this purpose shall be independent of the dose rate and shall provide a quantitative measurement of the dose received by the product itself. Dosimeters shall be inserted in the load in sufficient number and close enough together to ensure that there is always a dosimeter in the chamber. Where plastic dosimeters are used they shall be used within the time-limit of their calibration. Dosimeter absorbance shall be read shortly after exposure to radiation. Radiation-sensitive colour discs may be used to differentiate between packages that have been subjected to irradiation and those that have not; they are not indicators of successful sterilisation. The information obtained shall constitute part of the batch record. 6.11.1.11. Validation procedures shall ensure that consideration is given to the effects of variations in the density of the packages. 6.11.1.12. Material-handling procedures shall prevent any mix-up of irradiated and non irradiated materials. Each package shall carry a radiation-sensitive indicator to show whether or not it has been subjected to radiation treatment. 6.11.1.13. The total radiation dose shall be administered within a predetermined period. 6.11.1.14. Sterilisation by gases and fumigants shall only be used for finished products where there is no suitable alternative. 6.11.1.15. Various gases and fumigants may be used for sterilisation (e.g., ethylene oxide and hydrogen peroxide vapour). Ethylene oxide shall be used only when no other method is practicable. During process validation, it shall be shown that the gas has no damaging effect on the product and that the conditions and time allowed for degassing are to reduce any residual gas and reaction products to defined acceptable limits for the type of product or material concerned. These limits shall be incorporated in the specifications. 6.11.1.16. Direct contact between gas and microorganisms is essential; precautions shall, therefore, be taken to avoid the presence of organisms likely to be enclosed in materials such as crystals or dried protein. The nature and quantity of packaging materials can significantly affect the process. 6.11.1.17. Before exposure to the gas, materials shall be brought into equilibrium with the humidity and temperature required by the process. This requirement shall be balanced against the need to minimise the waiting time before sterilisation. 6.11.1.18. Each sterilisation cycle shall be monitored with suitable biological indicators, using the appropriate number of test pieces distributed throughout the load. The information thus obtained shall form part of the batch record. 6.11.1.19. Biological indicators shall be stored and used according to the manufacturer’s instructions and their performance checked by positive controls. 6.11.1.20. For each sterilization cycle, records shall be made of the time taken to complete the cycle, of the pressure, temperature and humidity within the chamber during the process and of the gas concentration. The pressure and temperature shall be recorded on a chart throughout the cycle. The records shall form part of the batch record. 6.11.1.21. After sterilisation, the load shall be stored in a controlled manner in ventilated conditions to allow concentration of residual gas and reaction products to fall to their prescribed levels. This process shall be validated. 6.11.2. Aseptic processing and sterilisation by filtration:- 6.11.2.1. The objective of aseptic processing is to maintain the sterility of a product that is assembled from components, each of which has been sterilised by one of the above methods. 6.11.2.2. The operating conditions shall be to prevent microbial contamination. 6.11.2.3. In order to maintain the sterility of the components and the product during aseptic processing, careful attention needs to be given to the following namely:- (a) the environment; (b) personnel; (c) critical surfaces; (d) container or closure sterilisation and transfer procedures; (e) the maximum holding period of the product before filling into the final container; and (f) the sterilising filter. 6.11.2.4. Certain solutions and liquids that cannot be sterilised in the final container can be filtered through a sterile filter of nominal pore size 0.22 µ (or less), or with at least equivalent microorganism-retaining properties, into a previously sterilised container. Such filters can remove bacteria and moulds, but not all viruses or mycoplasmas. Consideration shall be given to complementing the filtration process with some degree of heat treatment. Filtration alone is not considered sufficient when sterilisation in the final container is possible. Of the methods currently available, steam sterilisation is preferred. 6.11.2.5. Owing to the potential additional risks of the filtration method as compared with other sterilisation processes, a double-filter layer or second filtration through a further sterilised microorganism-retaining filter immediately prior to filling may be advisable. The final sterile filtration shall be carried out as close as possible to the filling point. 6.11.2.6. The fibre-shedding characteristics of filters shall be minimal (virtually zero). Asbestos-containing filters shall not be used under any circumstances. 6.11.2.7. The integrity of the sterilised filter shall be verified before use and shall be confirmed immediately after use by an appropriate method such as a bubble point, diffusive flow or pressure hold test. The time taken to filter a known volume of bulk solution and the pressure difference to be used across the filter shall be determined during validation and any significant difference from these during routine manufacturing shall be noted and investigated. Results of these checks shall be included in the batch record. The integrity of critical gas and air vent filters shall be confirmed after use. The integrity of other filters shall be confirmed at appropriate intervals. Consideration shall be given to increased monitoring of filter integrity in processes that involve harsh conditions, e.g., the circulation of high-temperature air. 6.11.2.8. The same filter shall not be used for more than one working day unless such use has been validated. 6.11.2.9. The filter shall not affect the product either by removing ingredients from it or by releasing substances into it. 6.11.3. Isolator technology 6.11.3.1. The use of isolator technology to minimise human interventions in processing areas may result in a significant decrease in the risk of microbial contamination of aseptically manufactured products from the environment. There are many possible designs of isolators and transfer devices. The isolator and the background environment shall be designed so that the required air quality for each zone can be realised. Isolators are constructed of various materials more or less prone to puncture and leakage. Transfer devices may vary from single-door to double-door designs to fully-sealed systems incorporating sterilisation mechanisms. 6.11.3.2. The transfer of materials into and out of the unit is one of the greatest potential sources of contamination. In general the area inside the isolator is the local zone for high risk manipulations, although it is recognised that unidirectional airflow may not exist in the working zone of all isolators and transfer devices. Explanation.- For the purpose of this paragraph “local zone” means an area inside the isolator for high risk manipulation. 6.11.3.3. The air classification required for the background environment depends on the design of the isolator and its application. It shall be controlled, and for aseptic processing it shall be at least Grade D. 6.11.3.4. Isolators shall be introduced only after appropriate validation. Validation shall take into account all critical factors of isolator technology, for example, the quality of the air inside and outside (background) the isolator, sanitisation of the isolator, the transfer process and isolator integrity. 6.11.3.5. Monitoring shall be done routinely and shall include frequent leak testing of the isolator and the glove or sleeve system. 6.11.4. Blow, Fill-Seal technology 6.11.4.1. Blow, Fill-Seal units are purpose-built machines in which, in one continuous operation, containers are formed from a thermoplastic granulate, filled and then sealed, all by the one automatic machine. Blow, Fill-Seal equipment used for aseptic production which is fitted with an effective Grade A air shower may be installed in at least a Grade C zone, provided that Grade A or B clothing is used. The environment shall comply with the viable and non-viable limits at rest and the viable limit only when in operation. Blow, Fill Seal equipment used for the production of products which are terminally sterilised shall be installed in at least a Grade D zone. 6.11.4.2. Because of this special technology, particular attention shall be paid to at least the following, namely:- (a) equipment design and qualification; (b) validation and reproducibility of cleaning-in-place and sterilisation-in-place; (c) background clean room environment in which the equipment is located; (d) operator training and clothing; and (e) interventions in the critical zone of the equipment including any aseptic assembly prior to the commencement of filling. 7. Personnel:- 7.1. Only the minimum number of personnel required shall be present in clean areas; this is particularly important during aseptic processes. As far as possible, inspections and controls shall be conducted from outside such areas. 7.2. All personnel (including those concerned with cleaning and maintenance) employed in such areas shall receive initial and regular training in disciplines relevant to the correct manufacture of sterile products, including hygiene and the basic elements of microbiology. When outside staff who have not received such training (e.g., building or maintenance contractors) need to be brought in, particular care shall be taken over their instruction and supervision. 7.3. Staff who have been engaged in the processing of animal-tissue materials or of cultures of microorganisms other than those used in the current manufacturing process shall not enter sterile-product areas unless rigorous and clearly defined decontamination procedures have been followed. 7.4. High standards of personal hygiene and cleanliness are essential and personnel involved in the manufacture of sterile preparations shall be instructed to report any conditions that may cause the shedding of abnormal numbers or types of contaminants; periodic health checks for such conditions are desirable. The action to be taken in respect of personnel who might be introducing undue microbial hazards shall be decided by a designated competent person. 7.5. Changing and washing shall follow a written procedure designed to minimise the contamination of clean-area clothing or the carry-through of contaminants to clean areas. The clothing and its quality shall be appropriate for the process and the grade of the working area. It shall be worn in such a way so as to protect the product from contamination. 7.6. Outdoor clothing shall not be brought into changing rooms leading to Grade B and C rooms. For every worker in a Grade A or B area, clean sterile (sterilised or adequately sanitized) protective garments shall be provided at each work session. Gloves shall be regularly disinfected during operations. Masks and gloves shall be changed at least every working session. Operators working in Grade A and B zone shall wear sanitised goggles. 7.7. Wrist-watches, cosmetics and jewellery shall not be worn in clean areas. 7.8. The clothing required for each grade is as follows: (i) Grade D: The hair and, where relevant, beard and moustache shall be covered. Protective clothing and appropriate shoes or overshoes shall be worn. Appropriate measures shall be taken to avoid any contamination from outside the clean area. (ii) Grade C: The hair and, where relevant, beard and moustache shall be covered. A one-piece jumpsuit, gathered at the wrists and with a high neck, and appropriate shoes or overshoes shall be worn. The clothing shall shed virtually no fibres or particulate matter. (iii) Grades A and B: Entry of personnel into Grade A zone shall be minimised. Headgear shall totally enclose the hair and, where relevant, beard and moustache. A one-piece jumpsuit, gathered at the wrists and with a high neck, shall be worn. The headgear shall be tucked into the neck of the suit. A facemask shall be worn to prevent the shedding of droplets. Sterilised, non-powdered gloves of appropriate material and sterilised or disinfected footwear shall be worn. Trouser bottoms shall be tucked inside the footwear and garment sleeves into the gloves. The protective clothing shall shed virtually no fibres or particulate matter and shall retain particles shed by the body. 7.9. Clothing used in clean areas shall be laundered or cleaned in such a way that it does not gather additional particulate contaminants that can later be shed. Separate laundry facilities for such clothing are desirable. If fibres are damaged by inappropriate cleaning or sterilisation, there may be an increased risk of shedding particles. Washing and sterilisation operations shall follow standard operating procedures. 8. Premises: 8.1. All premises shall as far as possible be designed to avoid the unnecessary entry of supervisory or control personnel. Grade A and B zone shall be designed so that all operations can be observed from outside. 8.2. In clean areas all exposed surfaces shall be smooth, impervious and unbroken to minimise the shedding or accumulation of particles or microorganisms and to permit the repeated application of cleaning agents and disinfectants, where used. 8.3. To reduce the accumulation of dust and to facilitate cleaning, there shall be no uncleanable recesses and a minimum of projecting ledges, shelves, cupboards and equipment. Doors shall be carefully designed to avoid uncleanable recesses; sliding doors may be undesirable for this reason. Swing doors shall open to the high pressure side and be provided with self-closers. Exceptions are permitted based on egress and site environmental, health and safety containment requirements. 8.4. False ceilings shall be sealed to prevent contamination from the void space above them. 8.5. Pipes and ducts and other utilities shall be installed so that they do not create recesses, unsealed openings and surfaces that are difficult to clean. Sanitary pipes and fittings shall be used and threaded pipe connections shall be avoided. 8.6. Sinks and drains shall be avoided wherever possible and shall be excluded from Grade A and B zone where aseptic operations are carried out. Where installed they shall be designed, located and maintained so as to minimise the risks of microbial contamination; they shall be fitted with effective, easily cleanable traps and with air breaks to prevent backflow. Any floor channels shall be open and easily cleanable and be connected to drains outside the area in a manner that prevents the ingress of microbial contaminants. 8.7. Changing rooms shall be designed as airlocks and used to provide physical separation of the different stages of changing tominimise microbial and particulate contamination of protective clothing. They shall be flushed effectively with filtered air. The final stage of the changing room shall, in the at rest state, be the same Grade as the zone into which it leads. The use of separate changing rooms for entering and leaving clean areas is sometimes desirable. In general hand washing facilities shall be provided only in the first stage of the changing rooms. There shall not be a change of more than one Grade between airlocks or passages and changing rooms, i.e., a Grade D passage can lead to a Grade C airlock, which leads to a Grade B changing room, which leads to a Grade B clean room. Changing rooms shall be of a sufficient size to allow for ease of changing. Changing rooms shall be equipped with mirrors so that personnel can confirm the correct fit of garments before leaving the changing room. 8.8. Airlock doors shall not be opened simultaneously. An interlocking system and a visual or audible or both warning system shall be operated to prevent the opening of more than one door at a time. 8.9. A filtered air supply shall be used to maintain a positive pressure and the airflow relative to surrounding areas of a lower Grade under all operational conditions; it shall flush the area effectively. Adjacent rooms of different Grades shall have a pressure differential of approximately 10 to 15 Pascal (guidance value). Particular attention shall be paid to the protection of the zone of greatest risk, i.e., the immediate environment to which the product and the cleaned components in contact with it are exposed. The recommendations regarding air supplies and pressure differentials may need to be modified where it becomes necessary to contain certain materials, e.g. pathogenic, highly toxic, radioactive or live viral or bacterial materials or products. The decontamination of the facilities and the treatment of air leaving a clean area may be necessary for some operations. 8.10. It shall be demonstrated that airflow patterns do not present a contamination risk; for example, care shall be taken to ensure that particles from a particle generating person, operation or machine are not conveyed to a zone of higher product risk. 8.11. A warning system shall be operated to indicate failure in the air supply. Indicators of pressure differentials shall be fitted between areas where this difference is important, and the pressure differentials shall be regularly recorded and failure alarmed. 8.12. Consideration shall be given to restricting unnecessary access to critical filling areas e.g., Grade A filling zones, by means of a physical barrier. 9. Equipment: 9.1. A conveyor belt shall not pass through a partition between a Grade A or B clean area and a processing area of lower air cleanliness, unless the belt itself is continuously sterilised (e.g., in a sterilising tunnel). 9.2. Whenever possible, equipment used for processing sterile products shall be chosen so that it can be effectively sterilised by steam or dry heat or other methods. 9.3. As far as possible, equipment fittings and services shall be designed and installed so that operations, maintenance and repairs can be carried out outside the clean area. Equipment that has to be taken apart for maintenance shall be re-sterilised after complete reassembly, wherever possible. 9.4. When equipment maintenance is carried out within a clean area, clean instruments and tools shall be used and the area shall be cleaned and disinfected again, where appropriate, before processing recommences, if the required standards of cleanliness or asepsis or both have not been maintained during the maintenance work. 9.5. All equipment such as sterilisers, air-handling and filtration systems, air vent and gas filters, water treatment, generation, storage and distribution systems shall be subject to validation and planned maintenance; their return to use shall be approved. 9.6. Water-treatment plants and distribution systems shall be designed, constructed and maintained so as to ensure a reliable source of water of an appropriate quality. They shall not be operated beyond their designed capacity. Consideration shall be given to include a testing programme in the maintenance of a water system. Water for injection shall be produced, stored and distributed in a manner which prevents the growth of microorganisms, e.g., by constant circulation at a temperature above 70 °C or not more than 4 °C. 10. Finishing of sterile products:- 10.1. Containers shall be closed by appropriately validated methods. Containers closed by fusion, e.g., glass or plastic ampoules, shall be subject to 100 percent integrity testing. Samples of other containers shall be checked for integrity according to appropriate procedures. 10.2. The container closure system for aseptically filled vials is not fully integral until the aluminium cap has been crimped into place on the stoppered vial. Crimping of the cap shall, therefore, be performed as soon as possible after stopper insertion. 10.3. As the equipment used to crimp vial caps can generate large quantities of non-viable particulates, the equipment shall be located at a separate station equipped with adequate air extraction. 10.4. Vial capping can be undertaken as an aseptic process using sterilised caps or as a clean process outside the aseptic core. Where this latter approach is adopted, vials shall be protected by Grade A conditions up to the point of leaving the aseptic processing area, and thereafter stoppered vials shall be protected with a Grade A air supply until the cap has been crimped. 10.5. Vials with missing or displaced stoppers shall be rejected prior to capping. Where human intervention is required at the capping station, appropriate technology shall be used to prevent direct contact with the vials and to minimise microbial contamination. 10.6. Restricted access barriers and isolators may be beneficial in assuring the required conditions and minimising direct human interventions into the capping operation. 10.7. Containers sealed under vacuum shall be tested for maintenance of that vacuum after an appropriate, predetermined period. 10.8. Filled containers of parenteral products shall be inspected individually for extraneous contamination or other defects. When inspection is carried out visually this shall be done under suitable and controlled conditions of illumination and background. Operators doing the inspection shall pass regular eyesight checks, using personal corrective lenses (e.g., spectacles or contact lenses) as required, and be allowed frequent breaks from inspection. Where other methods of inspection are used, the process shall be validated and the performance of the equipment shall be checked at intervals. Results shall be recorded. PART III SPECIFIC REQUIREMENTS FOR MANUFACTURING OF PHARMACEUTICAL PRODUCTS CONTAINING HAZARDOUS SUBSTANCES SUCH AS SEX HORMONES, STEROIDS (ANABOLIC, ANDROGENIC) OR CYTOTOXIC SUBSTANCES Note.-Good Manufacturing Practices for pharmaceutical products: Main principles as given in Part I Schedule shall be complied with, mutatis mutandis, for the manufacture of hazardous substances such as certain sex hormones, steroids (anabolic, androgenic) or cytotoxic substances. In addition to these requirements, the following specific requirements shall also be followed, namely:— 1. Introduction:- The areas to which this Part applies include all zones where the handling of products could lead to cross contamination, exposure of personnel, or discharge to the environment. Wherever possible products shall be manufactured in closed systems. 1.1. Facilities shall be designed and operated in accordance with the main good manufacturing practices principles, as follows:- (a) to ensure quality of product; (b) to protect the operators from possible harmful effects of products containing hazardous substances; and (c) to protect the environment from contamination and thereby protect the public from possible harmful effects of products containing hazardous substances. 1.2. The production of certain products containing hazardous substances shall generally be conducted in separate, dedicated, self-contained facilities. These self-contained facilities may be in the same building as another facility but shall be separated by a physical barrier and have e.g., separate entrances, staff facilities and air handling systems. The extent of the separation from adjacent facilities and sharing of common services shall be determined by risk assessment. 1.3. In general these manufacturing facilities shall be regarded as containment facilities. 1.4. The effective operation of a facility may require the combination of some or all of the following, namely:- (a) appropriate facility design and layout, with the emphasis on safely containing the materials being handled. Manufacturing processes using closed systems or barrier technology enhance operator and product protection; (b) manufacturing process controls including adherence to SOPs; (c) appropriately designed Environmental Controls Systems (ECS) or HVAC; (d) extraction systems; (e) Personal Protective Equipment (PPE); (f) appropriate de-gowning and decontamination procedures; (g) industrial hygiene (monitoring staff exposure levels); (h) medical surveillance (monitoring staff exposure levels); and (i) administrative controls. 2. Risk assessment:- 2.1. Not all products containing hazardous substances are equally potent and risk assessments shall be carried out to determine the potential hazards to operators and to the environment. The risk assessment shall also determine which phase of the product production and control cycles, from manufacture of the API to distribution of the finished product, would fall under the requirements of these guidelines. Risk assessments applicable to the environment shall include airborne contamination as well as liquid effluent contamination. 2.2. Assuming that the risk assessment determines that the products or materials being handled pose a risk to the operators or to the public or to the environment, the guidelines to be followed for the design and operation of the facility shall be as detailed in this Schedule. 2.3. The toxicological data available, such as permissible occupational exposure levels (OEL) for the product, shall be taken into account when conducting the risk assessment. 2.4. The risk assessment shall take into account occupational health and safety requirements for OELs in the work environment. 3. Product protection:- The requirement for producing quality products, with respect to protection from contamination and cross-contamination, clean room class of air, temperature and humidity shall be as for other pharmaceutical products. 4. Personal Protection Equipment and breathing air systems:- 4.1. The fundamental design principle for a facility and its production equipment is to provide product containment and operator protection. In case of the facility and equipment design is not providing adequate product containment, operator protection shall be provided. If facility and equipment design are adequate, a spillage or non-routine incident could cause a hazardous situation, in which case PPE shall be available. Unless otherwise specified in the material safety data sheet, operators shall be protected from exposure with an appropriate method, such as by wearing- (a) flash-spun, high-density polyethylene fibre material suits or impervious washable protective suits. Integral hoods may be required depending on the respirator type used; (b) flash-spun, high-density polyethylene fibre material shoes, lower leg covers or cleanable boots; (c) suitable single-use, disposable gloves. Double gloves shall be worn where direct active contact with the product cannot be avoided. Gloves shall be taped or sealed on to the protective suit sleeves; and (d) respirator eye and face protection with associated breathing air systems. 4.2. Where breathing air systems are used, these shall be provided to supply safe breathing air to the operators to prevent them from inhaling air from within the facility. Personnel shall be appropriately trained and assessed in the use of these systems before they enter the area. The breathing air systems shall comprise a protective face mask, which shall form an integral part of a protective suit. The breathing air systems could be any of the systems described below- (a) a central air supply system which connects to the operator’s facemask by means of flexible hoses and quick coupling sockets, also called an Airline Respirator (AR). The air connection shall incorporate a one-way air system to prevent contaminated air entering the face mask during connection or disconnection. The air supply shall be treated to ensure a temperature and level of humidity that are comfortable for the operator. The air source could be a high pressure fan or an air compressor. If an air compressor is used, it shall be of the oil-free type or have suitable oil removal filters fitted; (b) a Self-Contained Breathing Apparatus (SCBA) or Powered Air Purifying Respirator (PAPR) that is securely attached to the operator’s belt and connects to the operator’s face mask. This system draws air from the room in which the operator is working and the air supply is delivered to the face mask by means of a battery-driven fan. The AR provides superior protection to the PAPR apparatus; (c) for zones with lower contamination levels, a half-mask High Efficiency Particulate Air filter (HEPA) cartridge respirator of N95-type paper filter mask may be acceptable. 4.3. The selection of the respirator type is based on the relationship between the accepted OEL and the respirator certified Protection Factor (PF). 4.4. The air supplies shall be filtered through a final filter, which shall be a HEPA filter rated as an H13 filter according to European norms. The supply of breathing air in to the face mask or protective suit or both shall result in the interior of the mask and suit being at a positive pressure relative to the facility environment. 4.5. Central breathing air supply systems shall have a one hundred percent back-up system in the event of the main system failing. This could be in the form of a gas bottle system with atleast five minutes supply. Change over from the normal supply to the back-up supply shall be automatic. The system shall have a monitoring system and send alarm signals to a permanently manned location in the following situations, namely:- (i) failure of main air supply; (ii) temperature out of specification (OOS); (iii) humidity OOS; (iv) carbon dioxide (CO2) OOS; (v) carbon monoxide (CO) OOS; and (vi) sulfur dioxide (SO2) OOS. 4.6. Breathing air shall be filtered by means of pre-filters, coalescing filters and final filters to have the minimum air quality specifications of ISO standards and European norms. 4.7. Where air is delivered through a central system the piping shall not cause any contamination to be liberated into the air stream. Stainless steel piping is preferred. The final filters shall be as close as possible to the operator connection points. The operator hose connection to the air supply shall be a dedicated connection specific to the breathing air system to avoid inadvertent connection to a different gas system. 5. Environmental protection:- 5.1. Due to the hazardous nature of the products being handled in the facility, neither the product nor its residues shall be allowed to escape into the atmosphere or to be discharged directly to normal drainage systems. 5.2. The external atmosphere and the public in the vicinity of the facility shall be protected from possible harm from hazardous substances. 5.3. If liquid effluent poses a safety or contamination risk, the effluent shall be treated before being discharged to a municipal drain. 5.4. Exhaust air filtration to ensure environmental protection shall be as per paragraph 11. 6. Facility layout:- 6.1. The premises shall be designed and constructed to prevent the ingress or egress of contaminants. In drawing up the facility design, attention shall be paid to the level of containment provided by the equipment. 6.2. The link between the interior and exterior of the premises shall be through airlocks [Personnel Airlock (PAL), Material Airlock (MAL)], changing rooms, pass boxes, pass-through hatches, decontamination devices, etc. These entry and exit doors for materials and personnel shall have an interlock mechanism or other appropriate system to prevent the opening of more than one door at a time. 6.3. The changing rooms shall have an arrangement with a step-over- bench. The facilities on the exit side shall incorporate showers for the operators. 6.4. The premises shall be laid out and designed so as to facilitate the required pressure cascades and containment. 6.5. The premises and equipment shall be appropriately designed and installed to facilitate cleaning and decontamination. 6.6. The manufacturing site and buildings shall be described in sufficient detail by means of plans and written explanations to ensure that the designation and conditions of use of all the rooms are correctly shown. 6.7. The flow of people and products shall be clearly marked on the layouts and plans. 6.8. The activities carried out in the vicinity of the site shall be indicated. 6.9. Plans shall describe the ventilation systems, indicating inlets and outlets, in relation to other facility air inlet and outlet points. 6.10. The facility shall be a well-sealed structure with no air leakage through ceilings, cracks or service areas. 6.11. Areas of the facility where exposed product presents a risk shall be maintained at a negative air pressure relative to the environment. 7. Air-handling systems:- 7.1. The HVAC system shall be appropriately designed, installed and maintained to ensure protection of product, personnel and the environment. 7.2. Facilities and premises dealing with hazardous substances shall have the following basic air handling characteristics, namely:- (i) there shall be no direct venting of air to the outside; (ii) air-conditioning or ventilation shall result in a negative pressure relative to the outside. Air pressure differentials shall be such that there is no uncontrolled flow of air between the work area and the external environment; (iii) appropriate air pressure alarm systems shall be provided to warn of any pressure cascade reversal or loss of design pressure status. The appropriate design, alert and action limits shall be in place. System redundancies shall be in place to respond appropriately to pressure cascade failure; (iv) the starting and stopping of the supply and exhaust air fan shall be synchronized so that the premises remain at a negative pressure during start-up and shut-down; (v) the air pressure cascade within the facility, shall comply with normal pharmaceutical pressure cascade requirements with regards to product protection, dust containment and personnel protection; (vi) visual indication of the status of room pressures shall be provided in each room; (vii) air shall be exhausted to the outside through HEPA filters and not be re-circulated except to the same area, and provided that a further HEPA filtration stage is applied to the return air. Where HEPA filters are mentioned in the Schedule, this refers to HEPA filters with a minimum rating of H13 according to European norms; (viii) where possible, single-pass air-handling systems with no recirculation shall be provided; (ix) exhaust air or return air shall be filtered through a safe-change or bag- in-bag-out filter housing. The filter housing shall contain pre-filters and HEPA filters, both of which shall be removable with the safe bagging system; (x) changing rooms shall be supplied with air filtered to the same standard as that for the work area they serve; (xi) airlocks, pass-through hatches, etc., shall have supply and extract air to provide the necessary air pressure cascade and containment. The final, or containment perimeter, airlock or pass through hatch bordering on an external or non-good manufacturing practices area shall be at a positive pressure relative to the environment, to prevent the ingress of contaminants to the facility; (xii) if the facility provides insufficient containment, and operators’ garments are contaminated with dust, the operators leaving the containment area shall pass through a decontamination system e.g., air showers or a mist shower system, to assist with removing or controlling dust particles on their garments. Operators shall follow this route before de-gowning to use the ablutions or canteen facilities. All garments leaving the facility for laundering shall be safely bagged. Appropriate means for protecting laundry staff and prevention of contamination of other garments from non-hazardous facilities shall be in place. 7.3. If required, appropriate measures shall be taken to prevent airflow from the primary packing area (through the conveyor “mouse hole”) to the secondary packing area. Note.- This could be overcome by having a pass-through chamber over the “mouse hole” which is maintained at a negative pressure to both primary and secondary packing. This typical arrangement is illustrated in Figure below. This principle can be applied to other situations where containment from two E Shut offDamper s VFD Shut offDampe r EXHAUSTAI RFAN M M M SECONDARYFI LTER VFD=VelocitySensor V=Variable FrequencyDrive M= Filter PressureDifferensialGua ge V M M M HEPAFIL TER HEPABag In,Bag-OutUnits sides is required. The typical airflow pattern for contaminant shall be as specified in the figure below– 7.4. Where possible, HEPA filters in the supply air system shall be terminally mounted to provide protection against back-flow cross-contamination in the event of failure in the supply airflow. 7.5. In some cases consideration can be given to the use of biosafety cabinets, isolation systems or glove boxes as a means for containment and operator protection. 7.6. There shall be a system description including schematic drawings detailing the filters and their specifications, the number of air changes per hour, pressure gradients, clean room classes and related specifications. These shall be available for inspection. 7.7. There shall be an indication of pressure gradients that are monitored by means of digital or analogue pressure indicators. 7.8. Consideration shall be given to providing an emergency power supply, e.g., diesel generators, to ensure that safe operation of the premises and systems can be maintained at all times. 7.9. The principles of airflow direction, air filtration standards, temperature, humidity and related parameters shall be ensured and the filtration shall be consistent with the zone concepts and product protection required. 8. Air-Handling Units (AHU):- 8.1. The decision to use return air or re-circulated air shall be made on the basis of a risk assessment. 8.2. Where a full fresh-air or single-pass system is used, an energy recovery wheel could be considered. In such cases, there shall not be any potential for air leakage between the supply air and exhaust air as it passes through the wheel. The relative pressures between supply and exhaust air systems shall be such that the exhaust-air system operates at a lower pressure than the supply system. (Alternatives to the energy recovery wheel, such as crossover plate heat exchangers, heat pipes and water coil heat exchangers, may be used.) 8.3. Risk management principles shall be applied to address the potential of cross-contamination where energy wheels are used. 8.4. If return air is to be re-circulated it shall pass through a safe change filtration system before being introduced back into the supply AHU. The return air fan could form part of the AHU; however, the safe change filter shall be a dedicated unit. With this arrangement the return air passes through two sets of HEPA filters in series, i.e., the return air filters in the safe change housing and the supply air HEPA filters. The supply air HEPA filters could either be located in the AHU or terminally located at the supply diffusers, depending on the clean room classification of the facility. 8.5. The starting and stopping of the supply and exhaust air fans and associated system ventilation fans shall be synchronised such that the premises retain their design pressure and flow relationships during start up and shut-down. Processing shall stop when the fans are not running. This fan interlock sequence shall also apply if any fan shall fail, to ensure that there is no airflow reversal in the system. 9. Safe change filter housings:- 9.1. Safe change or bag-in-bag-out filter housings shall be suitably designed to provide operator protection and to prevent dust from the filters entering the atmosphere when filters are changed. The Safe change filter bypass arrangement shall be as specified in the figure below– DOP Injection Filterintegrity test &De-contamination by-pass duct E Shut offDamper s VFD Shut offDampe r EXHAUSTAI RFAN M M M SECONDARYFI LTER VFD=VelocitySensor V=Variable FrequencyDrive M= Filter PressureDifferensialGua ge V M M M HEPAFIL TER HEPABag In,Bag-OutUnits 9.2. The final filters on the safe change unit shall be HEPA filters with at least an H13 classification according to European norms filter standards. For dusty return, air pre-filtration may also be required to prolong the life of the HEPA filters. The pre-filtration filters shall also be removable through the bag-in-bag out method. 9.3. For exhaust systems where the discharge contaminant is considered particularly hazardous, two banks of HEPA filters in series shall be considered to provide additional protection the first filter fail. 9.4. All filter banks shall be provided with pressure differential indication gauges to indicate the filter dust loading and remaining lifespan of the filters. Connection to these gauges shall be copper or stainless steel and not plastic tubing, which could perish causing a contamination hazard. The tube connections on the filter casing shall be provided with stopcocks, for safe removal or calibration of gauges. 9.5. Monitoring of filters shall be done at regular intervals to prevent excessive filter loading that could force dust particles through the filter media, or could cause the filters to burst, resulting in ambient contamination. 9.6. Computer based data monitoring systems may be installed to monitor filter condition. 9.7. Filter pressure gauges shall be marked with the clean filter resistance and the change-out filter resistance. 9.8. Installed filter leakage tests shall be performed in accordance with ISO standards. Injection ports (upstream) and access ports (downstream) shall, therefore, be provided for this purpose. 9.9. The exhaust air fan on a safe change filter system shall be located after the filters so that the filter housing is maintained at a negative pressure. This poses a difficulty when carrying out filter integrity tests and for this reason a bypass damper system shall be provided, as illustrated in figure at paragraph 9.1, so that air can be circulated through the HEPA filters, while the scanning ports are open. Alternatively, an independent booster fan system can be used, with appropriate shut-off dampers. 9.10. The bypass arrangement as shown in figure at paragraph 9.1also permits decontamination of the filters by means of circulation of a sanitising agent. 9.11. All exhaust systems from the facility, including dust extraction systems, vacuum system exhaust, fluid bed drier exhaust and coating pan exhaust, shall be passed through safe change filter housings before being exhausted to the atmosphere. 9.12. All exhaust points outside the building shall be located as far as possible from air entry points and exit points shall be at a high level to minimise the possibility of re-entrainment of exhaust air. Dominant and seasonal wind directions shall be taken into account when positioning exhaust and supply points. 9.13. Where excessively dust-laden air is handled, a dust collector or bag house shall be considered with the dust collector being located in an enclosed room maintained at a negative pressure. Access control, maintenance staff, PPE and breathing air systems shall then be provided to protect the operators during removal of dust from the collector bins. 9.14. Portable vacuum cleaners and portable dust collectors shall be fitted with H13 HEPA filters. These types of units shall be emptied and cleaned in a room which is under negative pressure relative to the environment. Personnel shall be provided with suitable PPE. 9.15. Records of the safe disposal of all contaminated filters and dust shall be kept. 10. Personnel decontamination systems:- 10.1. If required, a means of preventing contaminants from leaving the facility on the garments of personnel shall be provided. This could be in the form of an air shower; mist shower, water shower or appropriate device. 10.2. An air shower comprises an airlock where high velocity air is supplied through air nozzles (e.g., from the sides of the airlock) in order to dislodge dust particles. Air extraction grilles (e.g., at low level) shall draw the air away and return it to the filtration system. Some air showers may also incorporate a vertical unidirectional airflow section at the exit end, to flush contaminants away. Note.- When air showers are used these shall be correctly designed to effectively extract dust. Air filtration of the supply air and return or exhaust air shall comply with the same filtration standards as used in the manufacturing facility. Normally the fan shall be activated by opening the door as the operator enters the shower, with a timing device on the exit door interlock to allow sufficient time for the decontamination process to be effective. 10.3. Flushing devices similar to air or mist showers for personnel could be used at material exits to assist with removing contaminants. 10.4. Wet mist or fog decontamination systems for operators can be employed for deactivating contaminants on the operators’ garments or causing contaminants to adhere to the garments so that they are not easily liberated. 10.5. Personnel shall change into clean garments after having taken a shower. 11. Effluent treatment:- 11.1. Liquid and solid waste effluent shall be handled in such a manner as not to present a risk of contamination to the product, personnel or to the environment. 11.2. All effluent shall be disposed of in a safe manner and the means of disposal shall be documented. Where external contractors are used for effluent disposal they shall have certification authorising them to handle and treat hazardous products. 12. Maintenance:- The efficient and safe operation of a facility handling hazardous materials is reliant on regular maintenance being carried out, to ensure that all parameters remain within specified tolerances. 13. Qualification and validation:- System qualification and validation shall be carried out. PART IV SPECIFIC REQUIREMENTS FOR MANUFACTURE OF BIOLOGICAL PRODUCTS Note.—Good Manufacturing Practices for pharmaceutical products: Main principles as given in Part I shall be complied with, mutatis mutandis, for the manufacture of Biological products. In addition to these requirements, the following specific requirements shall also be followed, namely:— 1. Principles and general considerations:- 1.1. Biological products can be defined according to their source material and method of manufacture. The source materials and methods employed in the manufacture of biological products for human use therefore represent critical factors in shaping their appropriate regulatory control. Biological products are derived from cells, tissues or microorganisms and reflect the inherent variability characteristic of living materials. The active substances in biological products are often too complex to be fully characterised by utilising physicochemical testing methods alone and may show a marked heterogeneity from one preparation or batch or both. Consequently, special considerations are needed when manufacturing biological products in order to maintain consistency in product quality. 1.2. The guidance provided in this Part applies to the manufacture, control and testing of biological products for human use from starting materials and preparations (including seed lots, cell banks and intermediates) to the finished product. 1.3. Manufacturing procedures within the scope of this Schedule includes- (a) growth of strains of microorganisms and eukaryotic cells; (b) extraction of substances from biological tissues, including human, animal and plant tissues, and fungi; (c) recombinant DNA (rDNA) techniques; (d) hybridoma techniques; and (e) propagation of microorganisms in embryos or animals. 1.4. Medicinal products of biological origin manufactured by these procedures include allergens, antigens, vaccines, certain hormones, cytokines, monoclonal antibodies (mAbs), enzymes, animal immune sera, products of fermentation (including products derived from rDNA), biological diagnostic reagents for in-vivo use and Advanced Therapy Medicinal Products (ATMPs) used for example in gene therapy and cell therapy. 1.5. The manufacture, control and administration of biological active substances and finished products require certain specific considerations and precautions arising from the nature of these products and their processes. Unlike conventional pharmaceutical products which are manufactured using chemical and physical techniques capable of a high degree of consistency, the manufacture of biological active substances and finished products involves biological processes and materials, such as cultivation of cells or extraction from living organisms. As these biological processes may display inherent variability, the range and nature of by-products may also be variable. As a result, QRM principles are particularly important for this class of materials and shall be used to develop the control strategy across all stages of manufacture so as to minimise variability and reduce the opportunity for contamination and cross-contamination. 1.6. Materials and processing conditions used in cultivation processes are designed to provide conditions for the growth of target cells and microorganisms. Therefore, extraneous microbial contaminants have the opportunity to grow. Furthermore, many biological products have limited ability to withstand certain purification techniques, particularly those designed to inactivate or remove adventitious viral contaminants. The design of the processes, equipment, facilities, utilities, the conditions of preparation and addition of buffers and reagents, sampling and training of the operators are key considerations in minimising such contamination events. Manufacturing shall be consistent with other specifications set out in the product summary files, marketing authorisation or clinical trial approvals [for example, number of generations (expressed as doublings or passages) between the seed lot or cell bank and the finished product]. 1.7. Many biological materials (such as live-attenuated bacteria and viruses) cannot be terminally sterilised by heat, gas or radiation. In addition, some products, such as certain live and adjuvant vaccines [for example, Bacilli Calmette Guerin (BCG) or Cholera], may not be sterilised by filtration processes. For these axenic products, processing shall be conducted aseptically to minimise the introduction of contaminants from the point where a potential contamination cannot be removed from the manufacturing process. The validation of specific and critical manufacturing steps such as virus removal or inactivation shall be carried out. Robust environmental controls and monitoring and, wherever feasible, in situ cleaning and sterilisation systems, together with the use of closed systems can significantly reduce the risk of accidental contamination and cross-contamination. 1.8. Control usually involves biological analytical techniques, which typically have a greater variability than physicochemical determinations. The combination of variability in starting materials and the potential for subtle changes during the manufacturing process of biological products also requires an emphasis on production consistency. This is of particular concern because of the need to link consistency to original clinical trials documenting the product’s safety and efficacy. A robust manufacturing process is therefore crucial and in-process controls take on a particular importance in the manufacture of biological active substances and medicinal products. 1.9. Because of the risks inherent in producing and manipulating pathogenic and transmissible microorganisms during the production and testing of biological materials, GMP shall prioritise the safety of the recipient to whom the biological product is administered, the safety of personnel during operation and the protection of the environment. 1.10. Biosafety considerations shall follow the guidelines issued by the Central Government in this regard. In the context of manufacturing pathogenic biological products of Biosafety Risk Group 3 and 4, close collaboration between such institutions is especially required to assure that both product contamination and environmental contamination levels are controlled within the acceptable limits. 2. Pharmaceutical quality system and quality risk management:- 2.1. Biological products, like any pharmaceutical product, shall be manufactured in accordance with the requirements of a pharmaceutical quality system (product quality system) based on a life-cycle approach, good manufacturing practices for pharmaceutical products. Main principles- This approach facilitates innovation and continual improvement and also strengthens the link between pharmaceutical development and manufacturing activities. 2.2. QRM principles shall be used to develop the control strategy across all manufacturing and control stages including materials sourcing and storage, personnel and materials flow, manufacture and packaging, quality control, quality assurance, storage and distribution activities, as described in this Part. Due to the inherent variability of biological processes and starting materials, ongoing trend analysis and periodic review are particularly important elements of product quality system. Thus, special attention shall be paid to starting material controls, change control, trend analysis and deviation management in order to ensure production consistency. Monitoring systems shall be designed so as to provide early detection of any unwanted or unanticipated factors that may affect the quality, safety and efficacy of the product. The effectiveness of the control strategy in monitoring, reducing and managing such risks shall be regularly reviewed and the systems updated as required taking into account scientific and technical progress. 3. Personnel:- 3.1. Personnel responsible for production and control shall have an adequate background in relevant scientific disciplines such as microbiology, biology, biometry, chemistry, medicine, pharmacy, pharmacology, virology, immunology, biotechnology and veterinary medicine, together with sufficient practical experience to enable them to perform their duties. 3.2. The health status of personnel shall be taken into consideration as part of ensuring product safety. Where necessary, personnel engaged in production, maintenance, testing and animal care (and inspections) shall be vaccinated with appropriate specific vaccines and have regular health checks. Any changes in the health status of personnel which could adversely affect the quality of the product shall preclude their working in the production area, and appropriate records kept. The scope and frequency of health monitoring shall be commensurate with the risk to the product and personnel. 3.3. Training in cleaning and disinfection procedures, hygiene and microbiology shall emphasise the risk of microbial and adventitious contamination and the nature of the target microorganisms and growth media routinely used. 3.4. Where required to minimise the opportunity for cross-contamination, restrictions on the movement of all personnel (including quality control, maintenance and cleaning staff) shall be defined on the basis of quality risk management principles. In general, all personnel including those not routinely involved in the production operation (such as management, engineering staff and validation staff or auditors) shall not pass from areas with exposure to live microorganisms, genetically modified microorganisms, animal tissue, toxins, venoms or animals, to areas where other products (inactivated or sterile) or different organisms are handled. If such passage is unavoidable during a working day, then contamination control measures (for example, clearly defined decontamination measures such as a complete change of appropriate clothing and shoes and showering, if applicable) shall be followed by all personnel visiting any such production area unless otherwise justified on the basis of QRM. 3.5. Because the risks are difficult to manage, personnel working in an animal facility shall be restricted from entering production areas where potential risks of cross-contamination exist. 3.6. Staff assigned to the production of Bacille Calmette-Guerin (BCG) products shall not work with other infectious agents. In particular, they shall not work with virulent strains of Mycobacterium tuberculosis, nor shall they be exposed to a known risk of tuberculosis infection. Additionally, they shall be carefully monitored with regular health checks that screen for tuberculosis infection. 3.7. If personnel working in BCG manufacturing and in animal quarters, need to be reassigned to other manufacturing units, they shall not be allowed into such units until they pass their health check. 4. Starting materials:- 4.1. The source, origin and suitability of active substances, starting materials (for example, cryo protectants and feeder cells), buffers and media (for example, reagents, growth media, serum, enzymes, cytokines, growth factors and amino acids) and other components of the finished product shall be clearly defined and controlled according to the principles set out in Part I of this Schedule. 4.2. Manufacturers shall retain information describing the source and quality of the biological materials used for at least one year after the expiry date of the finished products and according to regulations concerning biological products. It has been found that documents retained for longer periods may provide useful information related to Adverse Events Following Immunisation (AEFI) and other investigations. 4.3. All starting material suppliers (i.e., manufacturers) shall be initially qualified on the basis of documented criteria and a risk-based approach. Regular assessment of their status shall also be carried out. Particular attention shall be given to the identification and monitoring of any variability that may affect biological processes. When starting materials are sourced from brokers who could increase the risk of contamination by performing repackaging operations under GMP they shall be carefully qualified; an audit may form part of such qualification, as needed. 4.4. An identity test or equivalent, shall be performed on each batch of received starting materials prior to release. The number of containers sampled shall be justified on the basis of QRM principles and in agreement with all applicable guidelines. The identification of all starting materials shall be in compliance with the requirements appropriate to the stage of manufacture. The level of testing shall be commensurate with the qualification level of the supplier and the nature of the materials used. In the case of starting material used to manufacture active substances, the number of samples taken shall be based on statistically recognised criteria and QRM principles. However, for starting materials and intermediates used in the formulation of finished product, each container shall be sampled for identity testing in accordance with the main principles of GMP for pharmaceutical products unless reduced testing has been validated. 4.5. The sampling process shall not adversely affect the quality of the product. Incoming starting materials shall be sampled under appropriate conditions in order to prevent contamination and cross contamination. 4.6. Where justified (such as the special case of sterile starting materials) it may be acceptable to reduce the risk of contamination by not performing sampling at the time of receipt but to perform the testing later, on the samples taken at the time of use. In such cases, release of the finished product is conditional upon satisfactory results of these tests. 4.7. Where, the necessary tests for approving starting materials take a significantly long time, it may be permissible by exception to process starting materials before the test results are available. The use of these materials shall be clearly justified in a documented manner, and the risks shall be understood and assessed under the principles of QRM. In such cases, release of the finished product is conditional upon satisfactory results from the tests. It must be ensured that this is not standard practice and occurs only with justification of the risk taken. 4.8. The risk of contamination of starting materials during their passage along the supply chain shall be assessed, with particular emphasis on adventitious agents such as those causing Transmissible spongiform encephalopathies (TSEs). Other materials that come into direct contact with manufacturing equipment or with potential product contact surfaces (such as filter media, growth media during aseptic process simulations and lubricants) shall also be controlled. A quality risk assessment shall be performed to evaluate the potential for adventitious agents in biological starting materials. 4.9. Where required, the sterilisation of starting materials shall be carried out by heat, whenever possible. Where necessary, other appropriate validated methods may also be used for this purpose (such as irradiation and filtration). 4.10. The controls required for ensuring the quality of sterile starting materials and of the aseptic manufacturing process shall be based on the principles and guidance contained in Part II of this Schedule. 4.11. The transport of critical materials, reference materials, active substances, human tissues and cells to the manufacturing site shall be controlled as part of a written quality agreement between the responsible parties, if they are different commercial entities. Manufacturing sites shall have documentary evidence of adherence to the specified storage and transport conditions, including cold chain requirements, if required. The required traceability starting at tissue establishments through the recipients, and including the traceability of materials in contact with the cells or tissues shall be ensured, maintained and documented. 5. Seed lots and cell banks:- 5.1. The recommendations set out in GMP for API shall be followed taking into consideration specific guidance for API manufactured by cell culture or fermentation. 5.2. Where human or animal cells are used as feeder cells in the manufacturing process, appropriate controls over their sourcing, testing, transport and storage shall be in place. 5.3. In order to prevent the unwanted drift of genetic properties which might result from repeated subcultures or multiple generations, the production of biological products obtained by microbial culture, cell culture or propagation in embryos and animals shall be based on a system of master and working seed lots or cell banks or both; which is the beginning of the manufacturing process of certain biological products (for example, vaccines). 5.4. The number of generations (expressed as passages or doublings) between the seed lot or cell bank and the finished product, defined as maximum, shall be consistent with the marketing authorisation dossier and shall not be exceeded. 5.5. Cell-based medicinal products are often generated from a cell stock obtained from a limited number of passages. In contrast with the two-tier system of Master Cell Banks (MCBs) and Working Cell Banks (WCBs), the number of production runs from a cell stock is limited by the number of aliquots obtained after expansion and does not cover the entire life-cycle of the product. Cell stock changes shall be covered by a validation protocol and communicated to the National Regulatory Authority (NRA), as applicable. 5.6. Establishment and handling of the MCBs and WCBs shall be performed under conditions which are demonstrably appropriate. These shall include an appropriately controlled environment to protect the seed lot and the cell bank, and the personnel handling them. During the establishment of the seed lot and cell bank, no other living or infectious material (such as viruses, cell lines or microbial strains) shall be handled simultaneously in the same area or by the same persons. 5.7. Quarantine and release procedures for master and working cell banks or seed lots shall be followed, including adequate characterisation and testing for contaminants. Initially, full characterisation testing of the MCB shall be done, including genetic identification. A new MCB (from a previous initial clone, MCB or WCB) shall be subjected to the same established testing as the original MCB, unless otherwise justified. Thereafter, the viability, purity and other stability indicating attributes of seed lots and cell banks shall be checked regularly according to justified criteria. Evidence of the stability and recovery of the seed lots and banks shall be documented and records shall be kept in a manner that permits trend evaluation. 5.8. Each storage container shall be adequately sealed, clearly labelled and kept at an appropriate temperature. A stock inventory shall be kept. The storage temperature shall be recorded continuously and, where applicable, the liquid nitrogen level shall be monitored. Any deviation from the set limits, and any corrective and preventive action taken, shall be recorded. Temperature deviations shall be detected as early as possible (for example, through the use of an alarm system for temperature and nitrogen levels). 5.9. Seed lots and cell banks shall be stored and used in such a way so as to minimise the risks of contamination or alteration (for example, stored in qualified ultra-low temperature freezers or liquid nitrogen storage containers). Control measures for the storage of different seeds or cells or both in the same area or equipment shall prevent mix-up and shall take into account the infectious nature of the materials in order to prevent cross-contamination. 5.10. Master Seed Lots (MSLs), MCBs, and preferably also Working Seed Lots (WSLs) and WCBs, shall be stored in two or more controlled separate sites in order to minimise the risk of total loss due to natural disaster, equipment malfunction or human error. A contingency plan shall be in place. 5.11. The storage and handling conditions for the cell or seed banks shall be defined. Access shall be controlled and restricted to authorised personnel and appropriate access records maintained. Records of location, identity and inventory of individual containers shall also be kept. Once containers are removed from the seed lot or cell bank management system, they shall not be returned to the stock. 6. Premises and equipment:- 6.1. In general, preparations containing live microorganisms or live viruses shall not be manufactured and containers shall not be filled in areas used for the processing of other pharmaceutical products. However, if the manufacturer can demonstrate and validate effective containment and decontamination of the live microorganisms and viruses, then the use of multi-product facilities may be justifiable. In such cases, measures such as campaign production, closed systems or disposable systems or both shall be considered and shall be based on QRM principles 6.2. Documented QRM shall be carried out for every additional product in a biological manufacturing multi-product facility, which may include a potency and toxicological evaluation based on cross contamination risks. Other factors to be taken into account include facility or equipment design and use, personnel and material flows, microbiological controls, physicochemical characteristics of the active substance, process characteristics, cleaning processes and analytical capabilities relative to the relevant limits established from product evaluation. The outcome of the QRM process shall be the basis for determining the necessity for premises and equipment to be dedicated to a particular product or product family, and the extent to which this shall be the case. This may include dedicating specific product contact parts. 6.3. Inactivated vaccines, antisera and other biological products including those made by rDNA techniques, toxoids and bacterial extracts may, following inactivation, be manufactured on the same premises provided that adequate decontamination and cleaning measures are implemented on the basis of QRM. 6.4. Cleaning and sanitisation shall take into account the fact that processes often include the handling of growth media and other growth-promoting agents. Validation studies shall be carried out to ensure the effectiveness of cleaning, sanitisation and disinfection, including elimination of residues of used agents. Environmental and personnel safety precautions shall be taken during the cleaning and sanitisation processes. The use of cleaning and sanitising agents shall not pose any major risk to the performance of equipment. The use of closed systems to improve asepsis and containment shall be considered where practicable. Where open systems are utilised during processing (for example, during addition of growth supplements, media, buffers and gases, and during sampling and aseptic manipulations during the handling of live cells such as in cell-therapy products) control measures shall be put in place to prevent contamination, mix-up and cross-contamination. Logical and unidirectional flows of personnel, materials and processes, and the use of clean-in-place and sterilise-in-place systems, shall be considered wherever possible. Where sterile single-use systems such as bags and connectors are utilised, they shall be qualified with respect to suitability, extractables, leachables and integrity. 6.5. Because of the variability of biological products, and of the corresponding manufacturing processes, approved starting materials that have to be measured or weighed for the production process (such as growth media, solutions and buffers) may be kept in small stocks in the production area for a specified period of time according to defined criteria for the duration of manufacture of the batch or of the campaign. Appropriate storage conditions and controls shall be maintained during such temporary storage. These materials shall not be returned to the general stock. Materials used to formulate buffers, growth media and so on shall be weighed and made into a solution in a contained area using local protection (such as a classified weighing booth) and outside the aseptic processing areas in order to minimise particulate contamination of the later. 6.6. In manufacturing facilities, the mix-up of entry and exit of personnel shall be avoided through the use of separate changing rooms or through procedural controls where Biosafety Risk Group 3 or 4 organisms are handled. 7. Containment:- 7.1. Airborne dissemination of live microorganisms and viruses used for the production process, including those from personnel, shall be avoided. 7.2. Adequate precautions shall be taken to avoid contamination of the drainage system with dangerous effluents. Drainage systems shall be designed in such a way that effluents can be effectively neutralised or decontaminated to minimise the risk of cross-contamination. Specific and validated decontamination systems shall be considered for effluents when infectious or potentially infectious materials are used for production. Regulations issued by the Central Government in this regard shall be complied with in order to minimise the risk of contamination of the external environment according to the risk associated with the biohazardous nature of waste materials. 7.3. Dedicated production areas shall be used for the handling of live cells capable of persistence in the manufacturing environment, for pathogenic organisms of Biosafety Risk Group 3 or 4 or for spore forming organisms until the inactivation process is accomplished and verified. For Bacillus anthracis, Clostridium tetani and Clostridium botulinum strictly dedicated facilities shall be utilised for each individual product. Up to date information on these and other high-risk or “special” agents shall be sought from major information resources. Where campaign manufacture of spore-forming organisms occurs in a facility or suite of facilities, only one product shall be processed at any one time. 7.3.1. Use of any pathogenic organism above Biosafety Risk Group 3 may be allowed according to the biohazard classification of the organism, the risk assessment of the biological product and its emergency demand. 7.4. Production of BCG related product shall take place in a dedicated area and by means of dedicated equipment and utilities (such as HVAC systems) in order to minimise the hazard of cross-contamination. 7.5. Specific containment requirements apply to poliomyelitis vaccine to minimise poliovirus facility associated risk and for the safe production and quality control of inactivated poliomyelitis vaccine manufactured from wild polioviruses. The measures and procedures necessary for containment (i.e., for protecting the environment and ensuring the safety of the operator) shall not conflict with those for ensuring product quality. 7.6. Air-handling systems shall be designed, constructed and maintained to minimise the risk of cross contamination between different manufacturing areas as required. The need for dedicated air handling units or single pass systems shall be based on QRM principles, taking into account the biohazard classification and containment requirements of the relevant organism, and process and equipment risks. In the case of Biosafety Risk Group 3 organisms, air shall not be recirculated to any other area in the facility and shall be exhausted through HEPA filters that are regularly checked for performance. A dedicated non-recirculating ventilation system and HEPA filtering of exhaust air are required when handling Biosafety Risk Group 4 organisms. 7.7. Primary containment equipment shall be designed and initially qualified for integrity in order to ensure that the escape of biological agents or material into the immediate working area and outside environment is prevented. Thereafter, in line with relevant guidelines and quality risk management principles, periodical tests shall be performed to ensure that the equipment is in proper working condition. 7.8. Activities associated with the handling of live biological agents (such as centrifugation and blending of products which can lead to aerosol formation) shall be contained in such a way so as to prevent contamination of other products or the egress of live agents into the working or outside environment or both. The viability of such organisms and their biohazard classification shall be taken into consideration as part of the management of such risks. Accidental spillages, especially of live organisms, must be dealt with quickly and safely. Validated decontamination measures shall be available for each organism or groups of related organisms. Where different strains of a single bacteria species or very similar viruses are involved, the decontamination process may be validated with one representative strain, unless the strains vary significantly in their resistance to the decontaminating agents used. 7.9. Areas where Biosafety Risk Group 3 or 4 organisms are handled shall always have a negative air pressure relative to the environment. This will ensure the containment of the organism in unlikely events such as failure of the door interlock. Air-lock doors shall be interlocked to prevent them from being opened simultaneously. Differential pressure alarms shall be present wherever required and shall be validated and monitored. 7.10. Air vent filters shall be hydrophobic and subject to integrity testing at intervals determined by a QRM approach. 7.11. Where the filtration of exhaust air is necessary, the safe changing of filters shall be ensured or bag in-bag-out housings shall be employed. Once removed, filters shall be decontaminated and properly destroyed. In addition to HEPA filtration other inactivation technologies such as heat inactivation and steam scavenging may be considered for exhaust air to ensure effective inactivation of pathogenic organisms of Biosafety Risk Group 3 or 4. 8. Clean rooms:- 8.1. In order to address the specific manufacturing processes involved in the production of biological products, and particularly vaccines, the environmental monitoring of clean rooms in vaccine manufacturing facilities; points to consider for manufacturers of human vaccines guidance document may be used to develop the environmental classification requirements for biological manufacturing processes. As part of the control strategy, the degree of environmental control of particulate and microbial contamination of the production premises shall be adapted to the intermediate or finished product and also to the production step, taking into account the potential level of contamination of the starting materials and the risks to the finished product. 8.2. The environmental monitoring programme shall be supplemented with methods to detect the presence of the specific microorganisms used for production (for example, recombinant yeast and toxin or polysaccharide producing bacteria). The environmental monitoring programme may also include detection of the produced organisms and adventitious agents of production organisms, especially when campaign manufacture is applied on the basis of QRM principles. 9. Production:- 9.1. Since cultivation conditions, media and reagents are designed to promote the growth of cells or microbial organisms, typically in an axenic state, particular attention shall be paid to the control strategy for ensuring that effective steps are in place for preventing or minimising the occurrence of unwanted bioburden, endotoxins, viruses of animal and human origin and associated metabolites. 9.2. The QRM process shall be the basis for implementing the technical and organisational measures required to control the risks of contamination and cross-contamination. These could include, though are not limited to- (i) carrying out processing and filling in segregated areas; (ii) containing material transfer by means of an airlock and appropriate type of pass box with validated transfer procedures, clothing change and effective washing and decontamination of equipment; (iii) recirculation of only treated (HEPA filtered) air; (iv) acquiring knowledge of the key characteristics (for example, pathogenicity, detectability, persistence and susceptibility to inactivation) of all cells, organisms and any adventitious agents within the same facility; (v) when considering the acceptability of concurrent work in cases where production is characterised by multiple small batches from different starting materials (for example, cell-based products) taking into account factors such as the health status of donors and the risk of total loss of a product from or for specific patients during development of the cross-contamination control strategy; (vi) preventing the risk of live organisms and spores entering non-related areas or equipment by addressing all potential routes of cross-contamination (for example, through the HVAC system) through the use of single use components and closed systems; (vii) conducting environmental monitoring specific to the microorganism being manufactured in adjacent areas while paying attention to cross-contamination risks arising from the use of certain monitoring equipment (used for airborne particle monitoring) in areas handling live or spore forming organisms or both; and (viii) using campaign-based production. 9.3. When applicable, the inoculum preparation area shall be designed so as to effectively control the risk of contamination, and shall be equipped with a biosafety hood for primary containment. 9.4. If possible, growth media shall be sterilisedin situ by heat or in-line microbial-retentive filters. Additionally, in-line microbial-retentive filters shall be used for the routine addition of gases, media, acids, alkalis and so on to fermenters or bioreactors. 9.5. Data from continuous monitoring of certain production processes (fermentation) shall form part of the batch record. Where continuous culture is used, special consideration shall be given to parameters such as temperature, pH, pO2, CO2 and the rate of feed or carbon source with respect to growth of cells. 9.6. In cases where a viral inactivation or removal process is performed, measures shall be taken (for example, in relation to facility layout, unidirectional flow and equipment) to avoid the risk of recontamination of treated products by non-treated products. 9.7. A wide variety of equipment and components (for example, resins, matrices and cassettes) are used for purification purposes. QRM principles shall be applied to devise the control strategy regarding such equipment and associated components when used in campaign manufacture and in multi-product facilities. The reuse of components at different stages of processing of one product is discouraged but, if performed, shall be validated. Acceptance criteria, operating conditions, regeneration methods, lifespan and sanitisation or sterilisation methods, cleaning process, and hold time between the use of reused components shall be defined and validated. The reuse of components for different products is not acceptable. 9.8. Where adverse donor (human or animal) health information becomes available after procurement or processing or both, and this information relates to product quality, then appropriate measures shall be taken including product recall, if applicable. 9.9. Antibiotics may be used during the early stages of production to help prevent inadvertent microbial contamination or to reduce the bioburden of living tissues and cells. In this case, the use of antibiotics shall be well justified, and they shall be cleared from the manufacturing process at the stage specified in the marketing authorisation. Acceptable residual levels shall be defined and validated. Penicillin and other beta lactam antibiotics shall not be used at any stage of the process. 9.10. A procedure shall be in place to address equipment or accessories failure or both (air vent filter failure) which shall include a product impact review. If such failures are discovered following batch release, the Licensing Authority shall be notified and the need for a batch recall shall be considered. 10. Campaign production:- 10.1. The decision to use a facility or filling line for campaign manufacture shall be justified in a documented manner and shall be based on a systematic risk approach for each product (or strain) taking into account the containment requirements and the risk of cross-contamination to the next product. Campaign changeover procedures, including sensitive techniques used for the determination of residues, shall be validated and proper cleaning acceptance criteria shall be defined on a toxicology basis of product residues from the last campaign, as applicable. Equipment assigned to continued production or to campaign production of successive batches of the same intermediate product shall be cleaned at appropriate validated intervals to prevent build-up and carryover of contaminants (product degradants or objectionable levels of microorganisms). 10.2. For downstream operations of certain products (for example, pertussis or diphtheria vaccines) campaign production may be acceptable if well justified. For finishing operations (formulation and filling) the need for dedicated facilities or the use of campaigns in the same facility will depend on the specific characteristics of the biological product, on the characteristics of the other products (including any non-biological products), on the filling technologies used (single use closed systems). Labelling and packaging operations can be carried out in a multiproduct facility. 10.3. Campaign changeover involves intensive decontamination or sterilisation (if required) and cleaning of the equipment and manufacturing area. Decontamination or sterilisation (if required) and cleaning shall include all equipment and accessories used during production, as well as the facility itself. The following recommendations shall be considered, namely:- (i) waste shall be removed from the manufacturing area or sent to the bio-waste system in a safe manner; (ii) materials shall be transferred by a validated procedure; and (iii) the Quality Unit shall confirm area clearance by inspection, and review the campaign changeover data (including monitoring results) prior to releasing the area for the next product. 10.4. When required, the corresponding diluent for the product can be filled in the same facility in line with the defined campaign production strategy for finished product. 10.5. When campaign-based manufacturing is considered, the facility layout and the design of the premises and equipment shall permit effective cleaning and decontamination or sterilisation (if required) based on QRM principles and validated procedures following the production campaign. In addition, consideration may need to be given at the design stage of facility layout to the possible need for fumigation. 11. Labelling:- 11.1. The information provided on the inner label (also called the container label) and on the outer label (on the packaging) shall be readable and legible and the content approved by the Licensing Authority. 11.2. Minimal key information shall be printed on the inner label and additional information shall be provided on the outer label (for example, carton) or product leaflet or both. 11.3. The suitability of labels for low and ultra-low storage temperatures shall be verified, if applicable. The label shall remain properly attached to the container under different storage conditions during the shelf-life of the product. The label and its adhesive shall have no adverse effect on the quality of the product caused by leaching, migration or other means. 12. Validation:- 12.1. Biological processes, handling of live materials and using campaign-based production, if applicable, are the major aspects of biological product manufacturing which require process and cleaning validation. The validation of such processes given the typical variability of biological products, the possible use of harmful and toxic materials and the need for inactivation processes plays an important role in demonstrating production consistency and in proving that the critical process parameters and product attributes are controlled. 12.2. A QRM approach shall be used to determine the scope and extent of validation. 12.3. All critical biological processes (including inoculation, multiplication, fermentation, cell disruption, inactivation, purification, virus removal, removal of toxic and harmful additives, filtration, formulation and aseptic filling) are subject, as applicable, to process validation. Manufacturing control parameters to be validated may include specific addition sequences, mixing speeds, time and temperature controls, limits of light exposure and containment. 12.4. After initial process validation studies have been finalised and routine production has begun, critical processes shall be subject to monitoring and trending with the objective of assuring consistency and detecting any unexpected variability. The monitoring strategy shall be defined, taking into consideration factors such as the inherent variability, complexity of quality attributes and heterogeneity of biological products. A system or systems for detecting unplanned departures from the process as designed shall be in place to ensure that the process remains in a state of control. Collection and evaluation of information and data on the performance of the process will allow for detection of undesired process variability and will determine whether action shall be taken to prevent, anticipate or correct problems so that the process remains under control. 12.5. Cleaning validation shall be performed in order to confirm the effectiveness of cleaning procedures designed to remove biological substances, growth media, process reagents, cleaning agents, inactivation agents and so on. Careful consideration shall be given to cleaning validation when campaign-based production is practiced. 12.6. Critical processes for inactivation or elimination of potentially harmful microorganisms of Biosafety Risk Group 2 or above, including genetically modified ones, are subject to validation. 12.7. Process revalidation may be triggered by a process change as part of the change control system. In addition, because of the variability of processes, products and methods, process revalidation may be conducted at pre-determined regular intervals according to risk considerations. A detailed review of all changes, trends and deviations occurring within a defined time period for example, one year, based on the regular Product Quality Review (PQR) may indicate a need for process revalidation. 12.8. The integrity and specified hold times of containers used to store intermediate products shall be validated unless such intermediate products are freshly prepared and used immediately. 13. Quality Control:- 13.1. As part of quality control sampling and testing procedures for biological materials and products, special consideration shall be given to the nature of the materials being sampled (for example, the need to avoid contamination, ensure biocontainment or cold chain requirements) in order to ensure that the testing carried out is representative. 13.2. Samples for post-release use typically fall into one of two categories reference samples or retention samples for the purposes of analytical testing and identification respectively. For finished products the reference and retention samples will in many instances be presented identically as fully packaged units. In such circumstances, reference and retention samples may be regarded as interchangeable. 13.2.1. Reference samples of biological starting materials shall be retained under the recommended storage conditions for at least one year beyond the expiry date of the corresponding finished product. Reference samples of other starting materials (other than solvents, gases and water) as well as intermediates for which critical parameters cannot be tested in the final product shall be retained for at least two years after the release of the product if their stability allows for this storage period. Certain starting materials such as components of growth media need not necessarily be retained. 13.2.2. Retention samples of a finished product shall be stored in their final packaging at the recommended storage conditions for at least one year after the expiry date. 13.3. For cell-based products, microbiological tests (for example, sterility tests or purity checks) shall be conducted on cultures of cells or cell banks free of antibiotics and other inhibitory substances in order to provide evidence of the absence of bacterial and fungal contamination, and to be able to detect fastidious organisms where appropriate. Where antibiotics are used, they shall be removed by filtration at the time of testing. 13.4. The traceability, proper use and storage of reference standards shall be ensured, defined and recorded. The stability of reference standards shall be monitored, and their performance trended. The National or World Health Organisation (WHO) Recommendations for the preparation, characterisation and establishment of biological reference standards shall be followed. 13.5. All stability studies including real time or real condition stability, accelerated stability and stress testing shall be carried out. Trend analysis of the test results from the stability monitoring programme shall assure the early detection of any process or assay drift and this information shall be part of the PQR of biological products. 13.6. For products where on-going stability monitoring would normally require testing using animals and no appropriate alternative or validated techniques are available, the frequency of testing may take into account a risk-based approach. The principle of bracketing and matrix designs may be applied if scientifically justified in the stability protocol. 13.7. All analytical methods used in the quality control and in-process control of biological products shall be well characterised, validated and documented to a satisfactory standard in order to yield reliable results. The fundamental parameters of this validation include linearity, accuracy, precision, selectivity, specificity, sensitivity and reproducibility. 13.8. For test methods described in relevant pharmacopoeial monographs, qualification of the laboratory test equipment and personnel shall be performed. In addition, repeat precision and comparability precision shall be shown in the case of animal tests. Repeatability and reproducibility shall also be demonstrated by reviewing retrospective test data. In addition to the common parameters typically used for validating assays (accuracy and precision) additional measurements (for example, of the performance of references, critical reagents or cell lines or both) shall be considered during the validation of bioassays based on the biological nature of the assay and reagents used. 14. Documentation (batch processing records):- 14.1. In general, the processing records of regular production batches shall provide a complete account of the manufacturing activities of each batch of biological product showing that it has been produced, tested and dispensed into containers in accordance with the approved procedures. In the case of vaccines, a batch processing record and a summary protocol shall be prepared for each batch for the purpose of lot release by the Licensing Authority. The information included in the summary protocol for independent lot release of vaccines by regulatory authorities. The summary protocol and all associated records shall be of a type approved by the Licensing Authority. 14.2. Manufacturing batch records shall be retained for at least one year after the expiry date of the batch of the biological product and shall be readily retrievable for inspection by the Licensing Authority. It has been found that documents retained for longer periods may provide useful information related to AEFI and other investigations. 14.3. Starting materials may require additional documentation on source, origin, supply chain, method of manufacture and controls applied in order to ensure an appropriate level of control, including the microbiological quality, if applicable. 14.4. Some product types may require a specific definition of what materials constitute a batch particularly somatic cells in the context of ATMPs. For autologous and donor matched situations, the manufactured product shall be viewed as a batch. 15. Use of animals:- 15.1. A wide range of animals is used for the manufacture or quality control of biological products. Special considerations are required when animal facilities are present at a manufacturing site. 15.2. The presence of live animals in the production area shall be avoided unless otherwise justified. Embryonated eggs are allowed in the production area, if applicable. If the extraction of tissues or organs from animals is required then particular care shall be taken to prevent contamination of the production area (for example, appropriate disinfection procedures shall be undertaken). 15.3. Areas used for performing tests involving animals or microorganisms shall be well separated from premises used for the manufacturing of products and shall have completely separate ventilation systems and separate staff. The separation of different animal species before and during testing shall be considered, as the necessary animal acclimatisation process, as part of the test requirements. 15.4. In addition to monitoring compliance with TSE regulations and other adventitious agents that are of concern (including those causing zoonotic diseases and diseases in source animals) shall also be monitored and recorded in line with specialist advice on establishing such programmes. Instances of ill health occurring in the source or donor animals shall be investigated with respect to their suitability and the suitability of in-contact animals, for continued use (for example, in manufacture, as sources of starting materials and for quality control and safety testing). Decisions shall be documented. 15.5. A look-back procedure shall be in place in relation to the decision making process used to evaluate the continued suitability of the biological active substance or finished product in which animal sourced starting materials have been used or incorporated. This decision making process may include the retesting of reference samples from previous collections from the same donor animal (where applicable) to establish the last negative donation. The withdrawal period of therapeutic agents used to treat source or donor animals shall be documented and shall be taken into account when considering the removal of those animals from the programme for defined periods. 15.6. Particular care shall be taken to prevent and monitor infections in source or donor animals. Measures taken shall cover sourcing, facilities, husbandry, biosafety procedures, testing regimes, control of bedding and feed materials, one hundred percent fresh air supply, appropriate design of the HVAC system, water supply and appropriate temperature and humidity conditions for the species being handled. This is of special relevance to Specific Pathogen-Free (SPF) animals where pharmacopoeial monograph requirements shall be met. Housing and health monitoring shall also be defined for other categories of animals (for example, healthy flocks or herds). 15.7. For products manufactured from transgenic animals, traceability shall be maintained in the creation of such animals from the source animals. 15.8. For different animal species and lines, key criteria shall be defined, monitored and recorded. This may include the age, sex, weight and health status of the animals. 15.9. Animals, biological agents and tests carried out shall be appropriately identified to prevent any risk of mix-up and to control all identified hazards. 15.10. The facility layout shall ensure a unidirectional and segregated flow of healthy animals, inoculated animals and waste decontamination areas. Personnel and visitors shall also follow a defined flow in order to avoid cross-contamination. 16. Complaints:- 16.1. The person responsible for handling complaints and deciding on the measures to be taken to deal with them shall have appropriate training or experience in the specific features of the quality control of biological products. 16.2. There are basically two types of complaints, product quality complaints and adverse reactions or events. 16.3. The first type of complaint may be caused by problems such as faulty manufacture, product defects or deterioration as well as, particular to biological products, adulteration of the biological products. These complaints shall be recorded in detail and the causes thoroughly investigated (e.g., by comparison with the reference samples kept from the same batch). There shall also be written procedures to describe the action to be taken. 16.4. To address the second type of complaint, reports of any adverse reaction or event shall be entered in a separate register in accordance with requirements. An investigation shall be conducted to find out whether the adverse reaction or event is due to a quality problem and whether such reactions or events have already been reported in the literature or whether it is a new observation. In either case, complaint records shall be reviewed regularly to detect any specific or recurring problems requiring special attention and possible recall of marketed products. The safety monitoring of biological products shall be carried out through pharmacovigilance systems dealing with specific issues relating to adverse reactions and adverse events following treatment with biological products. 16.5. The licensing authority shall be kept informed of any complaints leading to a recall or restriction on supply and the records shall be available for inspection. 17. Product recalls:- Recall and Rapid Alert System for Drugs (including Biological and Vaccine) shall be in place for the product recall. PART V SPECIFIC REQUIREMENTS FOR RADIOPHARMACEUTICAL PRODUCTS Note.- Good Manufacturing Practices for pharmaceutical products: Main principles as given in Part I shall be complied for the manufacture of Radiopharmaceutical Products. In addition to these requirements, the following specific requirements shall also be followed, namely:— 1. Principles:- Radiopharmaceuticals shall be manufactured in accordance with the basic principles of GMP. The matters covered under this Part shall therefore be considered as supplementary to the general requirements for GMP and relate specifically to the production and control of radiopharmaceuticals. Many radiopharmaceuticals are released and administered to patients shortly after their production because of their short half-lives, so that quality control may sometimes be retrospective. In view of the same, strict adherence to GMP is mandatory. 2. Personnel:- 2.1. The manufacturing establishment, whether a hospital radiopharmacy, centralised radio-pharmacy, nuclear centre or institution, industrial manufacturer or Positron Emission Tomography (PET) Centre and its personnel shall be under the control of a person who has a proven record of academic achievement together with a demonstrated level of practical expertise and experience in radio-pharmacy and radiation hygiene. Supporting academic and technical personnel shall have the necessary post graduate or technical training and experience appropriate to their functions. 2.2. Personnel required to work in radioactive, clean and aseptic areas shall be selected with care, to ensure that they can be relied on to observe the appropriate codes of practice and are not subject to any disease or condition that can compromise the integrity of the product. Health checks on personnel shall be requested before employment and periodically thereafter. Any changes in personal health status (e.g., in haematology) may require the temporary exclusion of the person from further radiation exposure. 2.3. Only the minimum number of personnel required shall be present in clean and aseptic areas when work is in progress. Access to these areas shall be restricted during the preparation of radiopharmaceuticals, kits or sterile set-ups. Inspection and control procedures shall be conducted from outside these areas as far as possible. 2.4. During the working day, personnel may pass between radioactive and non-radioactive areas only if the safety rules of radiation control (health physics control) are followed. 2.5. The release of a batch may be approved only by an authorised person or a person with academic qualifications officially registered as a suitably qualified person, and with appropriate experience in the manufacture of radiopharmaceuticals. 2.6. To ensure the safe manufacture of radiopharmaceuticals, personnel shall be trained in GMP, the safe handling of radioactive materials and radiation safety procedures. They shall also be required to take periodic courses and receive training to keep abreast of the latest developments in their fields. 2.7. Training records shall be maintained and periodic assessments of the effectiveness of training programmes shall be made. 2.8. All personnel engaged in production, maintenance and testing shall follow the relevant guidelines for handling radioactive products and be monitored for possible contamination or irradiation exposure or both. 3. Premises and equipment:- 3.1. As a general principle, buildings must be located, designed, constructed, adapted and maintained to suit the operations to be carried out within them. Laboratories for the handling of radioactive materials must be specially designed to take into consideration aspects of radiation protection in addition to cleanliness and sterility. Interior surfaces (walls, floors and ceilings) shall be smooth, impervious and free from cracks; they shall not shed matter and shall permit easy cleaning and decontamination. Drains shall be avoided wherever possible and, unless essential, shall be excluded from aseptic areas. 3.2. Specific disposal systems shall be mandatory for radioactive effluents. These systems shall be effectively and carefully maintained to prevent contamination and exposure of personnel to the radioactive waste both within and outside the facility. 3.3. Sinks shall be excluded from aseptic areas. Any sink installed in other clean areas shall be of suitable material and be regularly sanitised. Adequate precautions shall be taken to avoid contamination of the drainage system with radioactive effluents. 3.4. Lighting, heating, ventilation and, if necessary, air-conditioning shall be designed to maintain a satisfactory temperature and relative humidity to ensure the comfort of personnel working in protective clothing. Buildings shall be in a good state of repair. The condition of the buildings shall be reviewed regularly and repairs carried out when and where necessary. Special care shall be exercised to ensure that building repair or maintenance operations do not compromise the products. Premises shall provide sufficient space for the operations to be carried out, allowing an efficient flow of work and effective communication and supervision. All buildings and rooms shall be clean, sanitary and free from radioactive contamination. 3.5. Ventilation of radiopharmaceutical production facilities shall meet the requirement to prevent the contamination of products and the exposure of working personnel to radioactivity. Suitable pressure and airflow patterns shall be maintained by appropriate isolation or enveloping methods. Air handling systems for both radioactive and non-radioactive areas shall be fitted with alarms so that the working personnel in the laboratory are warned of any failure of these systems. 3.6. Dedicated facilities and equipment shall be used for the manufacture of any radiopharmaceutical product derived from human blood or plasma. Autoclaves used in production areas for radio pharmaceuticals may be placed behind a lead shield to minimise the radiation exposure of the operators. Such autoclaves shall be checked for contamination immediately after use to minimise the possibility of cross-contamination by radioactivity of the products in the next autoclave cycles. 3.7. All containers of radiopharmaceutical substances, regardless of the stage of manufacture, shall be identified by securely attached labels. Cross-contamination shall be prevented by the adoption of some or all of the following measures, namely:- (i) processing and filling in segregated areas; (ii) avoiding the manufacture of different products at the same time, unless they are effectively segregated; (iii) containing material transfer by means of airlocks, air extraction, changing clothes and careful washing and decontamination of equipment; (iv) protecting against the risks of contamination caused by recirculation of untreated air or by accidental re-entry of extracted air; (v) using “closed systems” of manufacture; (vi) taking care to prevent aerosol formation; and (vii) using sterilised containers. 3.8. Positive pressure areas shall be used to process sterile products. In general, any radioactivity shall be handled within specifically designed areas maintained under negative pressures. The production of sterile radioactive products shall therefore be carried out under negative pressure surrounded by a positive pressure zone ensuring that appropriate air quality requirements are met. 3.9. Separate air-handling units shall be used for radioactive and non-radioactive areas. Air from operations involving radioactivity shall be exhausted through appropriate filters that are regularly checked for performance. 3.10. Pipework, valves and vent filters shall be properly designed to facilitate validated cleaning and decontamination. 4. Production:- 4.1. SOPs must be available for all operating procedures and shall be regularly reviewed and kept up to date for all manufacturing operations. All entries on batch records shall be initiated by the operator and independently checked by another operator or supervisor. 4.2. Specifications for starting materials shall include details of their source, origin and (where applicable) method of manufacture and of the controls used to ensure their suitability for use. Release of a finished product shall be conditional on satisfactory results being obtained in the tests on starting materials. 4.3. Careful consideration shall be given to the validation of sterilisation methods. 4.4. A wide variety of equipment is used in the preparation of radiopharmaceuticals. Equipment for chromatography shall, in general, be dedicated to the preparation and purification of one or several products labelled with the same radionuclide to avoid radioactive cross-contamination. The life span of columns shall be defined. Great care shall be taken in cleaning, sterilising and operating freeze-drying equipment used for the preparation of kits. 4.5. A list of critical equipment shall be drawn up, including any equipment such as a balance, pyrogen oven, dose calibrator, sterilising filter, etc., where an error in the reading or function could potentially cause harm to the patient being given the final product. These devices shall be calibrated or tested at regular intervals and shall be checked daily or before production is started. The results of these tests shall be included in the daily production records. 4.6. Specific equipment for radioactive measurements may be required as well as radioactive reference standards. For the measurement of very short half-lives, national central laboratories shall be contacted to calibrate the apparatus. Where this is not possible, alternative approaches, such as documented procedures, may be used. 4.7. In the case of labelling kits, freeze drying shall be carried out as an aseptic procedure. If an inert gas such as nitrogen is used to fill vials, it must be filtered to remove possible microbial contamination. 4.8. The dispensing, packaging and transportation of radiopharmaceuticals shall comply with the relevant provisions of the Atomic Energy Act 1962 and the rules made thereunder. 5. Labelling:- 5.1. All products shall be clearly identified by labels, which must remain permanently attached to the containers under all storage conditions. An area of the container shall be left uncovered to allow inspection of the contents. If the final container is not suitable for labelling, the label shall appear on its package. 5.2. The labels of radiopharmaceuticals shall comply with the requirements specified in rule 96. 5.3. The label on the container shall show- (a) the name of the drug product or the product identification code or both; (b) the name of the radionuclide; (c) the name of the manufacturer or the company and the person responsible for placing the drug on the market; (d) the radioactivity per unit dose- (i) for liquid preparations, the total radioactivity in the container, or the radioactive concentration per millilitre, at a stated date and, if necessary, hour, and the volume of liquid in the container; (ii) for solid preparations, such as freeze dried preparations, the total radioactivity at a stated date and, if necessary, hour; (iii) for capsules, the radioactivity of each capsule at a stated date and, if necessary, hour, and the number of capsules in the container; and (iv) where relevant, the international symbol for radioactivity. 5.4. The label on the package shall state- (a) the qualitative and quantitative composition; (b) the radioactive isotopes and the amount of radioactivity at the time of dispatch; (c) the route of administration; (d) the expiry date; (e) any special storage conditions; and (f) mandatory information related to transport regulations for radioactive materials. 5.5. The leaflet in the package shall contain the specific product information and indications for use. This information is especially important for preparation kits (cold kits), and shall include- (a) the name of the product and a description of its use; (b) the contents of the kit; (c) the identification and quality requirements concerning the radio labelling materials that can be used to prepare the radiopharmaceutical, namely- (i) the directions for preparing the radiopharmaceutical, including the range of activity and the volume, together with a statement of the storage requirements for the prepared radiopharmaceutical; (ii) a statement of the shelf-life of the prepared radio pharmaceutical; (iii) the indications and contraindications (pregnancy, children, drug reactions, etc.) in respect of the prepared radiopharmaceutical; (iv) warnings and precautions in respect of the components and the prepared radiopharmaceutical, including radiation safety aspects; (v) where applicable, the pharmacology and toxicology of the prepared radiopharmaceutical, including the route of elimination and the effective half-life; (vi) the radiation dose that a patient will receive from the prepared radiopharmaceutical; (vii) the precautions to be taken by users and patients during the preparation and administration of the product and the special precautions for the disposal of the container and any unconsumed portions; (viii) a statement of the recommended use of the prepared radio- pharmaceutical and the recommended dosage; (ix) a statement of the route of administration of the prepared radiopharmaceutical; and (x) if appropriate, for particular kits (i.e., those subject to variability beyond the recommended limits), the methods and specifications needed to check radiochemical purity. 6. Production and distribution records:- 6.1. The processing records of regular production batches must provide a complete account of the manufacturing history of each batch of a radiopharmaceutical, showing that it has been manufactured, tested, dispensed into containers and distributed in accordance with the written procedures. 6.2. Separate records for the receipt, storage, use and disposal of radioactive materials shall be maintained in accordance with the relevant provisions of the Atomic Energy Act 1962 and the rules made thereunder. 6.3. Distribution records shall be kept. Since the return of radioactive products is not practical, the purpose of recall procedures for such products is to prevent their use rather than an actual return. 7. Quality assurance and quality control:- 7.1. Radiopharmaceuticals are nearly always used before all quality control testing (e.g., tests for sterility, endotoxin, radionuclidic purity, etc.) has been completed. The implementation of and compliance with the quality assurance programme are therefore essential. 7.2. Quality assurance or quality control or both shall have the following principal responsibilities, namely- (a) the preparation of detailed instructions for each test and analysis; (b) ensuring the adequate identification and segregation of test samples to avoid mix-ups and cross contamination; (c) ensuring that environmental monitoring and equipment and process validation are conducted as appropriate for evaluating the adequacy of the manufacturing conditions; (d) the release or rejection of starting materials and intermediate products; (e) the release or rejection of packaging and labelling materials; (f) the release or rejection of each batch of finished preparation; (g) the evaluation of the adequacy of the conditions under which the starting materials, intermediate products and finished radiopharmaceutical preparations are stored; (h) the evaluation of the quality and stability of the finished products and, when necessary, of the starting materials and intermediate products; (i) the establishment of expiry dates on the basis of the validity period related to specified storage conditions; (j) the establishment and revision of the control procedures and specifications; (k) assuming the responsibility for retaining samples of radiopharmaceutical products; and (l) assuming the responsibility for keeping adequate records of the distribution of the radiopharmaceutical products. 7.3. Whenever the size of the establishment permits, quality assurance and quality control duties shall be organised in separate groups. Quality assurance shall also include the monitoring and validation of the production process. 7.4. A manufacturer’s quality control laboratory shall be separated from the production area. The control laboratory shall be designed, equipped and of such a size as to be a self-contained entity, with adequate provision for the storage of documents and samples, the preparation of records and the performance of the necessary tests. 7.5. The performance of all qualitative and quantitative tests mentioned in the specifications for the starting materials may be replaced by a system of certificates issued by the supplier of these materials, provided that- (a) there is a history of reliable production; (b) the producer or supplier is regularly audited; and (c) at least one specific identity test is conducted by the manufacturer of the finished radiopharmaceutical. 7.6. Samples of the intermediate and final products shall be retained in sufficient amounts and under appropriate storage conditions to allow repeated testing or verification of a batch control. These samples shall be kept for an appropriate period in accordance with the shelf-lives of the radioactive components concerned. However, this may sometimes not be applicable, e.g., for radiopharmaceuticals with a short half-life. 7.7. Sampling procedures may be adapted for the purposes of sampling, the type of controls being applied, and the nature of the material being sampled (e.g., a small batch size or its radioactive content or both). The procedure shall be described in a written protocol. PART VI SPECIFIC REQUIREMENTS FOR PHYTOPHARMACEUTICALS This Part shall apply to phytopharmaceutical drugs as defined under clause (eb) of rule 2,in addition to other relevant Parts based on the dosage form. Note.—Good Manufacturing Practices for pharmaceutical products: Main principles as given in Part I shall be complied for the manufacture of Phytopharmaceuticals. In addition to these requirements, the following specific requirements shall also be followed, namely:— 1. General:- 1.1. Unlike conventional pharmaceutical products, which are usually produced from synthetic materials by means of reproducible manufacturing techniques and procedures, phytopharmaceuticals are prepared from materials of plant origin, which are often obtained from varied geographical or commercial sources. As a result it may not always be possible to ascertain the conditions to which they may have been subjected. In addition, they may vary in composition and properties. Furthermore, the procedures and techniques used in the manufacture and quality control of phytopharmaceuticals are often substantially different from those employed for conventional pharmaceutical products. 1.2. Because of the inherent complexity of naturally grown medicinal plants and the often variable nature of cultivated ones, the examples of contamination with toxic medicinal plants or plant parts and the number and small quantity of defined active ingredients, the production and primary processing has a direct influence on the quality of Phytopharmaceuticals. For this reason, application of GMPs in the manufacture of Phytopharmaceuticals is an essential tool to assure their quality. 2. Quality assurance in the manufacture of Phytopharmaceuticals:- In addition to the use of modern analytical techniques (especially High Performance Thin-Layer Chromatography (HPTLC), Gas Chromatography (GC), High Performance Liquid Chromatography (HPLC), Capillary Electrophoresis (CE), Mass Spectrometry (MS) and Atomic Absorption (AA) to characterise phytopharmaceuticals, quality assurance also requires the control of starting materials, storage and processing. For this reason, an appropriate quality assurance system shall be applied in the manufacture of phytopharmaceuticals. 3. Good manufacturing practice for Phytopharmaceuticals:- The general principles of GMP are set out in the Part I. Cultivation and collection of medicinal plants, as the starting materials for phytopharmaceuticals are not covered under this Schedule. The first critical step of their production where the application of GMP starts shall be clearly designated. This is of particular importance for those products which consist solely of comminuted or powdered plant materials. 4. Sanitation and hygiene:- 4.1. Because of their origin, plant materials may contain microbiological contaminants. Furthermore, during the course of harvesting and processing, phytopharmaceuticals that may be especially prone to microbiological contamination are produced. To avoid alterations and to reduce contamination in general, a high level of sanitation and hygiene during manufacture is necessary. 4.2. Water supply to the manufacturing unit shall be monitored and if necessary treated appropriately to ensure consistency of quality. 4.3. Waste from the manufacturing unit shall be disposed of regularly so as to maintain a high standard of hygiene in the manufacturing area. Clearly marked waste bins shall be available, emptied and cleaned as needed, on daily basis. 5. Qualification and validation:- 5.1. Qualification of critical equipment, process validation and change control are particularly important in the production of Phytopharmaceuticals with unknown therapeutically active constituents. In this case, the reproducibility of the production process is the main means for ensuring consistency of quality, efficacy and safety between batches. 5.2. The written procedure shall specify critical process steps and factors (such as extraction time, temperature and solvent purity) and acceptance criteria, as well as the type of validation to be conducted (e.g., retrospective, prospective or concurrent) and the number of process runs. 5.3. A formal change control system shall be established to evaluate the potential effects of any changes on the quality of the Phytopharmaceuticals, particularly content of the active ingredients. Scientific judgement shall be used to determine which additional testing and validation studies are appropriate to justify a change in a validated process. 6. Complaints:- 6.1. The person responsible for handling complaints and deciding on the measures to be taken to deal with them shall have appropriate training or experience in the specific features of the quality control of Phytopharmaceuticals. 6.2. There are basically two types of complaints, product quality complaints and adverse reactions or events. 6.3. The first type of complaint may be caused by problems such as faulty manufacture, product defects or deterioration, particular to Phytopharmaceuticals, adulteration of the plant material. These complaints shall be recorded in detail and the causes thoroughly investigated (e.g., by comparison with the reference samples kept from the same batch). There shall also be written procedures to describe the action to be taken. 6.4. To address the second type of complaint, reports of any adverse reaction or event shall be entered in a separate register. An investigation shall be conducted to find out whether the adverse reaction or event is due to quality problem and whether such reactions or events have already been reported in the literature or whether it is a new observation. In either case, complaint records shall be reviewed regularly to detect any specific or recurring problems requiring special attention and possible recall of marketed products. 6.5. The licensing authority shall be kept informed of any complaints leading to a recall or restriction on supply and the records shall be made available for inspection. 7. Product recalls:-In case of quality failures or serious adverse events of life threatening situations, the products shall be recalled in prompt and effective manner up to the retailers’ level. There shall be a SOP for storage of recalled Phytopharmaceuticals in a secure segregated area. 8. Contract production and analysis:- 8.1. The contract partner shall have adequate premises and equipment for the production of Phytopharmaceuticals according to GMP. Validated methods shall be applied for cleaning the equipment and premises carefully before using them to produce different products. In the case of raw materials used for producing food, it is realistic to require manufacturing departments to be separated from those where the plant raw material will be cut or powdered for use in the preparation of drugs. 8.2. Technical aspects of the contract shall be drawn up by the competent persons suitably knowledgeable on the specific characteristics of Phytopharmaceuticals, including their production and quality control testing. 9. Self-inspection:-At least one member of the self-inspection team shall possess a thorough knowledge of Phytopharmaceuticals. 10. Personnel:- 10.1. The release of phytopharmaceuticals shall be authorised by a person who has been trained in the specific features of the processing and quality control of plant materials, plant preparations and finished phytopharmaceutical products. 10.2. Personnel dealing with the production and quality control of Phytopharmaceuticals shall have adequate qualifications and training in the specific issues relevant to Phytopharmaceuticals. 11. Training:- 11.1. The personnel shall have adequate training in appropriate fields such as pharmaceutical technology, taxonomic botany, phytochemistry, pharmacognosy, hygiene, microbiology and related subjects (such as traditional use of Phytopharmaceuticals). 11.2. Training records shall be maintained and periodic assessments of the effectiveness of training programmes shall be made. 12. Personal hygiene:- 12.1. Personnel entrusted with the handling of plant materials, plant preparations and finished plant products shall be required to have a high degree of personal hygiene and to have received adequate training in maintaining appropriate standards of hygiene. The personnel shall not work, if they have infectious diseases or skin diseases. Written procedures listing the basic hygiene requirements shall be made available. 12.2. Personnel must be protected from contact with toxic irritants and potentially allergenic plant materials by means of adequate protective clothing. They shall wear suitable gloves, caps, masks, work suits and shoes throughout the whole procedure from plant processing to product manufacture. 13. Premises:- 13.1. As a general principle, premises shall be designed, located, constructed, adapted and maintained to suit the operations to be carried out according to good manufacturing practices for pharmaceutical products as given in Part I. 13.2. Because of their potential for degradation and infestation with certain pests as well as their sensitivity to microbiological contamination, production and particularly storage of plant materials and plant preparations shall assume special importance. 13.3. Storage areas 13.3.1. Storage areas shall be well organised and tidy. Special attention shall be paid to cleanliness and good maintenance. Any accidental spillage shall be cleaned up immediately using methods that minimise the risk of cross- contamination of other materials and shall be reported. 13.3.2. The set-up of storage areas depends on the type of materials stored. The areas shall be well labelled and materials stored in such a way so as to avoid any risk of cross-contamination. An area shall be identified for the quarantine of all incoming plant materials. 13.3.3. Storage areas shall be laid out to permit effective and orderly segregation of the various categories of materials stored and to allow rotation of stock. Different plant materials shall be stored in separate areas. 13.3.4. To protect the stored material and reduce the risk of pest attacks, the duration of storage of any plant material in unpacked form shall be kept to a minimum. 13.3.5. Incoming fresh plant materials shall be processed, unless specified otherwise, as soon as possible. If appropriate, they shall be stored between 2 °C and 8 °C, whereas frozen materials shall be stored below –18 °C. 13.3.6. Where materials are stored in bulk, to reduce the risk of mould formation or fermentation, it is advisable to store them in aerated rooms or containers using natural or mechanical aeration and ventilation. These areas shall also be equipped in such a way as to protect against the entry of insects or animals, especially rodents. Effective measures shall be taken to limit the spread of animals and microorganisms brought in with the plant material and to prevent cross contamination. 13.3.7. Plant materials, even when stored in fibre drums, bags or boxes, shall be stored off the floor and suitably spaced to permit cleaning and inspection. 13.3.8. The storage of plants, extracts, tinctures and other preparations may require special conditions of humidity and temperature or protection from light; appropriate steps shall be taken to ensure that these conditions are provided, maintained, monitored and recorded. 13.3.9. Plant materials, including raw plant materials, shall be kept in a dry area protected from moisture and processed following the principle of “first in, first out” (FIFO). 13.4. Production areas 13.4.1. Production areas shall comply with the general requirements of good manufacturing practices for pharmaceutical products: main principles (see Part I). As a rule, campaign work in their processing is necessary. However, if feasible, the use of dedicated premises is encouraged. Moreover, the special nature of the production of Phytopharmaceuticals requires that particular attention be given to processing products that generate dust. When heating or boiling of the materials is necessary, a suitable air exhaust mechanism shall be employed to prevent accumulation of fumes and vapours. 13.4.2. To facilitate cleaning and to avoid cross-contamination, adequate precautions shall be taken during the sampling, weighing, mixing and processing of medicinal plants, e.g., by use of dust extraction and air-handling systems to achieve the desired differential pressure and net airflow. 14. Equipment:- 14.1. Processing of plant materials may generate dust or material which is susceptible to pest-infestation or microbiological contamination and cross- contamination. Effective cleaning of the equipment is therefore particularly important. 14.2. Vacuum or wet-cleaning methods are preferred. If wet-cleaning is done, the equipment shall be dried immediately after cleaning to prevent the growth of microorganisms. Cleaning with compressed air and brushes shall be done with care and avoided if possible, as these methods increase the risk of product contamination. 14.3. Non-wooden equipment shall be used unless tradition demands wooden material. Where it is necessary to use traditional equipment (such as wooden implements, clay pots, pallets, hoppers, etc.), this shall be dedicated, unless otherwise justified. When such equipment is used, it is advisable that it does not come into direct contact with chemicals or contaminated material. If the use of wooden equipment is unavoidable, special consideration must be given to its cleaning as wooden materials may retain odours, be easily discoloured and are easily contaminated. 15. Materials:- 15.1. All incoming plant materials shall be quarantined and stored under appropriate conditions that take into account the degradability of plant materials and plant preparations. 15.2. Only permitted substances shall be used for fumigation and allowable limits for their residues together with specifications for the apparatus used shall be set. 16. Reference samples and standards:- The reference standard for a phytopharmaceuticals may be a botanical sample of the plant material; a sample of the plant preparation, e.g., Extract; or a chemically defined substance, e.g., a known active constituent, a marker substance or a known impurity. The reference standard shall be of a quality appropriate to its purpose. If the phytopharmaceuticals is not described in a recognised pharmacopoeia, a herbarium sample of the flowering or fruiting top of the whole medicinal plant or part of the medicinal plant (e.g., if the whole medicinal plant is a tree) shall be available. All reference standards shall be stored under appropriate conditions to prevent degradation. Their expiry or revalidation date or both shall be determined and indicated. 17. Documentation:- The general principles for documentation are set out in Part I. 18. Specifications:- 18.1. The specifications for starting materials, for plant preparations and finished phytopharmaceuticals are primarily intended to define the quality rather than to establish full characterisation, and shall focus on those characteristics found to be useful in ensuring safety and efficacy. Consistent quality for Phytopharmaceuticals (finished products) can only be assured, if the starting plant materials are defined in a rigorous and detailed manner. In some cases more detailed information may be needed on aspects of collection or agricultural production. For instance, the selection of seeds, conditions of cultivation and harvesting are important aspects in producing a reproducible quality of Phytopharmaceuticals. Their characterisation (which also includes a detailed evaluation of the botanical and phytochemical aspects of the medicinal plant, manufacture of the Phytopharmaceutical preparation and the finished Phytopharmaceutical product) is therefore essential to allow the establishment of specifications which are both comprehensive and relevant. The specifications for plant materials shall as far as possible include, as a minimum, the following information- 18.1.1. Plant materials:- 18.1.1.1. The family and botanical name of the plant used according to the binomial system (genus, species, variety and the authority, i.e., the reference to the originator of the classification, e.g., Linnaeus). 18.1.1