pe-009-17-gmp-guide-part-i-basic-requirements-for-medicinal.pdf

PHARMACEUTICAL INSPECTION CONVENTION PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME PE 009-17 (Part I)...

PHARMACEUTICAL INSPECTION CONVENTION PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME PE 009-17 (Part I) 25 August 2023 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS PART I © PIC/S 2023 Reproduction prohibited for commercial purposes. Reproduction for internal use is authorised, provided that the source is acknowledged. Editor: PIC/S Secretariat 14 rue du Roveray CH-1207 Geneva e-mail: [email protected] web site: https://www.picscheme.org PE 009-17 (Part I) 25 August 2023  TABLE OF CONTENT CHAPTER 1 - PHARMACEUTICAL QUALITY SYSTEM............................................ 1 Principle............................................................................................................... 1 Pharmaceutical Quality System........................................................................... 1 Good Manufacturing Practice for Medicinal Products (GMP)............................... 4 Quality Control..................................................................................................... 5 Product Quality Review........................................................................................ 6 Quality Risk Management.................................................................................... 7 CHAPTER 2 - PERSONNEL....................................................................................... 8 Principle............................................................................................................... 8 General................................................................................................................ 8 Key Personnel..................................................................................................... 9 Training............................................................................................................. 11 Personnel Hygiene............................................................................................ 11 Consultants........................................................................................................ 12 CHAPTER 3 - PREMISES AND EQUIPMENT.......................................................... 13 Principle............................................................................................................. 13 Premises............................................................................................................ 13 General..................................................................................................... 13 Production Area........................................................................................ 13 Storage Areas........................................................................................... 15 Quality Control Areas................................................................................ 15 Ancillary Areas.......................................................................................... 16 Equipment......................................................................................................... 16 CHAPTER 4 - DOCUMENTATION........................................................................... 18 Principle............................................................................................................. 18 Required GMP Documentation (by type)............................................................ 18 Generation and Control of Documentation......................................................... 19 Good Documentation Practices......................................................................... 20 Retention of Documents.................................................................................... 20 Specifications.................................................................................................... 21 Specifications for starting and packaging materials................................... 21 Specifications for intermediate and bulk products..................................... 21 Specifications for finished products........................................................... 21 Manufacturing Formula and Processing Instructions.......................................... 22 Packaging Instructions.............................................................................. 23 Batch Processing Records........................................................................ 23 Batch Packaging Records......................................................................... 24 Procedures and Records................................................................................... 25 Receipt..................................................................................................... 25 PE 009-17 (Part I) -i- 25 August 2023  Table of contents Sampling.................................................................................................. 25 Testing...................................................................................................... 25 Other........................................................................................................ 25 CHAPTER 5 - PRODUCTION................................................................................... 27 Principle............................................................................................................. 27 General.............................................................................................................. 27 Prevention of Cross-contamination in Production............................................... 28 Validation........................................................................................................... 30 Starting Materials............................................................................................... 31 Processing Operations - Intermediate and Bulk Products.................................. 34 Packaging Materials.......................................................................................... 34 Packaging Operations........................................................................................ 34 Finished Products.............................................................................................. 36 Rejected, Recovered and Returned Materials.................................................... 36 Product Shortage due to Manufacturing Constraints.......................................... 37 CHAPTER 6 - QUALITY CONTROL......................................................................... 38 Principle............................................................................................................. 38 General.............................................................................................................. 38 Good Quality Control Laboratory Practice.......................................................... 39 Documentation......................................................................................... 39 Sampling.................................................................................................. 40 Testing...................................................................................................... 40 On-going Stability Programme.................................................................. 42 Technical Transfer of Testing Methods..................................................... 44 CHAPTER 7 - OUTSOURCED ACTIVITIES............................................................. 45 Principle............................................................................................................. 45 General.............................................................................................................. 45 The Contract Giver............................................................................................ 45 The Contract Acceptor....................................................................................... 46 The Contract...................................................................................................... 47 CHAPTER 8 - COMPLAINTS AND PRODUCT RECALL.......................................... 48 Principle............................................................................................................. 48 Personnel and Organisation............................................................................... 48 Procedures for Handling and Investigating Complaints Including Possible Quality Defects.................................................................................................. 49 Investigation and Decision-making..................................................................... 50 Root Cause Analysis and Corrective and Preventative Actions.......................... 51 Product Recalls and Other Potential Risk-Reducing Actions.............................. 51 CHAPTER 9 - SELF INSPECTION........................................................................... 54 Principle............................................................................................................. 54 PE 009-17 (Part I) - ii - 25 August 2023  Chapter 1 Pharmaceutical Quality System CHAPTER 1 PHARMACEUTICAL QUALITY SYSTEM PRINCIPLE The holder of a Manufacturing Authorisation must manufacture medicinal products so as to ensure that they are fit for their intended use, comply with the requirements of the Marketing Authorisation or Clinical Trial Authorisation, as appropriate, 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 by staff in many different departments and at all levels within the company, by the company’s suppliers and by its distributors. To achieve this quality objective reliably there must be a comprehensively designed and correctly implemented Pharmaceutical Quality System incorporating Good Manufacturing Practice and Quality Risk Management. It should be fully documented and its effectiveness monitored. All parts of the Pharmaceutical Quality System should be adequately resourced with competent personnel, and suitable and sufficient premises, equipment and facilities. There are additional legal responsibilities for the holder of the Manufacturing Authorisation and for the Authorised Person(s). The basic concepts of Quality Management, Good Manufacturing Practice (GMP) and Quality Risk Management are inter-related. They are described here in order to emphasise their relationships and their fundamental importance to the production and control of medicinal products. PHARMACEUTICAL QUALITY SYSTEM 1 1.1 Quality Management is a wide-ranging concept, which covers all matters, which individually or collectively influence the quality of a product. It is the sum total of the organised arrangements made with the objective of ensuring that medicinal products are of the quality required for their intended use. Quality Management therefore incorporates Good Manufacturing Practice. 1.2 GMP applies to the lifecycle stages from the manufacture of investigational medicinal products, technology transfer, commercial manufacturing through to product discontinuation. However the Pharmaceutical Quality System can extend to the pharmaceutical development lifecycle stage as described in ICH Q10, which while optional, should facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and manufacturing activities. 1 National requirements require manufacturers to establish and implement an effective pharmaceutical quality assurance system. The term Pharmaceutical Quality System is used in this chapter in the interests of consistency with ICH Q10 terminology. For the purposes of this chapter these terms can be considered interchangeable. PE 009-17 (Part I) -1- 25 August 2023  Chapter 1 Pharmaceutical Quality System 1.3 The size and complexity of the company’s activities should be taken into consideration when developing a new Pharmaceutical Quality System or modifying an existing one. The design of the system should incorporate appropriate risk management principles including the use of appropriate tools. While some aspects of the system can be company-wide and others site-specific, the effectiveness of the system is normally demonstrated at the site level. 1.4 A Pharmaceutical Quality System appropriate for the manufacture of medicinal products should ensure that: (i) Product realisation is achieved by designing, planning, implementing, maintaining and continuously improving a system that allows the consistent delivery of products with appropriate quality attributes; (ii) Product and process knowledge is managed throughout all lifecycle stages; (iii) Medicinal products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practice; (iv) Production and control operations are clearly specified and Good Manufacturing Practice adopted; (v) Managerial responsibilities are clearly specified; (vi) 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 from the approved supply chain; (vii) Processes are in place to assure the management of outsourced activities; (viii) A state of control is established and maintained by developing and using effective monitoring and control systems for process performance and product quality; (ix) The results of product and processes monitoring are 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; (x) All necessary controls on intermediate products, and any other in-process controls and validations are carried out; (xi) Continual improvement is facilitated through the implementation of quality improvements appropriate to the current level of process and product knowledge; (xii) Arrangements are in place for the prospective evaluation of planned changes and their approval prior to implementation taking into account regulatory notification and approval where required; (xiii) After implementation of any change, an evaluation is undertaken to confirm the quality objectives were achieved and that there was no unintended deleterious impact on product quality; PE 009-17 (Part I) -2- 25 August 2023  Chapter 1 Pharmaceutical Quality System (xiv) An appropriate level of root cause analysis should be applied during the investigation of deviations, suspected product defects and other problems. This can be determined using Quality Risk Management principles. In cases where the true root cause(s) of the issue cannot be determined, consideration should be given to identifying the most likely root cause(s) and to addressing those. Where human error is suspected or identified as the cause, this should be justified having taken care to ensure that process, procedural or system based errors or problems have not been overlooked, if present. Appropriate corrective actions and/or preventive actions (CAPAs) should be identified and taken in response to investigations. The effectiveness of such actions should be monitored and assessed, in line with Quality Risk Management principles; (xv) Medicinal products are not sold or supplied before an Authorised Person has certified that each production batch has been produced and controlled in accordance with the requirements of the Marketing Authorisation and any other regulations relevant to the production, control and release of medicinal products; (xvi) Satisfactory arrangements exist to ensure, as far as possible, that the medicinal products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life; (xvii) There is a process for self-inspection and/or quality audit, which regularly appraises the effectiveness and applicability of the Pharmaceutical Quality System. 1.5 Senior management has the ultimate responsibility to ensure an effective Pharmaceutical Quality System is in place, 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 leadership should ensure the support and commitment of staff at all levels and sites within the organisation to the Pharmaceutical Quality System. 1.6 There should be periodic management review, with the involvement of senior management, of the operation of the Pharmaceutical Quality System to identify opportunities for continual improvement of products, processes and the system itself. 1.7 The Pharmaceutical Quality System should be defined and documented. A Quality Manual or equivalent documentation should be established and should contain a description of the quality management system including management responsibilities. PE 009-17 (Part I) -3- 25 August 2023  Chapter 1 Pharmaceutical Quality System GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS 1.8 Good Manufacturing Practice is that part of Quality Management which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the Marketing Authorisation, Clinical Trial Authorisation or product specification. Good Manufacturing Practice is concerned with both production and quality control. The basic requirements of GMP are that: (i) All manufacturing processes are clearly defined, systematically reviewed in the light of experience and shown to be capable of consistently manufacturing medicinal products of the required quality and complying with their specifications; (ii) Critical steps of manufacturing processes and significant changes to the process are validated; (iii) All necessary facilities for GMP are provided including:  Appropriately qualified and trained personnel;  Adequate premises and space;  Suitable equipment and services;  Correct materials, containers and labels;  Approved procedures and instructions, in accordance with the Pharmaceutical Quality System;  Suitable storage and transport. (iv) Instructions and procedures are written in an instructional form in clear and unambiguous language, specifically applicable to the facilities provided; (v) Procedures are carried out correctly and operators are trained to do so; (vi) Records are made, manually and/or by recording instruments, during manufacture which demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the product was as expected; (vii) Any significant deviations are fully recorded, investigated with the objective of determining the root cause and appropriate corrective and preventive action implemented; (viii) Records of manufacture including distribution which enable the complete history of a batch to be traced are retained in a comprehensible and accessible form; (ix) The distribution of the products minimises any risk to their quality and takes account of good distribution practice; (x) A system is available to recall any batch of product, from sale or supply; PE 009-17 (Part I) -4- 25 August 2023  Chapter 1 Pharmaceutical Quality System (xi) Complaints about products are examined, the causes of quality defects investigated and appropriate measures taken in respect of the defective products and to prevent reoccurrence. QUALITY CONTROL 1.9 Quality Control is that part of Good Manufacturing Practice which is concerned with sampling, specifications and testing, and with the organisation, documentation and release procedures 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 satisfactory. The basic requirements of Quality Control are that: (i) Adequate facilities, trained personnel and approved procedures are available for sampling and testing starting materials, packaging materials, intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes; (ii) Samples of starting materials, packaging materials, intermediate products, bulk products and finished products are taken by approved personnel and methods; (iii) Test methods are validated; (iv) Records are made, manually and/or by recording instruments, which demonstrate that all the required sampling, inspecting and testing procedures were actually carried out. Any deviations are fully recorded and investigated; (v) The finished products contain active ingredients complying with the qualitative and quantitative composition of the Marketing Authorisation or Clinical Trial Authorisation, are of the purity required, and are enclosed within their proper containers and correctly labelled; (vi) Records are made of the results of inspection and that testing of materials, intermediate, bulk, and finished products is formally assessed against specification. Product assessment includes a review and evaluation of relevant production documentation and an assessment of deviations from specified procedures; (vii) No batch of product is released for sale or supply prior to certification by an Authorised Person that it is in accordance with the requirements of the relevant authorisations; (viii) Sufficient reference samples of starting materials and products are retained in accordance with Annex 19 to permit future examination of the product if necessary and that the sample is retained in the final pack. PE 009-17 (Part I) -5- 25 August 2023  Chapter 1 Pharmaceutical Quality System PRODUCT QUALITY REVIEW 1.10 Regular periodic or rolling quality reviews of all authorised medicinal products, including export only products, should be conducted with the objective of verifying the consistency of the existing process, the appropriateness of current specifications for both starting materials and finished product, to highlight any trends and to identify product and process improvements. Such reviews should normally be conducted and documented annually, taking into account previous reviews, and should include at least: (i) A review of starting materials including packaging materials used in the product, especially those from new sources and in particular the review of supply chain traceability of active substances; (ii) A review of critical in-process controls and finished product results; (iii) A review of all batches that failed to meet established specification(s) and their investigation; (iv) A review of all significant deviations or non-conformances, their related investigations, and the effectiveness of resultant corrective and preventive actions taken; (v) A review of all changes carried out to the processes or analytical methods; (vi) A review of Marketing Authorisation variations submitted, granted or refused, including those for third country (export only) dossiers; (vii) A review of the results of the stability monitoring programme and any adverse trends; (viii) A review of all quality-related returns, complaints and recalls and the investigations performed at the time; (ix) A review of adequacy of any other previous product process or equipment corrective actions; (x) For new Marketing Authorisations and variations to Marketing Authorisations, a review of post-marketing commitments; (xi) The qualification status of relevant equipment and utilities, e.g. HVAC, water, compressed gases, etc; (xii) A review of any contractual arrangements as defined in Chapter 7 to ensure that they are up to date. 1.11 The manufacturer and, where different, Marketing Authorisation holder should evaluate the results of the review and an assessment made as to whether corrective and preventive action or any revalidation should be undertaken, under the Pharmaceutical Quality System. There should be management procedures for the ongoing management and review of these actions and the effectiveness of these procedures verified during self-inspection. Quality reviews may be PE 009-17 (Part I) -6- 25 August 2023  Chapter 1 Pharmaceutical Quality System grouped by product type, e.g. solid dosage forms, liquid dosage forms, sterile products, etc. where scientifically justified. Where the Marketing Authorisation holder is not the manufacturer, there should be a technical agreement in place between the various parties that defines their respective responsibilities in producing the product quality review. The Authorised Person responsible for final batch certification together with the Marketing Authorisation holder should ensure that the quality review is performed in a timely manner and is accurate. QUALITY RISK MANAGEMENT 1.12 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. 1.13 The principles of Quality Risk Management are that: (i) The evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient; (ii) The level of effort, formality and documentation of the Quality Risk Management process is commensurate with the level of risk. Examples of the processes and applications of Quality Risk Management can be found inter alia in Annex 20 or ICHQ9. PE 009-17 (Part I) -7- 25 August 2023  Chapter 2 Personnel CHAPTER 2 PERSONNEL PRINCIPLE The correct manufacture of medicinal products relies upon people. For this reason there must be sufficient qualified personnel to carry out all the tasks which are the responsibility of the manufacturer. Individual responsibilities should be clearly understood by the individuals and recorded. All personnel should be aware of the principles of Good Manufacturing Practice that affect them and receive initial and continuing training, including hygiene instructions, relevant to their needs. GENERAL 2.1 The manufacturer should have an adequate number of personnel with the necessary qualifications and practical experience. Senior management should determine and provide adequate and appropriate resources (human, financial, materials, facilities and equipment) to implement and maintain the Pharmaceutical Quality System and continually improve its effectiveness. The responsibilities placed on any one individual should not be so extensive as to present any risk to quality. 2.2 The manufacturer must have an organisation chart in which the relationships between the heads of Production, Quality Control and where applicable Head of Quality Assurance or Quality Unit referred to in point 2.5 and the position of the Authorised Person(s) are clearly shown in the managerial hierarchy. 2.3 People in responsible positions should have specific duties recorded in written job descriptions and adequate authority to carry out their responsibilities. Their duties may be delegated to designated deputies of a satisfactory qualification level. There should be no gaps or unexplained overlaps in the responsibilities of those personnel concerned with the application of Good Manufacturing Practice. 2.4 Senior management has the ultimate responsibility to ensure an effective Pharmaceutical Quality System is in place to achieve the quality objectives, and, that roles, responsibilities, and authorities are defined, communicated and implemented throughout the organisation. Senior management should establish a quality policy that describes the overall intentions and direction of the company related to quality and should ensure continuing suitability and effectiveness of the Pharmaceutical Quality System and GMP compliance through participation in management review. PE 009-17 (Part I) -8- 25 August 2023  Chapter 2 Personnel KEY PERSONNEL 2.5 Senior Management should appoint Key Management Personnel including the head of Production, the head of Quality Control, and if at least one of these persons is not responsible for the release of products the Authorised Person(s) designated for the purpose. Normally, key posts should be occupied by full-time personnel. The heads of Production and Quality Control must be independent from each other. In large organisations, it may be necessary to delegate some of the functions listed in 2.7, 2.8 and 2.9. Additionally, depending on the size and organisational structure of the company, a separate Head of Quality Assurance or Head of the Quality Unit may be appointed. Where such a function exists usually some of the responsibilities described in 2.7, 2.8 and 2.9 are shared with the Head of Quality Control and Head of Production and senior management should therefore take care that roles, responsibilities, and authorities are defined. 2.6 The duties of the Authorised Person(s) are described in the national requirements and can be summarised as follows: a) An Authorised Person must ensure that each batch of medicinal products has been manufactured and checked in compliance with the laws in force in that country and in accordance with the requirements of the Marketing Authorisation; b) The Authorised Person(s) must meet the qualification requirements laid down in the national legislation, they shall be permanently and continuously at the disposal of the holder of the Manufacturing Authorisation to carry out their responsibilities; c) The responsibilities of an Authorised Person may be delegated, but only to other Authorised Person(s). 2.7 The head of Production generally has the following responsibilities: (i) To ensure that products are produced and stored according to the appropriate documentation in order to obtain the required quality; (ii) To approve the instructions relating to production operations and to ensure their strict implementation; (iii) To ensure that the production records are evaluated and signed by an authorised person; (iv) To ensure the qualification and maintenance of his department, premises and equipment; (v) To ensure that the appropriate validations are done; (vi) To ensure that the required initial and continuing training of his department personnel is carried out and adapted according to need. PE 009-17 (Part I) -9- 25 August 2023  Chapter 2 Personnel 2.8 The head of Quality Control generally has the following responsibilities: (i) To approve or reject, as he/she sees fit, starting materials, packaging materials, intermediate, bulk and finished products; (ii) To ensure that all necessary testing is carried out and the associated records evaluated; (iii) To approve specifications, sampling instructions, test methods and other Quality Control procedures; (iv) To approve and monitor any contract analysts; (v) To ensure the qualification and maintenance of his/her department, premises and equipment; (vi) To ensure that the appropriate validations are done; (vii) To ensure that the required initial and continuing training of his department personnel is carried out and adapted according to need. Other duties of Quality Control are summarised in Chapter 6. 2.9 The heads of Production, Quality Control and where relevant, Head of Quality Assurance or Head of Quality Unit, generally have some shared, or jointly exercised, responsibilities relating to quality including in particular the design, effective implementation, monitoring and maintenance of the Pharmaceutical Quality System. These may include, subject to any national regulations: (i) The authorisation of written procedures and other documents, including amendments; (ii) The monitoring and control of the manufacturing environment; (iii) Plant hygiene; (iv) Process validation; (v) Training; (vi) The approval and monitoring of suppliers of materials; (vii) The approval and monitoring of contract manufacturers and providers of other GMP related outsourced activities; (viii) The designation and monitoring of storage conditions for materials and products; (ix) The retention of records; (x) The monitoring of compliance with the requirements of Good Manufacturing Practice; PE 009-17 (Part I) - 10 - 25 August 2023  Chapter 2 Personnel (xi) The inspection, investigation, and taking of samples, in order to monitor factors which may affect product quality; (xii) Participation in management reviews of process performance, product quality and of the Pharmaceutical Quality System and advocating continual improvement; (xiii) Ensuring that a timely and effective communication and escalation process exists to raise quality issues to the appropriate levels of management. TRAINING 2.10 The manufacturer should provide training for all the personnel whose duties take them into production and storage areas or into control laboratories (including the technical, maintenance and cleaning personnel), and for other personnel whose activities could affect the quality of the product. 2.11 Besides the basic training on the theory and practice of the Pharmaceutical Quality System and Good Manufacturing Practice, newly recruited personnel should receive training appropriate to the duties assigned to them. Continuing training should also be given, and its practical effectiveness should be periodically assessed. Training programmes should be available, approved by either the head of Production or the head of Quality Control, as appropriate. Training records should be kept. 2.12 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, should be given specific training. 2.13 Visitors or untrained personnel should, preferably, not be taken into the production and quality control areas. If this is unavoidable, they should be given information in advance, particularly about personal hygiene and the prescribed protective clothing. They should be closely supervised. 2.14 The Pharmaceutical Quality System and all the measures capable of improving its understanding and implementation should be fully discussed during the training sessions. PERSONNEL HYGIENE 2.15 Detailed hygiene programmes should be established and adapted to the different needs within the factory. They should include procedures relating to the health, hygiene practices and clothing of personnel. These procedures should be understood and followed in a very strict way by every person whose duties take him into the production and control areas. Hygiene programmes should be promoted by management and widely discussed during training sessions. 2.16 All personnel should receive medical examination upon recruitment. It must be the manufacturer’s responsibility that there are instructions ensuring that health conditions that can be of relevance to the quality of products come to the PE 009-17 (Part I) - 11 - 25 August 2023  Chapter 2 Personnel manufacturer’s knowledge. After the first medical examination, examinations should be carried out when necessary for the work and personal health. 2.17 Steps should be taken to ensure as far as is practicable that no person affected by an infectious disease or having open lesions on the exposed surface of the body is engaged in the manufacture of medicinal products. 2.18 Every person entering the manufacturing areas should wear protective garments appropriate to the operations to be carried out. 2.19 Eating, drinking, chewing or smoking, or the storage of food, drink, smoking materials or personal medication in the production and storage areas should be prohibited. In general, any unhygienic practice within the manufacturing areas or in any other area where the product might be adversely affected should be forbidden. 2.20 Direct contact should be avoided between the operator’s hands and the exposed product as well as with any part of the equipment that comes into contact with the products. 2.21 Personnel should be instructed to use the hand-washing facilities. 2.22 Any specific requirements for the manufacture of special groups of products, for example sterile preparations, are covered in the annexes. CONSULTANTS 2.23 Consultants should have adequate education, training, and experience, or any combination thereof, to advise on the subject for which they are retained. Records should be maintained stating the name, address, qualifications, and type of service provided by these consultants. PE 009-17 (Part I) - 12 - 25 August 2023  Chapter 3 Premises and equipment CHAPTER 3 PREMISES AND EQUIPMENT PRINCIPLE Premises and equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. Their layout and design 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. PREMISES General 3.1. Premises should be situated in an environment which, when considered together with measures to protect the manufacture, presents minimal risk of causing contamination of materials or products. 3.2. Premises should be carefully maintained, ensuring that repair and maintenance operations do not present any hazard to the quality of products. They should be cleaned and, where applicable, disinfected according to detailed written procedures. 3.3. Lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the medicinal products during their manufacture and storage, or the accurate functioning of equipment. 3.4. Premises should be designed and equipped so as to afford maximum protection against the entry of insects or other animals. 3.5. Steps should be taken in order to prevent the entry of unauthorised people. Production, storage and quality control areas should not be used as a right of way by personnel who do not work in them. Production Areas 3.6 Cross-contamination should be prevented for all products by appropriate design and operation of manufacturing facilities. The measures to prevent cross- contamination should be commensurate with the risks. Quality Risk Management principles should be used to assess and control the risks. Depending of the level of risk, it may be necessary to dedicate premises and equipment for manufacturing and/or packaging operations to control the risk presented by some medicinal products. PE 009-17 (Part I) - 13 - 25 August 2023  Chapter 3 Premises and equipment Dedicated facilities are required for manufacturing when a medicinal product presents a risk because: i. the risk cannot be adequately controlled by operational and/ or technical measures, ii. scientific data from the toxicological evaluation does not support a controllable risk (e.g. allergenic potential from highly sensitising materials such as beta-lactams) or iii. relevant residue limits, derived from the toxicological evaluation, cannot be satisfactorily determined by a validated analytical method. Further guidance can be found in Chapter 5 and in Annexes 2, 3, 4, 5 & 6. 3.7. Premises should preferably be laid out in such a way 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. 3.8. The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimise the risk of confusion between different medicinal 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. 3.9. Where starting and primary packaging materials, intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth, free from cracks and open joints, and should not shed particulate matter and should permit easy and effective cleaning and, if necessary, disinfection. 3.10 Pipework, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses which are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas. 3.11. Drains should be of adequate size, and have trapped gullies. Open channels should be avoided where possible, but if necessary, they should be shallow to facilitate cleaning and disinfection. 3.12. Production areas should be effectively ventilated, with air control facilities (including temperature and, where necessary, humidity and filtration) appropriate both to the products handled, to the operations undertaken within them and to the external environment. 3.13 Weighing of starting materials usually should be carried out in a separate weighing room designed for such use. 3.14. In cases where dust is generated (e.g. during sampling, weighing, mixing and processing operations, packaging of dry products), specific provisions should be taken to avoid cross-contamination and facilitate cleaning. PE 009-17 (Part I) - 14 - 25 August 2023  Chapter 3 Premises and equipment 3.15. Premises for the packaging of medicinal products should be specifically designed and laid out so as to avoid mix-ups or cross-contamination. 3.16 Production areas should be well lit, particularly where visual on-line controls are carried out. 3.17. In-process controls may be carried out within the production area provided they do not carry any risk to production. Storage Areas 3.18. Storage areas should be of sufficient capacity to allow orderly storage of the various categories of materials and products: starting and packaging materials, intermediate, bulk and finished products, products in quarantine, released, rejected, returned or recalled. 3.19. Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Where special storage conditions are required (e.g. temperature, humidity) these should be provided, checked and monitored. 3.20 Receiving and dispatch bays should protect materials and products from the weather. Reception areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage. 3.21. 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 should give equivalent security. 3.22. There should normally be a separate sampling area for starting materials. If sampling is performed in the storage area, it should be conducted in such a way as to prevent contamination or cross-contamination. 3.23. Segregated areas should be provided for the storage of rejected, recalled or returned materials or products. 3.24. Highly active materials or products should be stored in safe and secure areas. 3.25. Printed packaging materials are considered critical to the conformity of the medicinal product and special attention should be paid to the safe and secure storage of these materials. Quality Control Areas 3.26. Normally, Quality Control laboratories should be separated from production areas. This is particularly important for laboratories for the control of biologicals, microbiologicals and radioisotopes, which should also be separated from each other. 3.27. Control laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mix-ups and cross- contamination. There should be adequate suitable storage space for samples and records. PE 009-17 (Part I) - 15 - 25 August 2023  Chapter 3 Premises and equipment 3.28. Separate rooms may be necessary to protect sensitive instruments from vibration, electrical interference, humidity, etc. 3.29. Special requirements are needed in laboratories handling particular substances, such as biological or radioactive samples. Ancillary Areas 3.30. Rest and refreshment rooms should be separate from other areas. 3.31. Facilities for changing clothes and for washing and toilet purposes should be easily accessible and appropriate for the number of users. Toilets should not directly communicate with production or storage areas. 3.32. Maintenance workshops should as far as possible be separated from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for that use. 3.33. Animal houses should be well isolated from other areas, with separate entrance (animal access) and air handling facilities. EQUIPMENT 3.34. Manufacturing equipment should be designed, located and maintained to suit its intended purpose. 3.35. Repair and maintenance operations should not present any hazard to the quality of the products. 3.36. Manufacturing equipment should be designed so that it can be easily and thoroughly cleaned. It should be cleaned according to detailed and written procedures and stored only in a clean and dry condition. 3.37. Washing and cleaning equipment should be chosen and used in order not to be a source of contamination. 3.38. Equipment should be installed in such a way as to prevent any risk of error or of contamination. 3.39. Production equipment should not present any hazard to products. Parts of production equipment that come into contact with the product must not be reactive, additive or absorptive to such an extent that it will affect the quality of the product and thus present any hazard. 3.40. Balances and measuring equipment of an appropriate range and precision should be available for production and control operations. 3.41. Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by appropriate methods. Adequate records of such tests should be maintained. 3.42. Fixed pipework should be clearly labelled to indicate the contents and, where applicable, the direction of flow. PE 009-17 (Part I) - 16 - 25 August 2023  Chapter 3 Premises and equipment 3.43. Distilled, deionised and, where appropriate, other water pipes should be sanitised according to written procedures that detail the action limits for microbiological contamination and the measures to be taken. 3.44. Defective equipment should, if possible, be removed from production and quality control areas, or at least be clearly labelled as defective. PE 009-17 (Part I) - 17 - 25 August 2023  Chapter 4 Documentation CHAPTER 4 DOCUMENTATION PRINCIPLE Good documentation constitutes an essential part of the quality assurance system and is key to operating in compliance with GMP requirements. The various types of documents and media used should be fully defined in the manufacturer's Quality Management System. Documentation may exist in a variety of forms, including paper-based, electronic or photographic media. The main objective of the system of documentation utilised must be to establish, control, monitor and record all activities which directly or indirectly impact on all aspects of the quality of medicinal products. The Quality Management System should include sufficient instructional detail to facilitate a common understanding of the requirements, in addition to providing for sufficient recording of the various processes and evaluation of any observations, so that ongoing application of the requirements may be demonstrated. There are two primary types of documentation used to manage and record GMP compliance: instructions (directions, requirements) and records/reports. Appropriate good documentation practice should be applied with respect to the type of document. Suitable controls should be implemented to ensure the accuracy, integrity, availability and legibility of documents. Instruction documents should be free from errors and available in writing. The term ‘written’ means recorded, or documented on media from which data may be rendered in a human readable form. REQUIRED GMP DOCUMENTATION (BY TYPE) Site Master File: A document describing the GMP related activities of the manufacturer. Instructions (directions, or requirements) type: Specifications: Describe in detail the requirements with which the products or materials used or obtained during manufacture have to conform. They serve as a basis for quality evaluation. Manufacturing Formulae, Processing, Packaging and Testing Instructions: Provide detail all the starting materials, equipment and computerised systems (if any) to be used and specify all processing, packaging, sampling and testing instructions. In-process controls and process analytical technologies to be employed should be specified where relevant, together with acceptance criteria. Procedures: (Otherwise known as Standard Operating Procedures, or SOPs), give directions for performing certain operations. PE 009-17 (Part I) - 18 - 25 August 2023  Chapter 4 Documentation Protocols: Give instructions for performing and recording certain discreet operations. Technical Agreements: Are agreed between contract givers and acceptors for outsourced activities. Record/Report type: Records: Provide evidence of various actions taken to demonstrate compliance with instructions, e.g. activities, events, investigations, and in the case of manufactured batches a history of each batch of product, including its distribution. Records include the raw data which is used to generate other records. For electronic records regulated users should define which data are to be used as raw data. At least, all data on which quality decisions are based should be defined as raw data. Certificates of Analysis: Provide a summary of testing results on samples of products or materials2 together with the evaluation for compliance to a stated specification. Reports: Document the conduct of particular exercises, projects or investigations, together with results, conclusions and recommendations. GENERATION AND CONTROL OF DOCUMENTATION 4.1 All types of document should be defined and adhered to. The requirements apply equally to all forms of document media types. Complex systems need to be understood, well documented, validated, and adequate controls should be in place. Many documents (instructions and/or records) may exist in hybrid forms, i.e. some elements as electronic and others as paper based. Relationships and control measures for master documents, official copies, data handling and records need to be stated for both hybrid and homogenous systems. Appropriate controls for electronic documents such as templates, forms, and master documents should be implemented. Appropriate controls should be in place to ensure the integrity of the record throughout the retention period. 4.2 Documents should be designed, prepared, reviewed, and distributed with care. They should comply with the relevant parts of Product Specification Files, Manufacturing and Marketing Authorisation dossiers, as appropriate. The reproduction of working documents from master documents should not allow any error to be introduced through the reproduction process. 4.3 Documents containing instructions should be approved, signed and dated by appropriate and authorised persons. Documents should have unambiguous contents and be uniquely identifiable. The effective date should be defined. 2 Alternatively the certification may be based, in-whole or in-part, on the assessment of real time data (summaries and exception reports) from batch related process analytical technology (PAT), parameters or metrics as per the approved Marketing Authorisation dossier. PE 009-17 (Part I) - 19 - 25 August 2023  Chapter 4 Documentation 4.4 Documents containing instructions should be laid out in an orderly fashion and be easy to check. The style and language of documents should fit with their intended use. Standard Operating Procedures, Work Instructions and Methods should be written in an imperative mandatory style. 4.5 Documents within the Quality Management System should be regularly reviewed and kept up-to-date. When a document has been revised, systems should be operated to prevent inadvertent use of superseded documents. 4.6 Documents should not be hand-written; although, where documents require the entry of data, sufficient space should be provided for such entries. GOOD DOCUMENTATION PRACTICES 4.7 Handwritten entries should be made in clear, legible, indelible way. 4.8 Records should be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of medicinal products are traceable. 4.9 Any alteration made to the entry on a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded. RETENTION OF DOCUMENTS 4.10 It should be clearly defined which record is related to each manufacturing activity and where this record is located. Secure controls must be in place to ensure the integrity of the record throughout the retention period and validated where appropriate. 4.11 Specific requirements apply to batch documentation which must be kept for one year after expiry of the batch to which it relates or at least five years after certification of the batch by the Authorised Person, whichever is the longer. For investigational medicinal products, the batch documentation must be kept for at least five years after the completion or formal discontinuation of the last clinical trial in which the batch was used. Other requirements for retention of documentation may be described in legislation in relation to specific types of product (e.g. Advanced Therapy Medicinal Products) and specify that longer retention periods be applied to certain documents. 4.12 For other types of documentation, the retention period will depend on the business activity which the documentation supports. Critical documentation, including raw data (for example relating to validation or stability), which supports information in the Marketing Authorisation should be retained whilst the authorisation remains in force. It may be considered acceptable to retire certain documentation (e.g. raw data supporting validation reports or stability reports) where the data has been superseded by a full set of new data. Justification for this should be documented and should take into account the requirements for PE 009-17 (Part I) - 20 - 25 August 2023  Chapter 4 Documentation retention of batch documentation; for example, in the case of process validation data, the accompanying raw data should be retained for a period at least as long as the records for all batches whose release has been supported on the basis of that validation exercise. The following section gives some examples of required documents. The quality management system should describe all documents required to ensure product quality and patient safety. SPECIFICATIONS 4.13 There should be appropriately authorised and dated specifications for starting and packaging materials, and finished products. Specifications for starting and packaging materials 4.14 Specifications for starting and primary or printed packaging materials should include or provide reference to, if applicable: a) A description of the materials, including: - The designated name and the internal code reference; - The reference, if any, to a pharmacopoeial monograph; - The approved suppliers and, if reasonable, the original producer of the material; - A specimen of printed materials; b) Directions for sampling and testing; c) Qualitative and quantitative requirements with acceptance limits; d) Storage conditions and precautions; e) The maximum period of storage before re-examination. Specifications for intermediate and bulk products 4.15 Specifications for intermediate and bulk products should be available for critical steps or if these are purchased or dispatched. The specifications should be similar to specifications for starting materials or for finished products, as appropriate. Specifications for finished products 4.16 Specifications for finished products should include or provide reference to: a) The designated name of the product and the code reference where applicable; b) The formula; c) A description of the pharmaceutical form and package details; PE 009-17 (Part I) - 21 - 25 August 2023  Chapter 4 Documentation d) Directions for sampling and testing; e) The qualitative and quantitative requirements, with the acceptance limits; f) The storage conditions and any special handling precautions, where applicable; g) The shelf-life. MANUFACTURING FORMULA AND PROCESSING INSTRUCTIONS Approved, written Manufacturing Formula and Processing Instructions should exist for each product and batch size to be manufactured. 4.17 The Manufacturing Formula should include: a) The name of the product, with a product reference code relating to its specification; b) A description of the pharmaceutical form, strength of the product and batch size; c) A list of all starting materials to be used, with the amount of each, described; mention should 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. 4.18 The Processing Instructions should include: a) A statement of the processing location and the principal equipment to be used; b) The methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilising); c) Checks that the equipment and work station are clear of previous products, documents or materials not required for the planned process, and that equipment is clean and suitable for use; d) Detailed stepwise processing instructions [e.g. checks on materials, pre- treatments, sequence for adding materials, critical process parameters (time, temp etc)]; e) The instructions for any in-process controls with their limits; f) Where necessary, the requirements for bulk storage of the products; including the container, labeling and special storage conditions where applicable; PE 009-17 (Part I) - 22 - 25 August 2023  Chapter 4 Documentation g) Any special precautions to be observed. Packaging Instructions 4.19 Approved Packaging Instructions for each product, pack size and type should exist. These should include, or have a reference to, the following: a) Name of the product; including the batch number of bulk and finished product; b) Description of its pharmaceutical form, and strength where applicable; 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, including quantities, sizes and types, with the code or reference number relating to the specifications of each packaging material; e) Where appropriate, an example or reproduction of the relevant printed packaging materials, and specimens indicating where to apply batch number references, and shelf life of the product; f) Checks that the equipment and work station are clear of previous products, documents or materials not required for the planned packaging operations (line clearance), and that equipment is clean and suitable for use; g) Special precautions to be observed, including a careful examination of the area and equipment in order to ascertain the line clearance before operations begin; h) A description of the packaging operation, including any significant subsidiary operations, and equipment to be used; i) Details of in-process controls with instructions for sampling and acceptance limits. Batch Processing Record 4.20 A Batch Processing Record should be kept for each batch processed. It should be based on the relevant parts of the currently approved Manufacturing Formula and Processing Instructions, and should contain the following information: a) The name and batch number of the product; b) Dates and times of commencement, of significant intermediate stages and of completion of production; c) Identification (initials) of the operator(s) who performed each significant step of the process and, where appropriate, the name of any person who checked these operations; PE 009-17 (Part I) - 23 - 25 August 2023  Chapter 4 Documentation d) The batch number and/or analytical control number as well as the quantities of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added); e) Any relevant processing operation or event and major equipment used; f) A record of the in-process controls and the initials of the person(s) carrying them out, and the results obtained; g) The product yield obtained at different and pertinent stages of manufacture; h) Notes on special problems including details, with signed authorisation for any deviation from the Manufacturing Formula and Processing Instructions; i) Approval by the person responsible for the processing operations. Note: Where a validated process is continuously monitored and controlled, then automatically generated reports may be limited to compliance summaries and exception / out-of-specification (OOS) data reports. Batch Packaging Record 4.21 A Batch Packaging Record should be kept for each batch or part batch processed. It should be based on the relevant parts of the Packaging Instructions. The batch packaging record should contain the following information: a) The name and batch number of the product; b) The date(s) and times of the packaging operations; c) Identification (initials) of the operator(s) who performed each significant step of the process and, where appropriate, the name of any person who checked these operations; d) Records of checks for identity and conformity with the packaging instructions, including the results of in-process controls; e) Details of the packaging operations carried out, including references to equipment and the packaging lines used; f) Whenever possible, samples of printed packaging materials used, including specimens of the batch coding, expiry dating and any additional overprinting; g) Notes on any special problems or unusual events including details, with signed authorisation for any deviation from the Packaging Instructions; h) 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 obtained product, in order to provide for an adequate reconciliation. Where there are robust electronic controls in place during packaging there may be justification for not including this information; PE 009-17 (Part I) - 24 - 25 August 2023  Chapter 4 Documentation i) Approval by the person responsible for the packaging operations. PROCEDURES AND RECORDS Receipt 4.22 There should be written procedures and records for the receipt of each delivery of each starting material, (including bulk, intermediate or finished goods), primary, secondary and printed packaging materials. 4.23 The records of the receipts should include: a) The name of the material on the delivery note and the containers; b) The "in-house" name and/or code of material (if different from a); c) Date of receipt; d) Supplier’s name and manufacturer’s name; e) Manufacturer’s batch or reference number; f) Total quantity and number of containers received; g) The batch number assigned after receipt; h) Any relevant comment. 4.24 There should be written procedures for the internal labeling, quarantine and storage of starting materials, packaging materials and other materials, as appropriate. Sampling 4.25 There should be written procedures for sampling, which include the methods and equipment to be used, the amounts to be taken and any precautions to be observed to avoid contamination of the material or any deterioration in its quality. Testing 4.26 There should be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to be used. The tests performed should be recorded. Other 4.27 Written release and rejection procedures should be available for materials and products, and in particular for the certification for sale of the finished product by the Authorised Person(s). All records should be available to the Authorised Person. A system should be in place to indicate special observations and any changes to critical data. PE 009-17 (Part I) - 25 - 25 August 2023  Chapter 4 Documentation 4.28 Records should be maintained for the distribution of each batch of a product in order to facilitate recall of any batch, if necessary. 4.29 There should be written policies, procedures, protocols, reports and the associated records of actions taken or conclusions reached, where appropriate, for the following examples: - Validation and qualification of processes, equipment and systems; - Equipment assembly and calibration; - Technology transfer; - Maintenance, cleaning and sanitation; - Personnel matters including signature lists, training in GMP and technical matters, clothing and hygiene and verification of the effectiveness of training; - Environmental monitoring; - Pest control; - Complaints; - Recalls; - Returns; - Change control; - Investigations into deviations and non-conformances; - Internal quality/GMP compliance audits; - Summaries of records where appropriate (e.g. product quality review); - Supplier audits. 4.30 Clear operating procedures should be available for major items of manufacturing and test equipment. 4.31 Logbooks should be kept for major or critical analytical testing, production equipment, and areas where product has been processed. They should be used to record in chronological order, as appropriate, any use of the area, equipment/method, calibrations, maintenance, cleaning or repair operations, including the dates and identity of people who carried these operations out. 4.32 An inventory of documents within the Quality Management System should be maintained. PE 009-17 (Part I) - 26 - 25 August 2023  Chapter 5 Production CHAPTER 5 PRODUCTION PRINCIPLE Production operations must follow clearly defined procedures; they must comply with the principles of Good Manufacturing Practice in order to obtain products of the requisite quality and be in accordance with the relevant manufacturing and marketing authorisations. GENERAL 5.1. Production should be performed and supervised by competent people. 5.2. All handling of materials and products, such as receipt and quarantine, sampling, storage, labelling, dispensing, processing, packaging and distribution should be done in accordance with written procedures or instructions and, where necessary, recorded. 5.3. All incoming materials should be checked to ensure that the consignment corresponds to the order. Containers should be cleaned where necessary and labelled with the prescribed information. 5.4. Damage to containers and any other problem which might adversely affect the quality of a material should be investigated, recorded and reported to the Quality Control Department. 5.5. Incoming materials and finished products should be physically or administratively quarantined immediately after receipt or processing, until they have been released for use or distribution. 5.6. Intermediate and bulk products purchased as such should be handled on receipt as though they were starting materials. 5.7. All materials and products should be stored under the appropriate conditions established by the manufacturer and in an orderly fashion to permit batch segregation and stock rotation. 5.8. Checks on yields, and reconciliation of quantities, should be carried out as necessary to ensure that there are no discrepancies outside acceptable limits. 5.9. Operations on different products should not be carried out simultaneously or consecutively in the same room unless there is no risk of mix-up or cross- contamination. 5.10. At every stage of processing, materials and products should be protected from microbial and other contamination. PE 009-17 (Part I) - 27 - 25 August 2023  Chapter 5 Production 5.11. When working with dry materials and products, special precautions should be taken to prevent the generation and dissemination of dust. This applies particularly to the handling of highly hazardous, including highly sensitising materials. 5.12. At all times during processing, all materials, bulk containers, major items of equipment and where appropriate rooms used should be labelled or otherwise identified with an indication of the product or material being processed, its strength (where applicable) and batch number. Where applicable, this indication should also mention the stage of production. 5.13. Labels applied to containers, equipment or premises should 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 (for example, quarantined, accepted, rejected, clean). 5.14. Checks should be carried out to ensure that pipelines and other pieces of equipment used for the transportation of materials and products from one area to another are connected in a correct manner. 5.15. Any deviation from instructions or procedures should be avoided as far as possible. If a deviation occurs, it should be approved in writing by a competent person, with the involvement of the Quality Control department when appropriate. 5.16. Access to production premises should be restricted to authorised personnel. PREVENTION OF CROSS-CONTAMINATION IN PRODUCTION 5.17. Normally, the production of non-medicinal products should be avoided in areas and with equipment destined for the production of medicinal products but, where justified, could be allowed where the measures to prevent cross-contamination with medicinal products described below and in Chapter 3 can be applied. The production and/or storage of technical poisons, such as pesticides (except where these are used for manufacture of medicinal products) and herbicides, should not be allowed in areas used for the manufacture and / or storage of medicinal products. 5.18. Contamination of a starting material or of a product by another material or product should be prevented. This risk of accidental cross-contamination resulting from the uncontrolled release of dust, gases, vapours, aerosols, genetic material or organisms from active substances, other materials (starting or in-process), and products in process, from residues on equipment, and from operators’ clothing should be assessed. The significance of this risk varies with the nature of the contaminant and that of the product being contaminated. Products in which cross- contamination is likely to be most significant are those administered by injection and those given over a long time. However, contamination of all products poses a risk to patient safety dependent on the nature and extent of contamination. 5.19. Cross-contamination should be prevented by attention to design of the premises and equipment as described in Chapter 3. This should be supported by attention to process design and implementation of any relevant technical or organizational PE 009-17 (Part I) - 28 - 25 August 2023  Chapter 5 Production measures, including effective and reproducible cleaning processes to control risk of cross-contamination. 5.20 A Quality Risk Management process, which includes a potency and toxicological evaluation, should be used to assess and control the cross-contamination risks presented by the products manufactured. Factors including; facility/equipment design and use, personnel and material flow, microbiological controls, physico- chemical characteristics of the active substance, process characteristics, cleaning processes and analytical capabilities relative to the relevant limits established from the evaluation of the products should also be taken into account. The outcome of the Quality Risk Management process should be the basis for determining the necessity for and extent to which premises and equipment should be dedicated to a particular product or product family. This may include dedicating specific product contact parts or dedication of the entire manufacturing facility. It may be acceptable to confine manufacturing activities to a segregated, self- contained production area within a multiproduct facility, where justified. 5.21 The outcome of the Quality Risk Management process should be the basis for determining the extent of technical and organisational measures required to control risks for cross-contamination. These could include, but are not limited to, the following: Technical Measures i. Dedicated manufacturing facility (premises and equipment); ii. Self-contained production areas having separate processing equipment and separate heating, ventilation and air-conditioning (HVAC) systems. It may also be desirable to isolate certain utilities from those used in other areas; iii. Design of manufacturing process, premises and equipment to minimize risk for cross-contamination during processing, maintenance and cleaning; iv. Use of “closed systems” for processing and material/product transfer between equipment; v. Use of physical barrier systems, including isolators, as containment measures; vi. Controlled removal of dust close to source of the contaminant e.g. through localised extraction; vii. Dedication of equipment, dedication of product contact parts or dedication of selected parts which are harder to clean (e.g. filters), dedication of maintenance tools; viii. Use of single use disposable technologies; ix. Use of equipment designed for ease of cleaning; x. Appropriate use of air-locks and pressure cascade to confine potential airborne contaminant within a specified area; xi. Minimising the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air; xii. Use of automatic clean in place systems of validated effectiveness; PE 009-17 (Part I) - 29 - 25 August 2023  Chapter 5 Production xiii. For common general wash areas, separation of equipment washing, drying and storage areas. Organisational Measures i. Dedicating the whole manufacturing facility or a self-contained production area on a campaign basis (dedicated by separation in time) followed by a cleaning process of validated effectiveness; ii. Keeping specific protective clothing inside areas where products with high risk of cross-contamination are processed; iii. Cleaning verification after each product campaign should be considered as a detectability tool to support effectiveness of the Quality Risk Management approach for products deemed to present higher risk; iv. Depending on the contamination risk, verification of cleaning of non product contact surfaces and monitoring of air within the manufacturing area and/or adjoining areas in order to demonstrate effectiveness of control measures against airborne contamination or contamination by mechanical transfer; v. Specific measures for waste handling, contaminated rinsing water and soiled gowning; vi. Recording of spills, accidental events or deviations from procedures; vii. Design of cleaning processes for premises and equipment such that the cleaning processes in themselves do not present a cross-contamination risk; viii. Design of detailed records for cleaning processes to assure completion of cleaning in accordance with approved procedures and use of cleaning status labels on equipment and manufacturing areas; ix. Use of common general wash areas on a campaign basis; x. Supervision of working behaviour to ensure training effectiveness and compliance with the relevant procedural controls. 5.22 Measures to prevent cross-contamination and their effectiveness should be reviewed periodically according to set procedures. VALIDATION 5.23 Validation studies should reinforce Good Manufacturing Practice and be conducted in accordance with defined procedures. Results and conclusions should be recorded. 5.24 When any new manufacturing formula or method of preparation is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to yield a product consistently of the required quality. PE 009-17 (Part I) - 30 - 25 August 2023  Chapter 5 Production 5.25 Significant amendments to the manufacturing process, including any change in equipment or materials, which may affect product quality and/or the reproducibility of the process, should be validated. 5.26 Processes and procedures should undergo periodic critical re-validation to ensure that they remain capable of achieving the intended results. STARTING MATERIALS 5.27 The selection, qualification, approval and maintenance of suppliers of starting materials, together with their purchase and acceptance, should be documented as part of the pharmaceutical quality system. The level of supervision should be proportionate to the risks posed by the individual materials, taking account of their source, manufacturing process, supply chain complexity and the final use to which the material is put in the medicinal product. The supporting evidence for each supplier / material approval should be maintained. Staff involved in these activities should have a current knowledge of the suppliers, the supply chain and the associated risks involved. Where possible, starting materials should be purchased directly from the manufacturer of the starting material. 5.28 The quality requirements established by the manufacturer for the starting materials should be discussed and agreed with the suppliers. Appropriate aspects of the production, testing and control, including handling, labelling, packaging and distribution requirements, complaints, recalls and rejection procedures should be documented in a formal quality agreement or specification. 5.29 For the approval and maintenance of suppliers of active substances and excipients, the following is required: Active substances Supply chain traceability should be established and the associated risks, from active substance starting materials to the finished medicinal product, should be formally assessed and periodically verified. Appropriate measures should be put in place to reduce risks to the quality of the active substance. The supply chain and traceability records for each active substance (including active substance starting materials) should be available and be retained by the manufacturer of the medicinal product. Audits should be carried out at the manufacturers and distributors of active substances to confirm that they comply with the relevant good manufacturing practice and good distribution practice requirements. The holder of the manufacturing authorisation shall verify such compliance either by himself/herself or through an entity acting on his/her behalf under a contract. For veterinary medicinal products, audits should be conducted based on risk. Audits should be of an appropriate duration and scope to ensure that a full and clear assessment of GMP is made; consideration should be given to potential cross- contamination from other materials on site. The report should fully reflect PE 009-17 (Part I) - 31 - 25 August 2023  Chapter 5 Production what was done and seen on the audit with any deficiencies clearly identified. Any required corrective and preventive actions should be implemented. Further audits should be undertaken at intervals defined by the quality risk management process to ensure the maintenance of standards and continued use of the approved supply chain. Excipients Excipients and excipient suppliers should be controlled appropriately based on the results of a formalised quality risk assessment in accordance with the PIC/S Guideline PI 045-1 ‘Guidelines on the formalised risk assessment for ascertaining the appropriate Good Manufacturing Practice for excipients of medicinal products for human use’. 5.30 For each delivery of starting material the containers should be checked for integrity of package, including tamper evident seal where relevant, and for correspondence between the delivery note, the purchase order, the supplier’s labels and approved manufacturer and supplier information maintained by the medicinal product manufacturer. The receiving checks on each delivery should be documented. 5.31 If one material delivery is made up of different batches, each batch must be considered as separate for sampling, testing and release. 5.32 Starting materials in the storage area should be appropriately labelled (see section 13). Labels should bear at least the following information: i. The designated name of the product and the internal code reference where applicable; ii. A batch number given at receipt; iii. Where appropriate, the status of the contents (e.g. in quarantine, on test, released, rejected); iv. Where appropriate, an expiry date or a date beyond which retesting is necessary. When fully computerised storage systems are used, all the above information need not necessarily be in a legible form on the label. 5.33 There should be appropriate procedures or measures to assure the identity of the contents of each container of starting material. Bulk containers from which samples have been drawn should be identified (see Chapter 6). 5.34 Only starting materials which have been released by the Quality Control department and which are within their retest date should be used. 5.35 Manufacturers of finished products are responsible for any testing of starting materials3 as described in the marketing authorisation dossier. They can utilise 3 A similar approach should apply to packaging materials as stated in section 5.45. PE 009-17 (Part I) - 32 - 25 August 2023  Chapter 5 Production partial or full test results from the approved starting material manufacturer but must, as a minimum, perform identification testing4 of each batch according to Annex 8. 5.36 The rationale for the outsourcing of this testing should be justified and documented and the following requirements should be fulfilled: i. Special attention should be paid to the distribution controls (transport, wholesaling, storage and delivery) in order to maintain the quality characteristics of the starting materials and to ensure that test results remain applicable to the delivered material; ii. The medicinal product manufacturer should perform audits, either itself or via third parties, at appropriate intervals based on risk at the site(s) carrying out the testing (including sampling) of the starting materials in order to assure compliance with Good Manufacturing Practice and with the specifications and testing methods described in the marketing authorisation dossier; iii. The certificate of analysis provided by the starting material manufacturer/supplier should be signed by a designated person with appropriate qualifications and experience. The signature assures that each batch has been checked for compliance with the agreed product specification unless this assurance is provided separately; iv. The medicinal product manufacturer should have appropriate experience in dealing with the starting material manufacturer (including experience via a supplier) including assessment of batches previously received and the history of compliance before reducing in-house testing. Any significant change in the manufacturing or testing processes should be considered; v. The medicinal product manufacturer should also perform (or via a separately approved contract laboratory) a full analysis at appropriate intervals based on risk and compare the results with the material manufacturer’s or supplier’s certificate of analysis in order to check the reliability of the latter. Should this testing identify any discrepancy then an investigation should be performed and appropriate measures taken. The acceptance of certificates of analysis from the material manufacturer or supplier should be discontinued until these measures are completed. 5.37 Starting materials should only be dispensed by designated persons, following a written procedure, to ensure that the correct materials are accurately weighed or measured into clean and properly labelled containers. 5.38 Each dispensed material and its weight or volume should be independently checked and the check recorded. 5.39 Materials dispensed for each batch should be kept together and conspicuously labelled as such. 4 Identity testing of starting materials should be performed according to the methods and the specifications of the relevant marketing authorisation dossier. PE 009-17 (Part I) - 33 - 25 August 2023  Chapter 5 Production PROCESSING OPERATIONS: INTERMEDIATE AND BULK PRODUCTS 5.40 Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues or documents not required for the current operation. 5.41 Intermediate and bulk products should be kept under appropriate conditions. 5.42 Critical processes should be validated (see "Validation" in this Chapter). 5.43 Any necessary in-process controls and environmental controls should be carried out and recorded. 5.44 Any signific