EU Guidelines for Good Manufacturing Practice for Medicinal Products (PDF)

EUROPEAN COMMISSION Brussels, 22.8.2022 C(2022) 5938 final GUIDELINES The Rules Governing Medicinal Products in the E...

EUROPEAN COMMISSION Brussels, 22.8.2022 C(2022) 5938 final GUIDELINES The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use EN EN  The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use Annex 1 Manufacture of Sterile Medicinal Products Legal context for publishing the detailed guidelines: Article 47 of Directive 2001/83/EC on the Community code relating to medicinal products for human use and Regulation 2019/6 on the Community code relating to veterinary medicinal products. This document provides technical guidance on the principles and guidelines of good manufacturing practice (GMP) for medicinal products as laid down in Commission Directive (EU) 2017/1572 for medicinal products for human use, Directive 91/412/EEC for veterinary use, and Commission Delegated Regulation (EU) 2017/1569 for investigational medicinal products for human use and arrangements for inspections supplementing Regulation (EU) No 536/2014 on clinical trials. This Annex is intended to assist national authorities in the application of the EU legislation. Only the Court of Justice of the European Union is competent to authoritatively interpret Union law. Status of the document: Revision of the 2007 version of Annex 1. Document History Previous version dated 30 May 2003, in operation since September 2003 Revision to align classification table of clean rooms, to includeguidance on media simultations, bioburden November 2005 to December 2007 monitoring and capping of vials 01 March 2009/01 March 2010 Date for coming into operation and superseding Note: Provisions on capping of vials were implemented on 01 March 2010. Reasons for changes: The GMP/GDP Inspectors Working Group and the PIC/S Committee jointly recommend that the current version of annex 1, on the manufacture of sterile medicinal products, is revised to reflect changes in regulatory and manufacturing environments. The new guideline should clarify how manufacturers can take advantage of new possibilities deriving from the application of an enhanced process understanding by using innovative tools as described in the ICH Q9 and Q10 guidelines. The revision of Annex 1 should also take into account related changes in other GMP chapters and annexes as well as in other regulatory documents. The revised guideline will seek to remove ambiguity and inconsistencies and will take account of advances in technologies. Deadline for coming into operation: - 25 August 2023 : one year from the date of publication in Eudralex Volume 4 - 25 August 2024 : two years from the date of publication in Eudralex Volume 4 for point 8.123 1 Document map Section Number General overview 1. Scope Includes additional areas (other than sterile products) where the general principles of the annex can be applied. 2. Principle General principles as applied to the manufacture of sterile products. 3. Pharmaceutical Quality Highlights the specific requirements of the PQS when applied System (PQS) to sterile products. 4. Premises General guidance regarding the specific needs for premises design and also guidance on the qualification of premises including the use of Barrier Technology. 5. Equipment General guidance on the design and operation of equipment. 6. Utilities Guidance regarding the special requirements of utilities such as water, gas and vacuum. 7. Personnel Guidance on the requirements for specific training, knowledge and skills. Also gives guidance regarding the qualification of personnel. 8. Production and specific Guidance on the approaches to be taken regarding aseptic and technologies terminal sterilization processes. Guidance on the approaches to sterilization of products, equipment and packaging components. Also guidance on different technologies such as lyophilization and Form-Fill-Seal where specific requirements apply. 9. Environmental and process This section differs from guidance given in section 4 in that the monitoring guidance here applies to ongoing routine monitoring regarding the design of systems and setting of action limits alert levels and reviewing trend data. The section also gives guidance on the requirements of Aseptic Process Simulations (APS). 10. Quality control (QC) Guidance on some of the specific Quality Control requirements relating to sterile products. 11. Glossary Explanation of specific terminology. 2 1 Scope The manufacture of sterile products covers a wide range of sterile product types (active substance, excipient, primary packaging material and finished dosage form), packed sizes (single unit to multiple units), processes (from highly automated systems to manual processes) and technologies (e.g. biotechnology, classical small molecule manufacturing systems and closed systems). This Annex provides general guidance that should be used in the design and control of facilities, equipment, systems and procedures used for the manufacture of all sterile products applying the principles of Quality Risk Management (QRM), to ensure that microbial, particulate and endotoxin/pyrogen contamination is prevented in the final product. QRM applies to this document in its entirety and will not, normally, be referred to in specific paragraphs. Where specific limits or frequencies or ranges are specified, these should be considered as a minimum requirement. They are stated due to historical regulatory experience of issues that have been identified and have impacted the safety of patients. The intent of the Annex is to provide guidance for the manufacture of sterile products. However, some of the principles and guidance, such as contamination control strategy, design of premises, cleanroom classification, qualification, validation, monitoring and personnel gowning, may be used to support the manufacture of other products that are not intended to be sterile such as certain liquids, creams, ointments and low bioburden biological intermediates, but where the control and reduction of microbial, particulate and endotoxin/pyrogen contamination is considered important. Where a manufacturer elects to apply guidance herein to non-sterile products, the manufacturer should clearly document which principles have been applied and acknowledge that compliance with those principles should be demonstrated. 2 Principle 2.1 The manufacture of sterile products is subject to special requirements in order to minimize risks of microbial, particulate and endotoxin/pyrogen contamination. The following key areas should be considered: i. Facility, equipment and process should be appropriately designed, qualified and/or validated and where applicable, subjected to ongoing verification according to the relevant sections of the Good Manufacturing Practices (GMP) guidelines. The use of appropriate technologies (e.g. Restricted Access Barriers Systems (RABS), isolators, robotic systems, rapid/alternative methods and continuous monitoring systems) should be considered to increase the protection of the product from potential extraneous sources of endotoxin/pyrogen, particulate and microbial contamination such as personnel, materials and the surrounding environment, and assist in the rapid detection of potential contaminants in the environment and the product. ii. Personnel should have adequate qualifications and experience, training and behaviour with a specific focus on the principles involved in the protection of sterile product during the manufacturing, packaging and distribution processes. iii. Processes and monitoring systems for sterile product manufacture should be designed, commissioned, qualified, monitored and regularly reviewed by personnel with appropriate process, engineering and microbiological knowledge. iv. Raw materials and packaging materials should be adequately controlled and tested to ensure that level of bioburden and endotoxin/pyrogen are suitable for use. 3 2.2 Processes, equipment, facilities and manufacturing activities should be managed in accordance with QRM principles to provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality. Where alternative approaches are used, these should be supported by appropriate rationale, risk assessment and mitigation, and should meet the intent of this Annex. In the first instance, QRM priorities should include appropriate design of the facility, equipment and processes, followed by the implementation of well-designed procedures, and finally application of monitoring systems as the element that demonstrates that the design and procedures have been correctly implemented and continue to perform in line with expectations. Monitoring or testing alone does not give assurance of sterility. 2.3 A Contamination Control Strategy (CCS) should be implemented across the facility in order to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical and organisational) and monitoring measures employed to manage risks to medicinal product quality and safety. The combined strategy of the CCS should establish robust assurance of contamination prevention. The CCS should be actively reviewed and, where appropriate, updated and should drive continual improvement of the manufacturing and control methods. Its effectiveness should form part of the periodic management review. Where existing control systems are in place and are appropriately managed, these may not require replacement but should be referenced in the CCS and the associated interactions between systems should be understood. 2.4 Contamination control and steps taken to minimize the risk of contamination from microbial, endotoxin/pyrogen and particle sources includes a series of interrelated events and measures. These are typically assessed, controlled and monitored individually but their collective effectiveness should be considered together. 2.5 The development of the CCS requires detailed technical and process knowledge. Potential sources of contamination are attributable to microbial and cellular debris (e.g. pyrogen, endotoxin) as well as particulate (e.g. glass and other visible and sub-visible particles). Elements to be considered within a CCS should include (but are not limited to): i. Design of both the plant and processes including the associated documentation. ii. Premises and equipment. iii. Personnel. iv. Utilities. v. Raw material controls – including in-process controls. vi. Product containers and closures. vii. Vendor approval – such as key component suppliers, sterilisation of components and single use systems (SUS), and critical service providers. viii. Management of outsourced activities and availability/transfer of critical information between parties, e.g. contract sterilisation services. ix. Process risk management. x. Process validation. xi. Validation of sterilisation processes. 4 xii. Preventative maintenance – maintaining equipment, utilities and premises (planned and unplanned maintenance) to a standard that will ensure there is no additional risk of contamination. xiii. Cleaning and disinfection. xiv. Monitoring systems - including an assessment of the feasibility of the introduction of scientifically sound, alternative methods that optimize the detection of environmental contamination. xv. Prevention mechanisms – trend analysis, detailed investigation, root cause determination, corrective and preventive actions (CAPA) and the need for comprehensive investigational tools. xvi. Continuous improvement based on information derived from the above. 2.6 The CCS should consider all aspects of contamination control with ongoing and periodic review resulting in updates within the pharmaceutical quality system as appropriate. Changes to the systems in place should be assessed for any impact on the CCS before and after implementation. 2.7 The manufacturer should take all steps and precautions necessary to assure the sterility of the products manufactured within its facilities. Sole reliance for sterility or other quality aspects should not be placed on any terminal process or finished product test. 3 Pharmaceutical Quality System (PQS) 3.1 The manufacture of sterile products is a complex activity that requires specific controls and measures to ensure the quality of products manufactured. Accordingly, the manufacturer’s PQS should encompass and address the specific requirements of sterile product manufacture and ensure that all activities are effectively controlled so that the risk of microbial, particulate and endotoxin/pyrogen contamination is minimized in sterile products. In addition to the PQS requirements detailed in Chapter 1 of the GMP guidelines (Part I - Basic Requirements for Medicinal Products), the PQS for sterile product manufacture should also ensure that: i. An effective risk management system is integrated into all areas of the product life cycle with the aim to minimize microbial contamination and to ensure the quality of sterile products manufactured. ii. The manufacturer has sufficient knowledge and expertise in relation to the products manufactured and the equipment, engineering and manufacturing methods employed that have an impact on product quality. iii. Root cause analysis of procedural, process or equipment failure is performed in such a way that the risk to product is correctly identified and understood so that suitable corrective and preventive actions (CAPA) are implemented. iv. Risk management is applied in the development and maintenance of the CCS, to identify, assess, reduce/eliminate (where applicable) and control contamination risks. Risk management should be documented and should include the rationale for decisions taken in relation to risk reduction and acceptance of residual risk. v. Senior management should effectively oversee the state of control throughout the facility and product lifecycle. Risk management outcome should be reviewed regularly as part of the on- 5  going quality management, during change, in the event of a significant emerging problem, and during the periodic product quality review. vi. Processes associated with the finishing, storage and transport of sterile products should not compromise the sterile product. Aspects that should be considered include: container integrity, risks of contamination and avoidance of degradation by ensuring that products are stored and maintained in accordance with the registered storage conditions. vii. Persons responsible for the certification/release of sterile products have appropriate access to manufacturing and quality information and possess adequate knowledge and experience in the manufacture of sterile products and the associated critical quality attributes. This is in order to allow such persons to determine if the sterile products have been manufactured in accordance with the registered specifications and approved process and are of the required quality. 3.2 All non-conformities, such as sterility test failures, environmental monitoring excursions or deviations from established procedures should be adequately investigated before certification/release of the batch. The investigation should determine the potential impact upon process and product quality and whether any other processes or batches are potentially impacted. The reason for including or excluding a product or batch from the scope of the investigation should be clearly justified and recorded. 4 Premises 4.1 The manufacture of sterile products should be carried out in appropriate cleanrooms, entry to which should be through change rooms that act as airlocks for personnel and airlocks for equipment and materials. Cleanrooms and change rooms should be maintained to an appropriate cleanliness standard and supplied with air that has passed through filters of an appropriate efficiency. Controls and monitoring should be scientifically justified and should effectively evaluate the state of environmental conditions of cleanrooms, airlocks and pass-through hatches. 4.2 The various operations of component preparation, product preparation and filling should be carried out with appropriate technical and operational separation measures within the cleanroom or facility to prevent mix up and contamination. 4.3 Restricted Access Barrier Systems (RABS) or isolators are beneficial in assuring required conditions and minimizing microbial contamination associated with direct human interventions in the critical zone. Their use should be considered in the CCS. Any alternative approaches to the use of RABS or isolators should be justified. 4.4 For the manufacture of sterile products, there are four grades of cleanroom/zone. Grade A: The critical zone for high-risk operations (e.g. aseptic processing line, filling zone, stopper bowl, open primary packaging or for making aseptic connections under the protection of first air). Normally, such conditions are provided by a localised airflow protection, such as unidirectional airflow workstations within RABS or isolators. The maintenance of unidirectional airflow should be demonstrated and qualified across the whole of the grade A area. Direct intervention (e.g. without the protection of barrier and glove port technology) into the grade A area by operators should be minimized by premises, equipment, process and procedural design. Grade B: For aseptic preparation and filling, this is the background cleanroom for grade A (where it is not an isolator). Air pressure differences should be continuously monitored. Cleanrooms of lower grade than grade B can be considered where isolator technology is used (see paragraph 4.20 ). 6  Grade C and D: These are cleanrooms used for carrying out less critical stages in the manufacture of aseptically filled sterile products or as a background for isolators. They can also be used for the preparation/filling of terminally sterilised products. (See section 8 for the specific details on terminal sterilisation activities). 4.5 In cleanrooms and critical zones, all exposed surfaces should be smooth, impervious and unbroken in order to minimize the shedding or accumulation of particles or micro-organisms. 4.6 To reduce accumulation of dust and to facilitate cleaning there should be no recesses that are difficult to clean effectively, therefore projecting ledges, shelves, cupboards and equipment should be kept to a minimum. Doors should be designed to avoid recesses that cannot be cleaned. Sliding doors may be undesirable for this reason. 4.7 Materials used in cleanrooms, both in the construction of the room and for items used within the room, should be selected to minimize generation of particles and to permit the repeated application of cleaning, disinfectant and sporicidal agents where used. 4.8 Ceilings should be designed and sealed to prevent contamination from the space above them. 4.9 Sinks and drains should be prohibited in the grade A and grade B areas. In other cleanrooms, air breaks should be fitted between the machine or sink and the drains. Floor drains in lower grade cleanrooms should be fitted with traps or water seals designed to prevent back flow and should be regularly cleaned, disinfected and maintained. 4.10 The transfer of equipment and materials into and out of the cleanrooms and critical zones is one of the greatest potential sources of contamination. Any activities with the potential to compromise the cleanliness of cleanrooms or the critical zone should be assessed and if they cannot be eliminated, appropriate controls should be implemented. 4.11 The transfer of materials, equipment, and components into the grade A or B areas should be carried out via a unidirectional process. Where possible, items should be sterilised and passed into these areas through double-ended sterilisers (e.g. through a double-door autoclave or depyrogenation oven/tunnel) sealed into the wall. Where sterilisation upon transfer of the items is not possible, a procedure which achieves the same objective of not introducing contamination should be validated and implemented, (e.g. using an effective transfer disinfection process, rapid transfer systems for isolators or, for gaseous or liquid materials, a bacteria-retentive filter). The removal of items from the grade A and B areas (e.g. materials, waste, environmental samples) should be carried out via a separate unidirectional process. If this is not possible, time-based separation of movement (incoming/exiting material) by procedure should be considered and controls applied to avoid potential contamination of incoming items. 4.12 Airlocks should be designed and used to provide physical separation and to minimize microbial and particle contamination of the different areas and should be present for material and personnel moving between different grades. Wherever possible, airlocks used for personnel movement should be separated from those used for material movement. Where this is not practical, time-based separation of movement (personnel/material) by procedure should be considered. Airlocks should be flushed effectively with filtered air to ensure that the grade of the cleanroom is maintained. The final stage of the airlock should, in the “at rest” state, be of the same cleanliness grade (viable and total particle) as the cleanroom into which it leads. The use of separate change rooms for entering and leaving the grade B area is desirable. Where this is not practical, time-based separation of activities (ingress/egress) by procedure should be considered. Where the CCS indicates that the risk of contamination is high, separate change rooms for entering and leaving production areas should be used. Airlocks should be designed as follows: 7  i. Personnel airlocks: Areas of increasing cleanliness used for entry of personnel (e.g. from the grade D area to the grade C area to the grade B area). In general hand washing facilities should be provided only in the first stage of the changing room and not be present in changing rooms directly accessing the grade B area. ii. Material airlocks: used for materials and equipment transfer. Only materials and equipment that have been included on an approved list and assessed during validation of the transfer process should be transferred into the grade A or grade B areas via an airlock or pass-through hatches. Equipment and materials (intended for use in the grade A area) should be protected when transiting through the grade B area. Any unapproved items that require transfer should be pre-approved as an exception. Appropriate risk assessment and mitigation measures should be applied and recorded as per the manufacturer's CCS and should include a specific disinfection and monitoring programme approved by quality assurance. Pass-through hatches should be designed to protect the higher-grade environment, for example by effective flushing with an active filtered air supply. The movement of material or equipment from lower grade or unclassified area to higher-grade clean areas should be subject to cleaning and disinfection commensurate with the risk and in line with the CCS. 4.13 For pass-through hatches and airlocks (for material and personnel), the entry and exit doors should not be opened simultaneously. For airlocks leading to the grade A and grade B areas, an interlocking system should be used. For airlocks leading to grade C and D areas, a visual and/or audible warning system should be operated as a minimum. Where required to maintain area segregation, a time delay between the closing and opening of interlocked doors should be established. 4.14 Cleanrooms should be supplied with a filtered air supply that maintains a positive pressure and/or an airflow relative to the background environment of a lower grade under all operational conditions and should flush the area effectively. Adjacent rooms of different grades should have an air pressure difference of a minimum of 10 Pascals (guidance value). Particular attention should be paid to the protection of the critical zone. The recommendations regarding air supplies and pressures may need to be modified where it is necessary to contain certain materials (e.g. pathogenic, highly toxic or radioactive products or live viral or bacterial materials). The modification may include positively or negatively pressurized airlocks that prevent the hazardous material from contaminating surrounding areas. Decontamination of facilities (e.g. the cleanrooms and the heating, ventilation, and air-conditioning (HVAC) systems) and the treatment of air leaving a clean area, may be necessary for some operations. Where containment requires air to flow into a critical zone, the source of the air should be from an area of the same or higher grade. 4.15 Airflow patterns within cleanrooms and zones should be visualised to demonstrate that there is no ingress from lower grade to higher grade areas and that air does not travel from less clean areas (such as the floor) or over operators or equipment that may transfer contamination to the higher grade areas. Where unidirectional airflow is required, visualisation studies should be performed to determine compliance, (see paragraphs 4.4 & 4.19). When filled, closed products are transferred to an adjacent cleanroom of a lower grade via a small egress point, airflow visualization studies should demonstrate that air does not ingress from the lower grade cleanrooms to the grade B area. Where air movement is shown to be a contamination risk to the clean area or critical zone, corrective actions, such as design improvement, should be implemented. Airflow pattern studies should be performed both at rest and in operation (e.g. simulating operator interventions). Video recordings of the airflow patterns should be retained. The outcome of the air visualisation studies should be documented and 8 considered when establishing the facility's environmental monitoring programme. 4.16 Indicators of air pressure differences should be fitted between cleanrooms and/or between isolators and their background. Set points and the criticality of air pressure differences should be considered within the CCS. Air pressure differences identified as critical should be continuously monitored and recorded. A warning system should be in place to instantly indicate and warn operators of any failure in the air supply or reduction of air pressure differences (below set limits for those identified as critical). The warning signal should not be overridden without assessment and a procedure should be available to outline the steps to be taken when a warning signal is given. Where alarm delays are set, these should be assessed and justified within the CCS. Other air pressure differences should be monitored and recorded at regular intervals. 4.17 Facilities should be designed to permit observation of production activities from outside the grade A and B areas (e.g. through the provision of windows or remote cameras with a full view of the area and processes to allow observation and supervision without entry). This requirement should be considered when designing new facilities or during refurbishment of existing facilities. Barrier Technologies 4.18 Isolators or RABS, which are different technologies, and the associated processes, should be designed to provide protection through separation of the grade A environment from the environment of the surrounding room. The hazards introduced from entry or removal of items during processing should be minimized and supported by high capability transfer technologies or validated systems that robustly prevent contamination and are appropriate for the respective technology. 4.19 The design of the technology and processes used should ensure appropriate conditions are maintained in the critical zone to protect the exposed product during operations. i. Isolators: a. The design of open isolators should ensure grade A conditions with first air protection in the critical zone and unidirectional airflow that sweeps over and away from exposed products during processing. b. The design of closed isolators should ensure grade A conditions with adequate protection for exposed products during processing. Airflow may not be fully unidirectional in closed isolators where simple operations are conducted. However, any turbulent airflow should not increase risk of contamination of the exposed product. Where processing lines are included in closed isolators, grade A conditions should be ensured with first air protection in the critical zone and unidirectional airflow that sweeps over and away from exposed products during processing c. Negative pressure isolators should only be used when containment of the product is considered essential (e.g. radiopharmaceutical products) and specialized risk control measures should be applied to ensure the critical zone is not compromised. ii. RABS: The design of RABS should ensure grade A conditions with unidirectional airflow and first air protection in the critical zone. A positive airflow from the critical zone to the supporting background environment should be maintained. 9 4.20 The background environment for isolators or RABS should ensure the risk of transfer of contamination is minimized. i. Isolators: a. The background environment for open isolators should generally correspond to a minimum of grade C. The background for closed isolators should correspond to a minimum of grade D. The decision on the background classification should be based on risk assessment and justified in the CCS. b. Key considerations when performing the risk assessment for the CCS of an isolator should include (but are not limited to); the bio-decontamination programme, the extent of automation, the impact of glove manipulations that may potentially compromise ‘first air’ protection of critical process points, the impact of potential loss of barrier/glove integrity, transfer mechanisms used and activities such as set-up or maintenance that may require the doors to be opened prior to the final bio-decontamination of the isolator. Where additional process risks are identified, a higher grade of background should be considered unless appropriately justified in the CCS. c. Airflow pattern studies should be performed at the interfaces of open isolators to demonstrate the absence of air ingress. ii. RABS: The background environment for RABS used for aseptic processing should correspond to a minimum of grade B and airflow pattern studies should be performed to demonstrate the absence of air ingress during interventions, including door openings if applicable. 4.21 The materials used for glove systems (for both isolators and RABS), should be demonstrated to have appropriate mechanical and chemical resistance. The frequency of glove replacement should be defined within the CCS. i. Isolators: a. For isolators, leak testing of the glove system should be performed using a methodology demonstrated to be suitable for the task and criticality. The testing should be performed at defined intervals. Generally glove integrity testing should be performed at a minimum frequency of the beginning and end of each batch or campaign. Additional glove integrity testing may be necessary depending on the validated campaign length. Glove integrity monitoring should include a visual inspection associated with each use and following any manipulation that may affect the integrity of the system. For manual aseptic processing activities where single unit or small batch sizes are produced, the frequency of integrity verification may be based on other criteria, such as the beginning and end of each manufacturing session. b. Integrity / leak testing of isolator systems should be performed at defined intervals. ii. RABS: For RABS, gloves used in the grade A area should be sterilised before installation and sterilised or effectively bio-decontaminated by a validated method prior to each manufacturing campaign. If exposed to the background environment during operation, disinfection using an approved methodology following each exposure should be completed. Gloves should be visually examined with each use, and integrity testing should be performed at periodic intervals. 10 4.22 Decontamination methods (cleaning and bio-decontamination, and where applicable inactivation for biological materials) should be appropriately defined and controlled. The cleaning process prior to the bio-decontamination step is essential; any residues that remain may inhibit the effectiveness of the decontamination process. Evidence should also be available to demonstrate that the cleaning and bio- decontamination agents used do not have adverse impact on the product produced within the RABS or isolator. i. For isolators The bio-decontamination process of the interior should be automated, validated and controlled within defined cycle parameters and should include a sporicidal agent in a suitable form (e.g. gaseous or vaporized form). Gloves should be appropriately extended with fingers separated to ensure contact with the agent. Methods used (cleaning and sporicidal bio-decontamination) should render the interior surfaces and critical zone of the isolator free from viable microorganisms. ii. For RABS The sporicidal disinfection should include the routine application of a sporicidal agent using a method that has been validated and demonstrated to robustly include all areas of the interior surfaces and ensure a suitable environment for aseptic processing. Cleanroom and clean air equipment qualification 4.23 Cleanrooms and clean air equipment such as unidirectional airflow units (UDAFs), RABS and isolators, used for the manufacture of sterile products, should be qualified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimize the risk of contamination of the product or materials being handled. Appropriate cleanliness levels in the “at rest” and “operational” states should be maintained. 4.24 Cleanrooms and clean air equipment should be qualified using methodology in accordance with the requirements of Annex 15. Cleanroom qualification (including classification) should be clearly differentiated from operational environmental monitoring. 4.25 Cleanroom and clean air equipment qualification is the overall process of assessing the level of compliance of a classified cleanroom or clean air equipment with its intended use. As part of the qualification requirements of Annex 15, the qualification of cleanrooms and clean air equipment should include (where relevant to the design/operation of the installation): i. Installed filter system leakage and integrity testing. ii. Airflow tests - volume and velocity. iii. Air pressure difference test. iv. Airflow direction test and visualisation. v. Microbial airborne and surface contamination. vi. Temperature measurement test. vii. Relative humidity test. 11  viii. Recovery test. ix. Containment leak test. Reference for the qualification of the cleanrooms and clean air equipment can be found in the ISO 14644 series of standards. 4.26 Cleanroom classification is part of the cleanroom qualification and is a method of assessing the level of air cleanliness against a specification for a cleanroom or clean air equipment by measuring the total particle concentration. Classification activities should be scheduled and performed in order to avoid any impact on process or product quality. For example, initial classification should be performed during simulated operations and reclassification performed during simulated operations or during aseptic process simulation (APS). 4.27 For cleanroom classification, the total of particles equal to or greater than 0.5 and 5 µm should be measured. This measurement should be performed both at rest and in simulated operations in accordance with the limits specified in Table 1. Table 1: Maximum permitted total particle concentration for classification Maximum limits for total particle Maximum limits for total particle Grade ≥ 0.5 µm/m3 ≥ 5 µm/m3 at rest in operation at rest in operation A 3 520 3 520 Not specified (a) Not specified (a) B 3 520 352 000 Not specified (a) 2 930 C 352 000 3 520 000 2 930 29 300 3 520 000 Not 29 300 Not D predetermined (b) predetermined (b) (a) Classification including 5µm particles may be considered where indicated by the CCS or historical trends. (b) For grade D, in operation limits are not predetermined. The manufacturer should establish in operation limits based on a risk assessment and routine data where applicable. 4.28 For classification of the cleanroom, the minimum number of sampling locations and their positioning can be found in ISO 14644 Part 1. For the aseptic processing area and the background environment (the grade A and grade B areas, respectively), additional sample locations should be considered and all critical processing areas such as the point of fill and container closure feeder bowls should be evaluated. Critical processing locations should be determined by documented risk assessment and knowledge of the process and operations to be performed in the area. 4.29 Cleanroom classification should be carried out in the “at rest” and “in operation” states. i. The definition of “at rest” state is the condition whereby the installation of all the utilities is complete including any functioning HVAC, with the main manufacturing equipment installed as specified but not operating and without personnel present in the room. 12  ii. The definition of “in operation” state is the condition where the installation of the cleanroom is complete, the HVAC system fully operational, equipment installed and functioning in the manufacturer’s defined operating mode with the maximum number of personnel present performing or simulating routine operational work. iii. The total particle limits given in Table 1 above for the “at rest” state should be achieved after a “clean up” period on completion of operations and line clearance/cleaning activities. The "clean up" period (guidance value of less than 20 minutes) should be determined during the qualification of the rooms, documented and adhered to in procedures to reinstate a qualified state of cleanliness if disrupted during operation. 4.30 The speed of air supplied by unidirectional airflow systems should be clearly justified in the qualification protocol including the location for air speed measurement. Air speed should be designed, measured and maintained to ensure that appropriate unidirectional air movement provides protection of the product and open components at the working position (e.g. where high-risk operations occur and where product and/or components are exposed). Unidirectional airflow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value) at the working position, unless otherwise scientifically justified in the CCS. Airflow visualization studies should correlate with the air speed measurement. 4.31 The microbial contamination level of the cleanrooms should be determined as part of the cleanroom qualification. The number of sampling locations should be based on a documented risk assessment and the results obtained from room classification, air visualization studies and knowledge of the process and operations to be performed in the area. The maximum limits for microbial contamination during qualification for each grade are given in Table 2. Qualification should include both “at rest” and “in operation” states. Table 2: Maximum permitted microbial contamination level during qualification Settle plates Contact plates Grade Air sample (diameter 90 mm) (diameter 55 CFU/m3 CFU/4 hours (a) mm) CFU/plate A No growth B 10 5 5 C 100 50 25 D 200 100 50 (a) Settle plates should be exposed for the duration of operations and changed as required after a maximum of 4 hours. Exposure time should be based on recovery studies and should not allow desiccation of the media used. Note 1: All methods indicated for a specific grade in the table should be used for qualifying the area of that specific grade. If one of the methods tabulated is not used, or alternative methods are used, the approach taken should be appropriately justified. Note 2: Limits are applied using CFU throughout the document. If different or new technologies are used that present results in a manner different from CFU, the manufacturer should scientifically justify the limits applied and where possible correlate them to CFU. Note 3: For the qualification of personnel gowning, the limits given for contact plates and glove prints in Table 6 should apply. Note 4: Sampling methods should not pose a risk of contamination to the manufacturing operations. 13 4.32 The requalification of cleanrooms and clean air equipment should be carried out periodically following defined procedures. The requalification should include at a minimum the following: - Cleanroom classification (total particle concentration). - Integrity test of final filters. - Airflow volume measurement. - Verification of air pressure difference between rooms. - Air velocity test (Note: For grade B, C and D the air velocity test should be performed according to a risk assessment documented as part of the CCS. However, it is required for filling zones supplied with unidirectional airflow (e.g. when filling terminally sterilised products or background to grade A and RABS). For grades with non-unidirectional airflow, a measurement of recovery testing should replace velocity testing). The maximum time interval for requalification of grade A & B areas, is 6 months. The maximum time interval for requalification of grade C & D areas, is 12 months. Appropriate requalification consisting of at least the above tests should also be carried out following completion of remedial action implemented to rectify an out of compliance equipment or facility condition or after changes to equipment, facility or processes as appropriate. The significance of a change should be determined through the change management process. Examples of changes to be considered include but are not limited to the following: i. Interruption of air movement which affects the operation of the installation. ii. Change in the design of the cleanroom or of the operational setting parameters of the HVAC system. iii. Special maintenance which affects the operation of the installation (e.g. change of final filters). Disinfection 4.33 The disinfection of cleanrooms is particularly important. They should be cleaned and disinfected thoroughly in accordance with a written programme. For disinfection to be effective, prior cleaning to remove surface contamination should be performed. Cleaning programmes should effectively remove disinfectant residues. More than one type of disinfecting agent should be employed to ensure that where they have different modes of action, their combined usage is effective against bacteria and fungi. Disinfection should include the periodic use of a sporicidal agent. Monitoring should be undertaken regularly in order to assess the effectiveness of the disinfection programme and to detect changes in types of microbial flora (e.g. organisms resistant to the disinfection regime currently in use). 4.34 The disinfection process should be validated. Validation studies should demonstrate the suitability and effectiveness of disinfectants in the specific manner in which they are used and on the type of surface material, or representative material if justified, and should support the in-use expiry periods of prepared solutions. 4.35 Disinfectants and detergents used in grade A and grade B areas should be sterile prior to use. Disinfectants used in grade C and D may also be required to be sterile where determined in the CCS. Where the disinfectants and detergents are diluted / prepared by the sterile product manufacturer, this 14 should be done in a manner to prevent contamination and they should be monitored for microbial contamination. Dilutions should be kept in previously cleaned containers (and sterilized where applicable) and should only be stored for the defined period. If the disinfectants and detergents are supplied “ready-made” then results from certificates of analysis or conformance can be accepted subject to successful completion of the appropriate vendor qualification. 4.36 Where fumigation or vapour disinfection (e.g. Vapour-phase Hydrogen Peroxide) of cleanrooms and associated surfaces are used, the effectiveness of any fumigation agent and dispersion system should be understood and validated. 5 Equipment 5.1 A written, detailed description of the equipment design should be available (including process and instrumentation diagrams as appropriate). This should form part of the initial qualification package and be kept up to date. 5.2 Equipment monitoring requirements should be defined in “user requirements specifications” during early stages of development, and confirmed during qualification. Process and equipment alarm events should be acknowledged and evaluated for trends. The frequency at which alarms are assessed should be based on their criticality (with critical alarms reviewed immediately). 5.3 As far as practicable, equipment, fittings and services should be designed and installed so that operations, maintenance, and repairs can be performed outside the cleanroom. If maintenance has to be performed in the cleanroom, and the required standards of cleanliness and/or asepsis cannot be maintained, then precautions such as restricting access to the work area to specified personnel, generation of clearly defined work protocols and maintenance procedures should be considered. Additional cleaning, disinfection and environmental monitoring should also be considered. If sterilisation of equipment is required, it should be carried out, wherever possible, after complete reassembly. 5.4 The cleaning process should be validated to be able to: i. Remove any residue or debris that would detrimentally impact the effectiveness of the disinfecting agent used. ii. Minimize chemical, microbial and particulate contamination of the product during the process and prior to disinfection. 5.5 For aseptic processes, direct and indirect product contact parts should be sterilised. Direct product contact parts are those that the product passes through, such as filling needles or pumps. Indirect product contact parts are equipment parts that do not contact the product, but may come into contact with other sterilised surfaces, the sterility of which is critical to the overall product sterility (e.g. sterilised items such as stopper bowls and guides, and sterilised components). 5.6 All equipment such as sterilisers, air handling systems (including air filtration) and water systems should be subject to qualification, monitoring and planned maintenance. Upon completion of maintenance, their return to use should be approved. 5.7 Where unplanned maintenance of equipment critical to the sterility of the product is to be carried out, an assessment of the potential impact to the sterility of the product should be performed and recorded. 5.8 A conveyor belt should not pass through a partition between a grade A or B area and a processing area of lower air cleanliness, unless the belt itself is continually sterilised (e.g. in a sterilising tunnel). 15 5.9 Particle counters, including sampling tubing, should be qualified. The manufacturer’s recommended specifications should be considered for tube diameter and bend radii. Tube length should typically be no longer than 1m unless justified and the number of bends should be minimized. Portable particle counters with a short length of sample tubing should be used for classification purposes. Isokinetic sampling heads should be used in unidirectional airflow systems. They should be oriented appropriately and positioned as close as possible to the critical location to ensure that samples are representative. 6 Utilities 6.1 The nature and extent of controls applied to utility systems should be commensurate with the risk to product quality associated with the utility. The impact should be determined via a risk assessment and documented as part of the CCS. 6.2 In general, higher risk utilities are those that: i. Directly contact product e.g. water for washing and rinsing, gases and steam for sterilisation. ii. Contact materials that will ultimately become part of the product. iii. Contact surfaces that come into contact with the product. iv. Otherwise directly impact the product. 6.3 Utilities should be designed, installed, qualified, operated, maintained and monitored in a manner to ensure that the utility system functions as expected. 6.4 Results for critical parameters and critical quality attributes of high risk utilities should be subject to regular trend analysis to ensure that system capabilities remain appropriate. 6.5 Records of utility system installation should be maintained throughout the system’s life-cycle. Such records should include current drawings and schematic diagrams, construction material lists and system specifications. Typically, important information includes attributes such as: i. Pipeline flow direction, slopes, diameter and length. ii. Tank and vessel details. iii. Valves, filters, drains, sampling and user points. 6.6 Pipes, ducts and other utilities should not be present in cleanrooms. If unavoidable, then they should be installed so that they do not create recesses, unsealed openings and surfaces which are difficult to clean. Installation should allow cleaning and disinfection of outer surface of the pipes. Water systems 6.7 Water treatment plant and distribution systems should be designed, constructed, installed, commissioned, qualified, monitored and maintained to prevent microbiological contamination and to ensure a reliable source of water of an appropriate quality. Measures should be taken to minimize the risk of presence of particulates, microbial contamination/proliferation and endotoxin/pyrogen (e.g. sloping of piping to provide complete drainage and the avoidance of dead legs). Where filters are included in the system, special attention should be given to their monitoring and maintenance. Water produced should comply with the current monograph of the relevant Pharmacopeia. 6.8 Water systems should be qualified and validated to maintain the appropriate levels of physical, 16 chemical and microbial control, taking the effect of seasonal variation into account. 6.9 Water flow should remain turbulent through the pipes in water distribution systems to minimize the risk of microbial adhesion, and subsequent biofilm formation. The flow rate should be established during qualification and be routinely monitored. 6.10 Water for injections (WFI) should be produced from water meeting specifications that have been defined during the qualification process, stored and distributed in a manner which minimizes the risk of microbial growth (e.g. by constant circulation at a temperature above 70°C). WFI should be produced by distillation or by a purification process that is equivalent to distillation. This may include reverse osmosis coupled with other appropriate techniques such as electrodeionization (EDI), ultrafiltration or nanofiltration. 6.11 Where WFI storage tanks are equipped with hydrophobic bacteria retentive vent filters, the filters should not be a source of contamination and the integrity of the filter tested before installation and after use. Controls should be in place to prevent condensation formation on the filter (e.g. by heating). 6.12 To minimize the risk of biofilm formation, sterilisation, disinfection or regeneration of water systems should be carried out according to a predetermined schedule and as a remedial action following out-of-limit or specification results. Disinfection of a water system with chemicals should be followed by a validated rinsing/flushing procedure. Water should be tested after disinfection/regeneration. Chemical testing results should be approved before the water system is returned to use and microbiological/endotoxin results verified to be within specification and approved before batches manufactured using water from the system are considered for certification/release. 6.13 Regular ongoing chemical and microbial monitoring of water systems should be performed to ensure that the water continues to meet compendial expectations. Alert levels should be based on the initial qualification data and thereafter periodically reassessed on data obtained during subsequent re-qualifications, routine monitoring, and investigations. Review of ongoing monitoring data should be carried out to identify any adverse trend in system performance. Sampling programmes should reflect the requirements of the CCS and should include all outlets and points of use, at a specified interval, to ensure that representative water samples are obtained for analysis on a regular basis. Sample plans should be based on the qualification data, should consider the potential worst case sampling locations and should ensure that at least one representative sample is included every day of the water that is used for manufacturing processes. 6.14 Alert level excursions should be documented and reviewed, and include an investigation to determine whether the excursion is a single (isolated) event or if results are indicative of an adverse trend or system deterioration. Each action limit excursion should be investigated to determine the probable root causes and any potential impact on the quality of products and manufacturing processes as a result of the use of the water. 6.15 WFI systems should include continuous monitoring systems such as Total Organic Carbon (TOC) and conductivity, as these may give a better indication of overall system performance than discrete sampling. Sensor locations should be based on risk. Steam used as a direct sterilising agent 6.16 Feed water to a pure steam (clean steam) generator should be appropriately purified. Pure steam generators should be designed, qualified and operated in a manner to ensure that the quality of steam produced meets defined chemical and endotoxin levels. 6.17 Steam used as a direct sterilising agent should be of suitable quality and should not contain 17 additives at a level that could cause contamination of product or equipment. For a generator supplying pure steam used for the direct sterilisation of materials or product-contact surfaces (e.g. porous hard-good autoclave loads), steam condensate should meet the current monograph for WFI of the relevant Pharmacopeia (microbial testing is not mandatory for steam condensate). A suitable sampling schedule should be in place to ensure that representative pure steam is obtained for analysis on a regular basis. Other aspects of the quality of pure steam used for sterilisation should be assessed periodically against validated parameters. These parameters should include the following (unless otherwise justified): non-condensable gases, dryness value (dryness fraction) and superheat. Gases and vacuum systems 6.18 Gases that come in direct contact with the product/primary container surfaces should be of appropriate chemical, particulate and microbial quality. All relevant parameters, including oil and water content, should be specified, taking into account the use and type of the gas, the design of the gas generation system and, where applicable, comply with the current monograph of the relevant Pharmacopeia or the product quality requirement. 6.19 Gases used in aseptic processes should be filtered through a sterilising grade filter (with a nominal pore size of a maximum of 0.22 µm) at the point of use. Where the filter is used on a batch basis (e.g. for filtration of gas used for overlay of aseptically filled products) or as product vessel vent filter, then the filter should be integrity tested and the results reviewed as part of the batch certification/release process. Any transfer pipework or tubing that is located after the final sterilising grade filter should be sterilised. When gases are used in the process, microbial monitoring of the gas should be performed periodically at the point of use. 6.20 Where backflow from vacuum or pressure systems poses a potential risk to the product, there should be mechanism(s) to prevent backflow when the vacuum or pressure system is shut off. Heating and cooling and hydraulic systems 6.21 Major items of equipment associated with hydraulic, heating and cooling systems should, where possible, be located outside the filling room. There should be appropriate controls to contain any spillage and/or cross contamination associated with the system fluids. 6.22 Any leaks from these systems that would present a risk to the product should be detectable (e.g. an indication system for leakage). 7 Personnel 7.1 The manufacturer should ensure that there are sufficient appropriate personnel, suitably qualified, trained and experienced in the manufacture and testing of sterile products, and any of the specific manufacturing technologies used in the site’s manufacturing operations, to ensure compliance with GMP applicable to the manufacture and handling of sterile products. 7.2 Only the minimum number of personnel required should be present in cleanrooms. The maximum number of operators in cleanrooms should be determined, documented and considered during activities such as initial qualification and APS, so as not to compromise sterility assurance. 7.3 All personnel including those performing cleaning, maintenance, monitoring and those that access cleanrooms should receive regular training, gowning qualification and assessment in disciplines relevant to the correct manufacture of sterile products. This training should include the basic elements of microbiology and hygiene, with a specific focus on cleanroom practices, contamination control, aseptic techniques and the protection of sterile products (for those operators entering the grade B cleanrooms and/or intervening into grade A) and the potential safety implications to the patient if the product is not sterile. The level of training should be based on the 18 criticality of the function and area in which the personnel are working. 7.4 The personnel accessing grade A and B areas should be trained for aseptic gowning and aseptic behaviours. Compliance with aseptic gowning procedures should be confirmed by assessment and periodic reassessment at least annually, and should involve both visual and microbial assessment (using monitoring locations such as gloved fingers, forearms, chest and hood (facemask / forehead). See paragraph 9.30 for the expected limits). The unsupervised access to the grade A and grade B areas where aseptic operations are or will be conducted should be restricted to appropriately qualified personnel, who have passed the gowning assessment and have participated in a successful APS. 7.5 Unqualified personnel should not enter grade B cleanrooms or grade A in operation. If needed in exceptional cases, manufacturers should establish written procedures outlining the process by which unqualified personnel are brought into the grade B and A areas. An authorized person from the manufacturer should supervise the unqualified personnel during their activities and should assess the impact of these activities on the cleanliness of the area. Access by these persons should be assessed and recorded in accordance with the PQS. 7.6 There should be systems in place for the disqualification of personnel from working in or given unsupervised entry into cleanrooms that is based on aspects including ongoing assessment and/or identification of an adverse trend from the personnel monitoring programme and/or after being implicated in a failed APS. Once disqualified, retraining and requalification should be completed before permitting the operator to have any further involvement in aseptic practices. For operators entering grade B cleanrooms or performing intervention into grade A, this requalification should include consideration of participation in a successful APS. 7.7 High standards of personal hygiene and cleanliness are essential to prevent excessive shedding or increased risk of introduction of microbial contamination. Personnel involved in the manufacture of sterile products should be instructed to report any specific health conditions or ailments that may cause the shedding of abnormal numbers or types of contaminants and therefore preclude cleanroom access. Health conditions and actions to be taken with regard to personnel who could be introducing an undue microbial hazard should be provided by the designated competent person and described in procedures. 7.8 Personnel who have been engaged in the processing of human or animal tissue materials or of cultures of micro-organisms, other than those used in the current manufacturing process, or any activities that may have a negative impact to quality (e.g. microbial contamination), should not enter clean areas unless clearly defined and effective decontamination and entry procedures have been followed and documented. 7.9 Wristwatches, make-up, jewellery, other personal items such as mobile phones and any other non-essential items should not be allowed in clean areas. Electronic devices used in cleanrooms, e.g. mobile phones and tablets, that are supplied by the manufacturer solely for use in the cleanrooms, may be acceptable if suitably designed to permit cleaning and disinfection commensurate with the grade in which they are used. The use and disinfection of such equipment should be included in the CCS. 7.10 Cleanroom gowning and hand washing should follow a written procedure designed to minimize contamination of cleanroom clothing and/or the transfer of contaminants to the clean areas. 7.11 The clothing and its quality should be appropriate for the process and the grade of the working area. It should be worn in such a way as to protect the product from contamination. When the type of clothing chosen needs to provide the operator protection from the product, it should not compromise the protection of the product from contamination. Garments should be visually checked for cleanliness and integrity immediately prior to and after gowning. Gown integrity should also be 19 checked upon exit. For sterilised garments and eye coverings, particular attention should be taken to ensure they have been subject to the sterilisation process, are within their specified hold time and that the packaging is visually inspected to ensure it is integral before use. Reusable garments (including eye coverings) should be replaced if damage is identified, or at a set frequency that is determined during qualification studies. The qualification of garments should consider any necessary garment testing requirements, including damage to garments that may not be identified by visual inspection alone. 7.12 Clothing should be chosen to limit shedding due to operators’ movement. 7.13 A description of typical clothing required for each cleanliness grade is given below: i. Grade B (including access / interventions into grade A): appropriate garments that are dedicated for use under a sterilised suit should be worn before gowning (see paragraph 7.14). Appropriately sterilised, non-powdered, rubber or plastic gloves should be worn while donning the sterilised garments. Sterile headgear should enclose all hair (including facial hair) and where separate from the rest of the gown, it should be tucked into the neck of the sterile suit. A sterile facemask and sterile eye coverings (e.g. goggles) should be worn to cover and enclose all facial skin and prevent the shedding of droplets and particles. Appropriate sterilised footwear (e.g. over-boots) should be worn. Trouser legs should be tucked inside the footwear. Garment sleeves should be tucked into a second pair of sterile gloves worn over the pair worn while donning the gown. The protective clothing should minimize shedding of fibres or particles and retain particles shed by the body. The particle shedding and the particle retention efficiencies of the garments should be assessed during the garment qualification. Garments should be packed and folded in such a way as to allow operators to don the gown without contacting the outer surface of the garment and to prevent the garment from touching the floor. ii. Grade C: Hair, beards and moustaches should be covered. A single or two-piece trouser suit gathered at the wrists and with high neck and appropriately disinfected shoes or overshoes should be worn. They should minimize the shedding of fibres and particles. iii. Grade D: Hair, beards and moustaches should be covered. A general protective suit and appropriately disinfected shoes or overshoes should be worn. Appropriate measures should be taken to avoid any ingress of contaminants from outside the clean area. iv. Additional gowning including gloves and facemask may be required in grade C and D areas when performing activities considered to be a contamination risk as defined by the CCS. 7.14 Cleanroom gowning should be performed in change rooms of an appropriate cleanliness grade to ensure gown cleanliness is maintained. Outdoor clothing including socks (other than personal underwear) should not be brought into changing rooms leading directly to grade B and C areas. Single or two-piece facility trouser suits, covering the full length of the arms and the legs, and facility socks covering the feet, should be worn before entry to change rooms for grades B and C. Facility suits and socks should not present a risk of contamination to the gowning area or processes. 7.15 Every operator entering grade B or A areas should gown into clean, sterilised protective garments (including eye coverings and masks) of an appropriate size at each entry. The maximum period for which the sterilised gown may be worn before replacement during a shift should be defined as part of the garment qualification. 7.16 Gloves should be regularly disinfected during operations. Garments and gloves should be changed immediately if they become damaged and present any risk of product contamination. 7.17 Reusable clean area clothing should be cleaned in a laundry facility adequately segregated from production operations, using a qualified process ensuring that the clothing is not damaged and/or contaminated by fibres or particles during the repeated laundry process. Laundry facilities used should not introduce risk of contamination or cross-contamination. Inappropriate handling and use of 20 clothing may damage fibres and increase the risk of shedding of particles. After washing and before packing, garments should be visually inspected for damage and visual cleanliness. The garment management processes should be evaluated and determined as part of the garment qualification programme and should include a maximum number of laundry and sterilisation cycles. 7.18 Activities in clean areas that are not critical to the production processes should be kept to a minimum, especially when aseptic operations are in progress. Movement of personnel should be slow, controlled and methodical to avoid excessive shedding of particles and organisms due to over-vigorous activity. Operators performing aseptic operations should adhere to aseptic technique at all times to prevent changes in air currents that may introduce air of lower quality into the critical zone. Movement adjacent to the critical zone should be restricted and the obstruction of the path of the unidirectional (first air) airflow should be avoided. A review of airflow visualisation studies should be considered as part of the training programme. 8 Production and Specific Technologies Terminally sterilised products 8.1 Preparation of components and materials should be performed in at least a grade D cleanroom in order to limit the risk of microbial, endotoxin/pyrogen and particle contamination, so that the product is suitable for sterilisation. Where the product is at a high or unusual risk of microbial contamination (e.g. the product actively supports microbial growth, the product must be held for long periods before filling or the product is not processed mostly in closed vessels), then preparation should be carried out in at least a grade C environment. Preparation of ointments, creams, suspensions and emulsions should be carried out in at least a grade C environment before terminal sterilisation. Specific guidance regarding terminally sterilised veterinary medicinal products can be found within Annex 4 of the GMP guidelines. 8.2 Primary packaging containers and components should be cleaned using validated processes to ensure that particle, endotoxin/pyrogen and bioburden contamination is appropriately controlled. 8.3 Filling of products for terminal sterilisation should be carried out in at least a grade C environment. 8.4 Where the CCS identifies that the product is at an unusual risk of contamination from the environment because, for example, the filling operation is slow, the containers are wide necked or are necessarily exposed for more than a few seconds before closing, then the product should be filled in grade A with at least a grade C background. 8.5 Processing of the bulk solution should include a filtration step with a microorganism retaining filter, where possible, to reduce bioburden levels and particles prior to filling into the final product containers and there should be a maximum permissible time between preparation and filling. 8.6 Examples of operations to be carried out in the various grades are given in Table 3. Table 3: Examples of operations and grades for terminally sterilised preparation and processing operations Grade A - Filling of products, when unusually at risk. Grade C - Preparation of solutions, when unusually at risk. - Filling of products. Grade D - Preparation of solutions and components for subsequent filling. 21 Aseptic preparation and processing 8.7 The aseptic process should be clearly defined. The risks associated with the aseptic process, and any associated requirements, should be identified, assessed and appropriately controlled. The site’s CCS should clearly define the acceptance criteria for these controls, requirements for monitoring and the review of their effectiveness. Methods and procedures to control these risks should be described and implemented. Accepted residual risks should be formally documented. 8.8 Precautions to minimize microbial, endotoxin/pyrogenic and particle contamination should be taken, as per the site’s CCS, during the preparation of the aseptic environment, during all processing stages (including the stages before and after bulk product sterilisation), and until the product is sealed in its final container. The presence of materials liable to generate particles and fibres should be minimized in cleanrooms. 8.9 Where possible, the use of equipment such as RABS, isolators or other systems, should be considered in order to reduce the need for critical interventions into grade A and to minimize the risk of contamination. Robotics and automation of processes can also be considered to eliminate direct human critical interventions (e.g. dry heat tunnel, automated lyophilizer loading, sterilisation in place). 8.10 Examples of operations to be carried out in the various environmental grades are given in Table 4. Table 4: Examples of operations and grades for aseptic preparation and processing operations - Aseptic assembly of filling equipment. - Connections made under aseptic conditions (where sterilised product contact surfaces are exposed) that are post the final sterilising grade filter. These connections should be sterilised by steam-in-place whenever possible. - Aseptic compounding and mixing. - Replenishment of sterile bulk product, containers and closures. Grade A - Removal and cooling of unprotected (e.g. with no packaging) items from sterilisers. - Staging and conveying of sterile primary packaging components in the aseptic filling line while not wrapped. - Aseptic filling, sealing of containers such as ampoules, vial closure, transfer of open or partially stoppered vials. - Loading of a lyophilizer. - Background support for grade A (when not in an isolator). Grade B - Conveying or staging, while protected from the surrounding environment, of equipment, components and ancillary items for introduction into grade A. Grade C - Preparation of solutions to be filtered including sampling and dispensing. - Cleaning of equipment. - Handling of components, equipment and accessories after cleaning. Grade D - Assembly under HEPA filtered airflow of cleaned components, equipment and accessories prior to sterilisation. - Assembly of closed and sterilised SUS using intrinsic sterile connection devices. 22  8.11 For sterile products where the final formulation cannot be filtered, the following should be considered: i. All product and component contact equipment should be sterilised prior to use. ii. All raw materials or intermediates should be sterilised and aseptically added. iii. Bulk solutions or intermediates should be sterilised. 8.12 The unwrapping, assembly and preparation of sterilised equipment, components and ancillary items with direct or indirect product contact should be treated as an aseptic process and performed in grade A with a grade B background. The filling line set-up and filling of the sterile product should be treated as an aseptic process and performed in grade A with a grade B background. Where an isolator is used, the background should be in accordance with paragraph 4.20. 8.13 Preparation and filling of sterile products such as ointments, creams, suspensions and emulsions should be performed in grade A with a grade B background when the product and components are exposed to the environment and the product is not subsequently filtered (via a sterilising grade filter) or terminally sterilised. Where an isolator or RABS is used, the background should be in accordance with paragraph 4.20. 8.14 Aseptic connections should be performed in grade A with a grade B background unless subsequently sterilised in place or conducted with intrinsic sterile connection devices that minimize any potential contamination from the immediate environment. Intrinsic sterile connection devices should be designed to mitigate risk of contamination. Where an isolator is used, the background should be in accordance with paragraph 4.20. Aseptic connections should be appropriately assessed and their effectiveness verified. For requirements regarding intrinsic sterile connection devices see paragraphs 8.129 and 8.130. 8.15 Aseptic manipulations (including non-intrinsic sterile connection devices) should be minimized through the use of engineering design solutions such as preassembled and sterilised equipment. Whenever feasible, product contact piping and equipment should be pre-assembled, and sterilised in place. 8.16 There should be an authorized list of allowed and qualified interventions, both inherent and corrective, that may occur during production (see paragraph 9.34). Interventions should be carefully designed to ensure that the risk of contamination of the environment, process and product is effectively minimized. The process of designing interventions should include the consideration of any impact on air-flows and critical surfaces and products. Engineering solutions should be used whenever possible to minimize incursion by operators during the intervention. Aseptic technique should be observed at all times, including the appropriate use of sterile tools for manipulations. The procedures listing the types of inherent and corrective interventions, and how to perform them, should be first evaluated via risk management and APS and be kept up to date. Non-qualified interventions should only be used in exceptional circumstances, with due consideration of the risks associated with the intervention and with the authorisation of the quality unit. The details of the intervention conducted should be subject to risk assessment, recorded and fully investigated under the manufacturer's PQS. Any non-qualified interventions should be thoroughly assessed by the quality department and considered during batch disposition. 8.17 Interventions and stoppages should be recorded in the batch record. Each line stoppage or intervention should be sufficiently documented in batch records with the associated time, duration of the event, and operators involved (ref to paragraph 9.34). 23 8.18 The duration of each aspect of aseptic preparation and processing should be minimized and limited to a defined and validated maximum time, including: i. The holding time between equipment, component, and container cleaning, drying and sterilisation. ii. The holding time for sterilised equipment, components, and containers before use and during filling/assembly. iii. The holding time for a decontaminated environment, such as the RABS or isolator before use. iv. The time between the start of the preparation of a product and its sterilisation or filtration through a microorganism-retaining filter (if applicable), through to the end of the aseptic filling process. There should be a maximum permissible time for each product that takes into account its composition and the prescribed method of storage. v. The holding time for sterilised product prior to filling. vi. The aseptic processing time. vii. The filling time. 8.19 Aseptic operations (including APS) should be observed on a regular basis by personnel with specific expertise in aseptic processing to verify the correct performance of operations including operator behaviour in the cleanroom and address inappropriate practices if detected. Finishing of sterile products 8.20 Open primary packaging containers should be maintained under grade A conditions with the appropriate background for the technology as described in paragraph 4.20. For partially stoppered vials or prefilled syringes (see paragraph 8.126). 8.21 Final containers should be closed by appropriately validated methods. 8.22 Where final containers are closed by fusion, e.g. Blow-Fill-Seal (BFS), Form-Fill-Seal (FFS), Small and Large Volume Parenteral (SVP & LVP) bags, glass or plastic ampoules, the critical parameters and variables that affect seal integrity should be evaluated, determined, effectively controlled and monitored during operations. Glass ampoules, BFS units and small volume containers (≤100 ml) closed by fusion should be subject to 100% integrity testing using validated methods. For large volume containers (>100 ml) closed by fusion, reduced sampling may be acceptable where scientifically justified and based on data demonstrating the consistency of the existing process, and a high level of process control. It should be noted that visual inspection is not considered as an acceptable integrity test method. 8.23 Samples of products using systems other than fusion should be taken and checked for integrity using validated methods. The frequency of testing should be based on the knowledge and experience of the container and closure systems being used. A scientifically justified sampling plan should be used. The sample size should be based on information such as supplier management, packaging component specifications and process knowledge. 8.24 Containers sealed under vacuum should be tested for maintenance of vacuum after an appropriate pre-determined period prior to certification/release and during shelf life. 24 8.25 The container closure integrity validation should take into consideration any transportation or shipping requirements that may negatively impact the integrity of the container (e.g. by decompression or extreme temperatures). 8.26 Where the equipment used to crimp vial caps can generate large quantities of non-viable particle, measures to prevent particle contamination such as locating the equipment at a physically separate station equipped with adequate air extraction should be taken. 8.27 Vial capping of aseptically filled products can be undertaken as an aseptic process using sterilised caps or as a clean process outside the aseptic processing area. Where the latter approach is adopted, vials should be protected by grade A conditions up to the point of leaving the aseptic processing area, and thereafter stoppered vials should be protected with a grade A air supply until the cap has been crimped. The supporting background environment of grade A air supply should meet at least grade D requirements. Where capping is a manual process, it should be performed under grade A conditions either in an appropriately designed isolator or in grade A with a grade B background. 8.28 Where capping of aseptically filled sterile product is conducted as a clean process with grade A air supply protection, vials with missing or displaced stoppers should be rejected prior to capping. Appropriately qualified, automated methods for stopper height detection should be in place. 8.29 Where human intervention is required at the capping station, appropriate technological and organizational measures should be used to prevent direct contact with the vials and to minimize contamination. RABS and isolators may be beneficial in assuring the required conditions 8.30 All filled containers of parenteral products should be inspected individually for extraneous contamination or other defects. Defect classification and criticality should be determined during qualification and based on risk and historical knowledge. Factors to consider include, but are not limited to, the potential impact of the defect to the patient and the route of administration. Different defect types should be categorized and batch performance analysed. Batches with unusual levels of defects, when compared with routine defect numbers for the process (based on routine and trend data), should be investigated. A defect library should be generated and maintained which captures all known classes of defects. The defect library should be used for the training of production and quality assurance personnel. Critical defects should not be identified during any subsequent sampling and inspection of acceptable containers. Any critical defect identified subsequently should trigger an investigation as it indicates a possible failure of the original inspection process. 8.31 When inspection is performed manually, it should be conducted under suitable and controlled conditions of illumination and background. Inspection rates should be appropriately controlled and qualified. Operators performing the inspection should undergo visual inspection qualification (whilst wearing corrective lenses, if these are normally worn) at least annually. The qualification should be undertaken using appropriate samples from the manufacturer's defect library sets and taking into consideration worst case scenarios (e.g. inspection time, line speed where the product is transferred to the operator by a conveyor system, container size or fatigue) and should include consideration of eyesight checks. Operator distractions should be minimized and frequent breaks, of an appropriate duration, should be taken from inspection. 8.32 Where automated methods of inspection are used, the process should be validated to detect known defects (which may impact product quality or safety) and be equal to, or better than, manual inspection methods. The performance of the equipment should be challenged using representative defects prior to start up and at regular intervals throughout the batch. 8.33 Results of the inspection should be recorded and defect types and numbers trended. Reject levels for the various defect types should also be trended based on statistical principles. Impact to product on the market should be assessed as part of the investigation when adverse trends are observed. 25 Sterilisation 8.34 Where possible, finished product should be terminally sterilised, using a validated and controlled sterilisation process, as this provides a greater assurance of sterility than a validated and controlled sterile filtration process and/or aseptic processing. Where it is not possible for a product to undergo terminal sterilisation, consideration should be given to using post-aseptic processing terminal heat treatment, combined with aseptic process to give improved sterility assurance. 8.35 The selection, design and location of the equipment and cycle/programme used for sterilisation should be based on scientific principles and data which demonstrate repeatability and reliability of the sterilisation process. All parameters should be defined, and where critical, these should be controlled, monitored and recorded. 8.36 All sterilisation processes should be validated. Validation studies should take into account the product composition, storage conditions and maximum time between the start of the preparation of a product or material to be sterilised and its sterilisation. Before any sterilisation process is adopted, its suitability for the product and equipment, and its efficacy in consistently achieving the desired sterilising conditions in all parts of each type of load to be processed should be validated notably by physical measurements and where appropriate by Biological Indicators (BI). For effective sterilisation, the whole of the product, and surfaces of equipment and components should be subject to the required treatment and the process should be designed to ensure that this is achieved. 8.37 Particular attention should be given when the adopted product sterilisation method is not described in the current edition of the Pharmacopoeia, or when it is used for a product which is not a simple aqueous solution. Where possible, heat sterilisation is the method of choice. 8.38 Validated loading patterns should be established for all sterilisation processes and load patterns should be subject to periodic revalidation. Maximum and minimum loads should also be considered as part of the overall load validation strategy. 8.39 The validity of the sterilizing process should be reviewed and verified at scheduled intervals based on risk. Heat sterilization cycles should be revalidated with a minimum frequency of at least annually for load patterns that are considered worst case. Other load patterns should be validated at a frequency justified in the CCS. 8.40 Routine operating parameters should be established and adhered to for all sterilisation processes, e.g. physical parameters and loading patterns. 8.41 There should be mechanisms in place to detect a sterilisation cycle that does not conform to the validated parameters. Any failed sterilisation or sterilisation that deviated from the validated process (e.g. have longer or shorter phases such as heating cycles) should be investigated. 8.42 Suitable BIs placed at appropriate locations should be considered as an additional method to support the validation of the sterilisation process. BIs should be stored and used according to the manufacturer’s instructions. Where BIs are used to support validation and/or to monitor a sterilisation process (e.g. with ethylene oxide), positive controls should be tested for each sterilisation cycle. If BIs are used, strict precautions should be taken to avoid transferring microbial contamination to the manufacturing or other testing processes. BI results in isolation should not be used to override other critical parameters and process design elements. 8.43 The reliability of BIs is important. Suppliers should be qualified and transportation and storage conditions should be controlled in order that BI quality is not compromised. Prior to use of a new batch/lot of BIs, the population, purity and identity of the indicator organism of the batch/lot should be verified. For other critical parameters, e.g. D-value, Z-value, the batch certificate provided by the qualified supplier can normally be used. 26 8.44 There should be a clear means of differentiating products, equipment and components, which have not been subjected to the sterilisation process from those which have. Equipment such as baskets or trays used to carry products, other items of equipment and/or components should be clearly labelled (or electronically tracked) with the product name and batch number and an indication of whether or not it has been sterilised. Indicators such as autoclave tape, or irradiation indicators may be used, where appropriate, to indicate whether or not a batch (or sub-batch material, component, equipment) has passed through a sterilisation process. However, these indicators show only that the sterilisation process has occurred; they do not indicate product sterility or achievement of the required sterility assurance level. 8.45 Sterilisation records should be available for each sterilisation run. Each cycle should have a unique identifier. Their conformity should be reviewed and approved as part of the batch certification/release procedure. 8.46 Where required, materials, equipment and components should be sterilised by validated methods appropriate to the specific material. Suitable protection after sterilisation should be provided to prevent recontamination. If sterilised items are not used immediately after sterilisation, these should be stored using appropriately sealed packaging and a maximum hold time should be established. Where justified, components that have been packaged with multiple sterile packaging layers need not be stored in a cleanroom if the integrity and configuration of the sterile pack allows the items to be readily disinfected during transfer by operators into grade A (e.g. by the use of multiple sterile coverings that can be removed at each transfer from lower to higher grade). Where protection is achieved by containment in sealed packaging, this packaging process should be undertaken prior to sterilisation. 8.47 Where materials, equipment, components and ancillary items are sterilised in sealed packaging and then transferred into grade A, this should be done using appropriate validated methods (for example, airlocks or pass-through hatches) with accompanying disinfection of the exterior of the sealed packaging. The use of rapid transfer port technology should also be considered. These methods should be demonstrated to effectively control the potential risk of contamination of the grade A and grade B areas and, likewise, the disinfection procedure should be demonstrated to be effective in reducing any contamination on the packaging to acceptable levels for entry of the item into the grade B and grade A areas. 8.48 Where materials, equipment, components and ancillary items are sterilised in sealed packaging or containers, the packaging should be qualified for minimizing the risk of particulate, microbial, endotoxin/pyrogen or chemical contamination, and for compatibility with the selected sterilisation method. The packaging sealing process should be validated. The validation should consider the integrity of the sterile protective barrier system, the maximum hold time before sterilisation and the maximum shelf life assigned to the sterilised items. The integrity of the sterile protective barrier system for each of the sterilised items should be checked prior to use. 8.49 For materials, equipment, components and ancillary items that are not a direct or indirect product contact part and are necessary for aseptic processing but cannot be sterilised, an effective and validated disinfection and transfer process should be in place. These items, once disinfected, should be protected to prevent recontamination. These items, and others representing potential routes of contamination, should be included in the environmental monitoring programme. 27 Sterilisation by heat 8.50 Each heat sterilisation cycle should be recorded either electronically or by hardcopy, using equipment with suitable accuracy and precision. The system should have safeguards and/or redundancy in its control and monitoring instrumentation to detect a cycle not conforming to the validated cycle parameter requirements and abort or fail this cycle (e.g. by the use of duplex/double probes connected to independent control and monitoring systems). 8.51 The position of the temperature probes used for controlling and/or recording should be determined during the validation and selected based on system design and in order to correctly record and represent routine cycle conditions. Validation studies should be designed to demonstrate the suitability of system control and recording probe locations, and should include the verification of the function and location of these probes by the use of an independent monitoring probe located at the same position during validation. 8.52 The whole of the load should reach the required temperature before measurement of the sterilising time-period starts. For sterilisation cycles controlled by using a reference probe within the l