Webinar. The New EU-GMP Annex 1 draft Dupont. GOP-Innovations your Partner for Practical Training and e-learning. 8 June 2018

Transcription

1 Webinar The New EU-GMP Annex 1 draft Dupont 8 June 2018 GOP-Innovations your Partner for Practical Training and e-learning

2 Milenko Pavičić Pharmaceutical microbiologist, consultant, trainer, coach 10 years of research experience Vrije Universiteit Amsterdam (Medical and Oral Microbiology) Intervet International B.V. (Antibiotics R&D) 20 years of production and QC experience Pharmaceutical companies (NL, B, D, F) Hospital pharmacies (NL, B) Member of the NVZA (Dutch Society of Hospital Pharmacists) work group Microbiology and Hygiene Member of the User Committee of the NWO project Rapid Micro Statistics (TU/e, Prof. E. v/d Heuvel)

3 Pavičić Pharmaceutical Microbiology and GOP-Innovations Consultancy Courses Training Practical Training E-learning Microbiology, Aseptic production, Cleanrooms, Sterilisation, Cleaning, Disinfection, cgmp, Pharmacopoeias, Annex 1, QC, Validation, Qualification, Behavior, SOPs, Media fills, Environmental monitoring, Water systems, Sampling, Hygienic Design, Contamination Risk, Biosafety, Biosecurity

4 Subjects for today s webinar European GMP The Annex 1 and its history The new Annex 1 draft What s new for cleanroom garment and gowning Further new items which might be important for you

5 European GMP guidelines Eudralex Volume 4 of The rules governing medicinal products in the European Union Eudralex Volume 4 contains guidance for the interpretation of the principles and guidelines of good manufacturing practices for medicinal products for human and veterinary use EU-GMP Annex 1: Manufacture of Sterile Medicinal Products

6 EU-GMP Annex 1 revision history The EU-GMP was introduced in 1992/1993 The EU-GMP Annex 1 is based on the Annex 1 of the Orange Guide (UK) Partial revisions in 1996, 2003 en 2007 The current draft is the first complete revision since 1993

7 New Annex 1 Not a revision, a rewrite 50 pages compared to 15 pages 269 paragraphs compared to 127 paragraphs More than 100 new paragraphs, 14 paragraphs deleted Only 40 out of 127 paragraphs unchanged New focus: Quality Risk Management (QRM) 92 times Risk compared to 20 times now 113 times Contamination compared to 35 times now 15 times reference to QRM Specific reference to the importance of QRM in the chapter Scope

8 New Annex 1 Not a revision, a rewrite More detail for some subjects such as: Cleanroom clothing type and management (compulsory eye wear in A/B, dedicated socks) Trending of environmental monitoring results Many new subjects such as: Single use technologies Aseptic operator qualification Application of Quality Risk Management Cleaning validation for cleanroom surfaces Closed manufacturing systems

9 Definitions (1) glossary Clean Area or Clean Zone: An area with defined particle and microbiological cleanliness standards. Cleanroom: A room designed, maintained, and controlled to prevent particle and microbiological contamination of drug products. Such a room is assigned and reproducibly meets an appropriate air cleanliness classification.

10 Definitions (2) glossary Clean Non Classified (CNC) area: An area that does not meet any of the formal predetermined grades of cleanliness included in the Annex, i.e. grades A to D, but where a manufacturer defined level of microbial control is still required. The area should be subject to a formal cleaning/disinfection regime and formal environmental monitoring program to achieve the defined level of control. It is possible that different CNC areas within the same facility may have different approaches to control and monitoring, based on differing risks to processes and products.

11 Definitions (3) glossary Critical Area or Critical Zone: An area or zone designed to maintain sterility of sterile materials. Sterilized product, containers, closures, and equipment may be exposed in critical areas or zones such as the grade A area or a closed system. Critical surfaces - Surfaces that may come into contact with, or directly affect, a sterilized product or its containers or closures. Critical surfaces are rendered sterile prior to the start of the manufacturing operation, and sterility is maintained throughout processing.

12 Definitions (4) glossary Laminar flow: An airflow moving in a single direction and in parallel layers at constant velocity from the beginning to the end of a straight line vector. Unidirectional flow: An airflow moving in a single direction, in a robust and uniform manner, and at sufficient speed, to reproducibly sweep particles away from the critical processing or testing area.

13 Chapters (new) 1. Scope 2. Principle 3. Pharmaceutical Quality System (PQS) 4. Personnel 5. Premises 6. Equipment 7. Utilities 8. Production and specific technologies 9. Viable and non-viable environmental and process monitoring 10. Quality control (QC) 11. Glossary

14 Scope Mandatory for: all sterile medicines and sterile API Recommended for: non-sterile products where contamination control is important Use QRM to prevent contamination of the final product

15 Principle (1) To apply QRM principles is essential Adequate contamination control Facility, equipment and process design (state of the art) Personnel (skills, attitude, training) Process and monitoring systems Risk assessments should be used to justify alternative approaches only if these alternative approaches are equivalent or better

16 Principle (2) Contamination control strategy Living document Annex 1 gives 15 examples of relevent elements, e.g. process risk assessment, process validation, preventative maintenance Holistic approach of contamination control

17 New content Annex 1 (1) 4.4 Compliance with aseptic gowning procedures should be assessed and confirmed and this should be periodically reassessed at least annually and should involve both visual and microbiological assessment (using additional locations such as arms and chest). The microbial monitoring of personnel in the grade A/B area should be performed to assess their aseptic behaviour. This monitoring should take place immediately after completion of a critical intervention and upon each exit from the cleanroom. It should be noted that there should also be an ongoing continuous monitoring program for personnel including some consideration of periodic monitoring under the supervision of the quality unit. 4.5 There should be systems in place for disqualification of personnel from entry into cleanrooms, based on.

18 New content Annex 1 (2) 4.7 [.] periodic health checks for such conditions (any specific health conditions or ailments which may cause the shedding of abnormal numbers or types of contaminants) should be performed. 4.8 Staff who have been engaged in [ ] any activities that may have a negative impact to quality, e.g. microbial contamination, should not enter sterile product areas unless rigorous, clearly defined and effective entry procedures have been followed.

19 New content Annex 1 (3) Garments: 4.10 [ ] Garments should be visually checked for cleanliness and integrity prior to entry to the clean room. For sterilized garments, particular attention should be taken to ensure that [ ] their packaging is integral before use. Reusable garments should be replaced based at a set frequency determined by qualification or if damage is identified; 4.12 Grade A/B: Sterile headgear [ ] sterile suit, a sterile face mask and sterile eye coverings [ ] appropriate sterilized, nonpowdered rubber or plastic gloves and sterilized footwear should be worn.

20 New content Annex 1 (4) Garments: 4.12 [ ] Garments should be packed and folded in such a way as to allow operators to change into the garments with contact to the outer surfaces of the garment reduced to a minimum [ ] facility suits, including dedicated socks 4.15 After washing and before sterilization, garments should be checked for integrity.

21 New content Annex 1 (5) 5.6 Materials liable to generate fibres should not be permitted in clean areas 5.9 [ ] typically airlocks used for personnel movement are separate to those used for material movement. The use of separate changing rooms for entering and leaving clean areas is generally desirable. (i) Pass through hatches without active filtered air supply should be avoided. (ii) For airlocks leading to grade A and B areas, only materials and equipment that have been included as part of the qualification list should be allowed to be transferred into the grade A/B area

22 New content Annex 1 (6) 5.27 The microbial load of the clean rooms should be determined as part of the clean room qualification Clean rooms should be requalified periodically and after changes to equipment, facility or processes based on the principles of QRM. For grade A and B zones, the maximum time interval for requalification is 6 months. For grades C and D, the maximum time interval for requalification is 12 months.

23 New content Annex 1 (7) 5.31 [ ] More than one type of disinfecting agent should be employed, and should include the periodic use of a sporicidal agent. Cleaning programs should be effective in the removal of disinfectant residues.

24 New content Annex 1 (8) 8.7 The site s contamination control strategy 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. Residual risks should be justified. 8.8 Materials liable to generate fibres should not be permitted in clean areas.

25 New content Annex 1 (9) 8.42 Transfer of materials, equipment, and components into an aseptic processing area should be via a unidirectional process (e.g. through a double-door autoclave, a depyrogenation oven, effective transfer disinfection, or, for gaseous or liquid materials, a bacteriaretentive filter).

26 New content Annex 1 (10) 8.44 Where materials, equipment, components and ancillary items are sterilized in sealed packaging or containers, the integrity of the sterile protective barrier should be qualified for the maximum hold time, and the process should include inspection of each sterile item prior to its use to ensure that the sterile protective measures have remained integral For materials, equipment, components and ancillary items that are necessary for aseptic processing but cannot be sterilized, 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 program.

27 New content Annex 1 (11) 8.54 [ ] Each item sterilized should be inspected for damage, seal and packaging material integrity and moisture on removal from the autoclave. Seal and packaging integrity should also be inspected immediately prior to use. Any items found not to be fit for purpose should be removed from the manufacturing area and an investigation performed.