EMA Guideline on Sterilization of Medicinal Products PDF

6 March 2019 EMA/CHMP/CVMP/QWP/850374/2015 Committee for Medicinal Products for Human use (CHMP) Committee for Medicinal Products for Veterinary use (CVMP) Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container Draft agreed by QWP and BWP...

6 March 2019 EMA/CHMP/CVMP/QWP/850374/2015 Committee for Medicinal Products for Human use (CHMP) Committee for Medicinal Products for Veterinary use (CVMP) Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container Draft agreed by QWP and BWP December 2015 Adopted by CHMP for release for consultation January 2016 Adopted by CVMP for release for consultation February 2016 Start of public consultation 13 April 2016 End of consultation (deadline for comments) 13 October 2016 Agreed by BWP July 2018 Agreed by CAT September 2018 Agreed by QWP and GMDP IWG October 2018 Adopted by CHMP for publication 15 November 2018 Adopted by CVMP for publication 6 December 2018 Date for coming into effect 1 October 2019 This guideline replaces the document Decision trees for the selection of sterilisation methods (CPMP/QWP/054/98), which is an annex to the note for guidance on development pharmaceutics (CPMP/QWP/155/96); and the document Decision trees for the selection of sterilisation methods (EMEA/CVMP/065/99) which is an annex to the note for guidance: Development pharmaceutics for veterinary medicinal products (EMEA/CVMP/315/98). Official address Domenico Scarlattilaan 6 1083 HS Amsterdam The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2019. Reproduction is authorised provided the source is acknowledged. Keywords Active substance, Aseptic processing, Container, Decision trees, Excipients, Filtration, Finished Dosage form, Sterilisation, Sterilisation assurance level, Terminal sterilisation, Post-aseptic processing terminal heat treatment. Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container EMA/CHMP/CVMP/QWP/850374/2015 Page 2/25 Guideline on sterilisation of the medicinal product, active substance, excipient and primary container Table of contents 1. Introduction (background)......................................................................4 2. Scope.......................................................................................................4 3. Legal basis...............................................................................................5 4. General requirements..............................................................................5 4.1. Requirements for the manufacture of sterile medicinal products and sterile components6 4.1.1. Steam sterilisation............................................................................................7 4.1.2. Dry heat sterilisation.........................................................................................9 4.1.3. Ionization radiation sterilisation........................................................................10 4.1.4. Gas sterilisation..............................................................................................11 4.1.5. Sterile filtration..............................................................................................12 4.1.6. Aseptic processing..........................................................................................14 4.2. Good manufacturing practice for sterile active substances, sterile excipients and sterile containers...............................................................................................................14 4.2.1. Active substances...........................................................................................15 4.2.2. Excipients......................................................................................................15 4.2.3. Containers.....................................................................................................15 4.3. Selection of sterilisation method..........................................................................16 5. Decision trees........................................................................................18 6. Definitions.............................................................................................21 7. References.............................................................................................24 Guideline on sterilisation of the medicinal product, active substance, excipient and primary container EMA/CHMP/CVMP/QWP/850374/2015 Page 3/25 Executive summary Guidance is provided on the selection of appropriate methods of sterilisation for sterile products. Although, terminal sterilisation using a reference condition of the European Pharmacopoeia (Ph. Eur.) is the method of choice whenever possible, this guideline provides information on when other terminal sterilisation processes, sterilising filtration or aseptic processing, (either alone or when combined with an additional post-aseptic processing terminal heat treatment), could be accepted as an alternative. Guidance is provided on the documentation expected for sterile finished products, sterile active substances, sterile excipients and sterile primary containers (referred to as container in this guideline) in a new marketing authorisation application or a variation application for a medicinal product, (called quality dossier throughout the guideline). Terminology definitions are included at the end of the document. 1. Introduction (background) Sterility is a critical quality attribute for all sterile substances, products and containers. Sterility cannot be assured by testing, it needs to be assured by the use of a suitably designed, validated and controlled manufacturing process. Sterility is achieved by controlling several factors such as the bioburden, the sterilisation procedure, the integrity of the container closure system and in the case of aseptic processing, the use of satisfactory aseptic technique. Terminal sterilisation is preferred to sterilisation by filtration and/or aseptic processing because it is lethal to micro-organisms and a reliable sterility assurance level (SAL) is possible to calculate, validate and control, and thus incorporates a safety margin. For sterile filtration followed by aseptic processing, this is not applicable as accidental contamination caused by inadequate technique cannot be reliably eliminated by monitoring and control. Therefore, terminal sterilisation provides the highest assurance of sterility and should be used whenever possible. For highly sensitive products, such as most biological products, where terminal sterilisation of the finished product is not possible, sterile filtration and/or aseptic processing under validated and controlled conditions can be accepted. Sterile filtration and aseptic processing are closely related and difficult to consider separately, since sterile filtration in most cases is followed by at least one aseptic processing step such as filling. In order to focus on the most important aspect of filtration and aseptic processing at each section of this guideline, only one of the two steps may be mentioned, even if both steps are related. In addition to those finished products where the formulation itself prohibits the possibility of terminal sterilisation, the use of aseptic processing can be accepted in certain situations, even if the formulation itself can be terminally sterilised, if other benefits are gained for patients or users of the product. These situations are specified below in section 4.3. Container integrity is discussed in ICH Q8, (adopted for human medicinal products only, nevertheless the same principles are also applicable to veterinary medicinal products and containers of sterile substances and containers). 2. Scope The guideline applies to chemical and biological medicinal products for human and veterinary use but is not applicable to immunological veterinary medicinal products. Guideline on sterilisation of the medicinal product, active substance, excipient and primary container EMA/CHMP/CVMP/QWP/850374/2015 Page 4/25 It is acknowledged that the recommendations provided for in this guideline may require some adaptation to the specific characteristics of Advanced Therapy Medicinal Products (ATMPs) for human use (e.g. difficulties to differentiate between starting material, active substance and finished product in some cases, scarcity of starting materials/active substance/finished product (autologous products and matched-donor scenario), small volumes of production). The level of documentation that is expected to be included in marketing authorisation applications for ATMPs may be adapted provided that this is justified under a risk-based approach. For veterinary cell based novel therapies, cross reference is made to EMA/CVMP/ADVENT/751229/2016 Questions and Answers on allogenic stem cell-based products for veterinary use: specific questions on sterility. Guidance is provided on the choice of sterilisation method, the development data and manufacturing data required to demonstrate the suitability of the selected sterilisation process. The same principles (choice of method of sterilisation, development data and manufacturing data) apply to sterile active substances, excipients and primary containers. Only the information expected in the quality dossier, including information related to Good Manufacturing Practice (GMP) certificates, is described. Not all GMP requirements (e.g. environmental monitoring, sterilisation of manufacturing equipment) are referenced in the guideline, only those that are considered specifically relevant for the quality dossier. The scope of this document includes:  Terminal sterilisation by steam, dry heat and ionising irradiation using the reference conditions of Ph. Eur. 5.1.1 “Methods of preparation of sterile products” or other conditions stated in that monograph  Sterilisation by filtration and aseptic processing  Sterilisation by gas The concepts in this guideline refer only to absence or removal of bacteria, fungi and bacterial endotoxins. The absence, removal or inactivation of viruses, mycoplasma, prions and other adventitious agents, which could contaminate a product, are not considered. For virus validation reference is made to the Guideline Virus validation studies: the design, contribution and interpretation of studies validating the inactivation and removal of viruses, CPMP/BWP/268/95. 3. Legal basis This guideline should be read in conjunction with Directive 2001/83/EC on the community code relating to medicinal products for human use, Directive 2001/82/EC on medicinal products for veterinary use as amended and also the current Ph. Eur. In addition, this guideline should be read in conjunction with all other relevant directives and regulations, and all relevant Commission, (V)ICH and CXMP guidelines, Q&A documents and other documents as linked to or published on the EMA website (www.ema.europa.eu). 4. General requirements The guideline concerns specific requirements related to sterility, sterilisation processes and aseptic processing of sterile products and product components. Guideline on sterilisation of the medicinal product, active substance, excipient and primary container EMA/CHMP/CVMP/QWP/850374/2015 Page 5/25 4.1. Requirements for the manufacture of sterile medicinal products and sterile components The choice of sterilisation method or aseptic processing should be justified, see section 4.3 Selection of sterilisation method. All sterilisation processes should be carried out according to the instructions of the Ph. Eur. unless justified. All sterilisation procedures for the finished product, active substance, the excipient(s) or the containers and the name and address of the sterilisation site should be stated. A description of the sterilisation method and/or aseptic processing, including in-process controls and validation data should be provided. When parametric release of sterility is proposed, the Guideline on real time release testing (formerly Guideline on parametric release), EMA/CHMP/QWP/811210/2009-Rev1 (human products only), the Guideline on Parametric release, EMEA/CVMP/QWP/339588/2005 (veterinary products only) and the text of Ph. Eur. Chapter 5.1.1 should be taken into account. The bioburden control criteria should be specified prior to all sterilisation processes. High bioburden acceptance criteria should not be justified by the capacity of the sterilisation process or any bioburden reducing step before sterilisation. Acceptance criteria for bioburden are discussed under the relevant sub-sections of 4.1 below. The levels of bacterial endotoxins in the finished product can be impacted by the bioburden and bacterial endotoxins in the components (i.e. active substance, excipients and containers), and by microbiological contaminants introduced during manufacture. To ensure an acceptable level of bacterial endotoxins in the finished product, the level of microbiological contaminants of the components should be minimal. Acceptance criteria for bioburden and, where relevant, bacterial endotoxins in components and bulk solutions should be specified. All filters used in the manufacture of the finished product that come in contact with the finished product, or with any component (substance or intermediate product) incorporated in the finished product should be described and the information stated in Table3, section 4.1.5 should be provided in the quality dossier. The information should be in line with the requirements stated in Eudralex GMP Annex 1. For ATMPs, the Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products should be followed. If a secondary container (e.g. secondary pouch for infusion bags or blisters intended to keep the outside of the container sterile) is used to provide a specific protection to the medicinal product, the packaging process should be described, including a risk assessment, since it may affect the sterility of the finished product; for example, trapping moisture between the primary and secondary containers. Information should be provided as to when the packaging step is performed (before or after sterilisation) and any aseptic techniques employed. The proposed processes should be justified from a microbiological perspective. If the use of a secondary container means additional sterilisation of the finished product is performed, this should be justified with regard to sterility assurance and any potential impact on finished product quality. Documentation regarding sterilisation and aseptic processing to be included in the quality dossier is presented below. The documentation could, for practical reasons, be presented in connection with the item which is to be sterilised if a reference to the location of the documents is provided in section 3.2.P.3.3 or in Part 2 B. The documents may be provided for human products in sections 3.2.S.2 Manufacture, 3.2.P.2 Pharmaceutical development, 3.2.P.3 Manufacture, 3.2.P.4 Control of excipients, Guideline on sterilisation of the medicinal product, active substance, excipient and primary container EMA/CHMP/CVMP/QWP/850374/2015 Page 6/25 or 3.2.P.7 Container closure system, or for veterinary products in Part 2 A.4 Development pharmaceutics, Part 2 B.1 Manufacturing method, Part 2 C.1 Active substance, Part 2 C.2 Excipients or Part 2 C.3 Container closure systems. The documentation should be provided for all sites performing sterilisation or aseptic processing, regardless of whether the processes are performed in-house or outsourced. Process parameters such as processing and holding times are assessed and agreed during the evaluation of the quality dossier. These may be further reviewed during GMP inspections, which may result in changes to the registered dossier being required. 4.1.1. Steam sterilisation All steam sterilisation processes require a minimum lethality of F0 ≥ 8 minutes and a minimum process hold temperature of 110 °C. Sterilisation processes of different levels of lethality are presented in Table 1, along with the documentation to be included in the quality dossier. The processes in the table are presented with decreasing lethality when read from top to bottom, thus the first feasible process should be selected. For sterilisation using a reference condition of the Ph. Eur. 5.1.1 (≥121 °C, ≥15 min in all units) validation data for the sterilisation cycle is not required to be submitted in the quality dossier. If used as an additional control to measure the process lethality, F0, should be stated, together with the lowest temperature measured by the temperature sensors to determine F0. Steam sterilisation performed with finished product temperature below 115 °C during the holding phase is an exceptional case and should be scientifically justified and supported by additional data as described in Table 1. If temperatures below 110 °C are included (during heat-up and cool-down) in the determination of F0, this should be justified. Information regarding the F0 concept and microbial reduction is provided in Ph. Eur. 5.1.5 Application of the F0 concept to steam sterilisation of aqueous preparations. The bioburden limit should be in line with any pre-sterilisation bioburden reduction process capability (e.g. filtration). For aqueous solutions, the limits stated in Table 1 are acceptable for active substances and drug product formulations without further justification. Other testing regimes and limits to control bioburden at the defined level should be justified. Moist heat processes with an F0 < 8 min may be suitable as a post-aseptic processing terminal heat treatment for formulations that cannot withstand a complete terminal sterilisation cycle. Such processes may further ensure a SAL of sterile filtered (or otherwise sterilised) bulk components, which have been aseptically filled. Post-aseptic processing terminal heat treatments are also presented in Table 1. It is emphasised that this additional post-aseptic processing terminal heat treatment should not compensate for poor aseptic manufacturing practice. The same requirements for the aseptic part of the process apply as for finished products manufactured without such an additional post-aseptic processing terminal heat treatment. Guideline on sterilisation of the medicinal product, active substance, excipient and primary container EMA/CHMP/CVMP/QWP/850374/2015 Page 7/25 1 Table 1 Cycles for steam sterilisation and post-aseptic processing terminal heat treatment and corresponding data required in the quality 2 dossier Cycle Type of process Information in Bioburden level before steam sterilisation or terminal Bioburden Process hold dossier* heat treatment Characterised temperature Ph. Eur. 5.1.1 Sterilisation 1, 6 100 CFU/100ml (non-routine) No ≥ 121 °C for ≥15 Reference Cycle minutes Overkill cycle Sterilisation 1, 2, 3, 4, 7 100 CFU/100ml (non-routine) No ≥ 121 °C Fo >12 min Fo > 8 min Sterilisation 1, 2, 3, 4, 7 100 CFU/100ml (routine) No > 115 °C Fo > 8 min Sterilisation 1, 2, 3, 5, 7, 8 100 CFU/100ml (routine) Yes** > 115 °C Fo > 8 min Sterilisation 1, 2, 3, 4, 7 100 CFU/100ml (routine) Yes > 110 °C Fo > 8 min Sterilisation 1, 2, 3, 5, 7, 8 100 CFU/100ml (routine) Yes** > 110 °C Fo 110 °C**** terminal heat treatment terminal heat treatment (routine) Fo 110 °C**** terminal heat treatment terminal heat treatment (routine) 3 * For clarification of the code numbers, see below 4 ** In-process control demonstrating acceptable heat resistance of bioburden 5 *** The bioburden prior to the sterilisation step (i.e. filtration) should be characterised for heat resistance 6 **** Temperatures below 110 °C may be used if justified. The requirement for additional documentation for such cycles is evaluated on a case by case basis 7 Clarification of the information to be presented in the quality dossier 8 1: Sterilisation time, temperature profile 9 2: Sterilisation method (for instance saturated steam cycle, air/steam-overpressure cycle, vacuum phase) description including SAL 10 3: Validation of F0Phys and F0Bio 11 4: Biological indicator with a D121 ≥ 1.5 minutes used in the validation 12 5: Biological indicator with a D121 < 1.5 minutes used in the validation 13 6: No validation data requested in the dossier, only a confirmation that validation has been performed. 14 7: Validation data to be provided in the dossier is presented below 15 8: Additional validation data to be provided in the dossier is presented below Guideline on sterilisation of the medicinal product, active substance, excipient and primary container EMA/CHMP/CVMP/QWP/850374/2015 Page 8/25 Validation data to be provided in the quality dossier for all steam sterilisation processes that do not fulfil the requirements of Ph. Eur. 5.1.1 standard process (required information 7 in Table 1):  Load mapping of the chamber and load mapping distribution of the items in the chamber (including the slowest to heat locations); summary or confirmation of performance.  Physical and biological cycle effect confirmation summary of at least three sterilisation runs demonstrating an SAL ≤10-6, as described in Ph. Eur. 5.1.1 ensuring:  Demonstration that the sterilisation load in the steriliser chamber achieves the specified cycle parameters, including time, temperature, pressure and F0, if applicable;  Acceptable temperature differences between temperature sensors in the load;  Acceptable F0 variability within the load;  Relationship between physical and biological validation. For the biological validation, a biological indicator as described in Ph. Eur. chapter 5.1.2 Biological indicators and related microbial preparations used in the manufacture of sterile products with a D121-value of ≥1.5 minutes should be used. The SAL should be determined, its microbiological basis should be justified and details of calculations provided in the quality dossier. Preferably it should be calculated from the maximum bioburden per container and the D-value of the biological indicator used in the validation. Additional validation data to be provided in the quality dossier for low energy steam processes or where a bio-indicator with a D121-value of 12 minutes. For example a process that provides at least a 12 log reduction of biological indicator micro- organisms having a minimum D value of 1 minute. Ph. Eur. sterilisation reference conditions The reference conditions for sterilisation specified in Ph. Eur. 5.1.1, i.e. terminal steam sterilisation at ≥121 °C for 15 min, terminal dry heat sterilisation at ≥160 °C for ≥2 h or terminal ionising radiation of 25 kGy. Post-aseptic processing terminal heat treatment A terminal moist heat process employed after aseptic processing which has been demonstrated to provide a SAL ≤10-6, but where the requirements of steam sterilisation (for example, F0≥8 min) are not fulfilled. SAL Sterility Assurance Level. The SAL for a given sterilisation process is expressed as the probability of micro-organisms surviving in a product item after exposure to the process. An SAL of 10-6, for example, denotes a probability of not more than 1 non-sterile item in 1 × 106 sterilised items of the final product. Slowest to heat locations Location in the load that remains coldest or where the temperature is raising slowest during the sterilisation process. It could, in a figurative sense, also be used for other sterilisation methods for the location in the load achieving the lowest level of sterilising energy. Steam sterilisation Reference is made to the description in Ph. Eur. 5.1.1. Sterilisation A suitably designed, validated and controlled process that inactivates or removes viable micro- organisms in a product until sterility is obtained. Guideline on sterilisation of the medicinal product, active substance, excipient and primary container EMA/CHMP/CVMP/QWP/850374/2015 Page 22/25 Sterility Sterility is the absence of viable microorganisms, as defined by a sterility assurance level equal to or less than 10−6. The inactivation of microorganisms by physical or chemical means follows an exponential law; thus there is always a finite statistical probability that a micro-organism may survive the sterilising process. For a given process, the probability of survival is determined by the number, types and resistance of the microorganisms present and by the environment in which the organisms exist during treatment. TAMC Total aerobic microbial count: The total aerobic microbial count (TAMC) is considered to be equal to the number of CFU found using casein soya bean digest agar. Terminal process A process where a finished product is processed in its primary container, for example terminal sterilisation or post-aseptic processing terminal heat treatment. Validation Establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. Worst case A set of conditions encompassing upper and lower processing limits and circumstances, including those within standard operating procedures, that pose the greatest chance of process or product failure (when compared to ideal conditions). Such conditions do not necessarily induce product or process failure. z-value The z-value is the change in temperature required to alter the D-value by a factor of 10. Guideline on sterilisation of the medicinal product, active substance, excipient and primary container EMA/CHMP/CVMP/QWP/850374/2015 Page 23/25 7. References Decision trees for the selection of sterilisation methods, CPMP/QWP/054/98; Note for Guidance: Development Pharmaceutics for veterinary medicinal products: Decision tree for the selection of sterilisation methods, EMEA/CVMP/065/99; Note for guidance on manufacture of the finished dosage form, CPMP/QWP/486/95; Note for Guidance: Manufacture of the finished dosage form, EMEA/CVMP/126/95; ICH guideline Q8 (R2) on pharmaceutical development, EMA/CHMP/ICH/167058/2004; European Pharmacopoeia general chapter 5.1.1 ‘Methods of preparation of sterile products’; Note for Guidance: Virus validation studies: the design, contribution and interpretation of studies validating the inactivation and removal of viruses, EMA/CPMP/BWP/268/95; Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, as amended; Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal products, as amended; Guideline on real time release testing (formerly Guideline on parametric release), EMA/CHMP/QWP/811210/2009-Rev1; Guideline on Parametric release, EMEA/CVMP/QWP/339588/2005; EudraLex - Volume 4 Good manufacturing practice (GMP) Guidelines; European Pharmacopoeia general chapter 5.1.5 ‘Application of the F0 concept to steam sterilisation of aqueous preparations’; European Pharmacopoeia general chapter 5.1.2 ‘Biological indicators and related microbial preparations used in the manufacture of sterile products’; NfG on The use of Ionisation Radiation in the Manufacture of Medicinal products 3AQ4A; EN/ISO 11137, Sterilisation of health care products – Radiation; ICH guideline M7 on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk (EMA/CHMP/ICH/83812/2013); European Pharmacopoeia general chapter 5.1.7 ‘Viral Safety’ Human cell-based medicinal products, EMEA/CHMP/410869/2006 Questions and Answers on allogenic stem cell-based products for veterinary use: specific questions on sterility EMA/CVMP/ADVENT/751229/2016 Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products, EMA/CAT/80183/2014 I.S. EN ISO 20857 Sterilization of health care products - dry Heat - Requirements for the development, validation and routine control of a sterilization process for medical devices I.S. EN ISO 11135 Sterilization of health-care products - Ethylene Oxide - Requirements for the development, validation and routine control of a sterilization process for medical devices I.S. EN ISO Guideline on sterilisation of the medicinal product, active substance, excipient and primary container EMA/CHMP/CVMP/QWP/850374/2015 Page 24/25 17665-1 Sterilization of health care products - Moist heat - Part 1: Requirements for the development, validation and routine control of a sterilization process for medical devices ISO/TS 17665-2 Sterilization of health care products -- Moist heat -- Part 2: Guidance on the application of ISO 17665-1 I.S. EN ISO 11137-1 Sterilization of health care products - Radiation - Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices I.S. EN ISO 11137-2 Sterilization of health care products - Radiation - Part 2: Establishing the sterilization dose I.S. EN ISO 11137-3 Sterilization of health care products - Radiation - Part 3: Guidance on dosimetric aspects of development, validation and routine control ICH Q3A (R2) Impurities in new drug substances, CPMP/ICH/2737/99 ICH Q3B (R2) Impurities in New Drug Products, CPMP/ICH/2738/99; VICH GL10 Impurities in new veterinary drug substances, CVMP/VICH/837/99 Rev.1 VICH GL11 Guideline on impurities in new veterinary medicinal products, EMEA/CVMP/VICH/838/99 Rev.1. Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to Advanced therapy medicinal products, EMA/CAT/CPWP/686637/2011). Guideline on sterilisation of the medicinal product, active substance, excipient and primary container EMA/CHMP/CVMP/QWP/850374/2015 Page 25/25