1. Regulatory update Overview and Introduction Annex 1 Revision
Greg McGurk, Senior Inspector
Veterinary Medicines Information Day
June 13th , 2018

2. Rationale for Revision Stakeholders Current status Key Points
Scope
History
Process of Revision
Rationale for Revision
Stakeholders
Current status
Key Points
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3. Annex 1 - History, Process & Rationale for Revision

4. History First issued in 1971
Number of revisions since then, but not full revisions
2012 first proposal to revise
Proposal Re-issued in 2014
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5. Combined Working Group – EU, PICS and WHO
Revision Process
Combined Working Group – EU, PICS and WHO
Tasked with assessing need and extent for revision
3 Options:
1. Update Q&A
2. Revise Annex 1
3. Full Review & Rewrite
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6. Rationale
Introduction of principles of Quality Risk Management & Contamination Control Strategy
New & Innovative processes & technologies:
Reinforcing the need of manufacturers to keep up with current technologies
Single use closed systems
Disposable systems
Rapid Microbial test methods
Clarify ambiguities – more detail needed
Restructure – more logical flow
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7. Stakeholders

8. Regulatory Stakeholders
EU – 28 member states
PICS – 54 Agencies (Human & Vet)
WHO – 194 members
Relevant to the whole world
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9. Industry Stakeholders
Big Pharma
Small Pharma
Hospitals
Academic Institutes
Virtual operations
Multiple technologies – Automated processes, manual processes, BFS, Form Fill Seal, Lyo, LVP, SVP, Powders, Liquids
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10. Annex 1 Working group UK Japan Germany Ireland Poland Switzerland
Australia US
Singapore
Canada
Taiwan
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11. Annex 1 - Current Status

12. Annex 1 Revision Process & Current Status
Public Consultation phase ended 20th March 2018
EC review and adoption December 2017
IWG & PICs review – Adopted Feb 2017
Comments assessed
Two rounds of review - circulated to PIC/S and IWG Mid 2016 & November 2016
Subgroups – tasked with drafting various sections
Joint working group between PIC/S and EMA
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13. Working group will be busy over the coming months : - Review comments
Next Phase
Working group will be busy over the coming months :
- Review comments
- Final Draft – Aim is End of August
- IWG – September
- PICS , WHO
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14. Annex 1 - Key Points / Changes

15. Annex 1 – Format Section Number General overview 1.Scope
Additional areas (other than sterile medicinal products) where the general principles of the annex can be applied
2.Principles
General principles as applied to the manufacture of medicinal products. Includes requirements for Contamination Control Strategy
3. Pharmaceutical Quality System (PQS)
Highlights the specific requirements of the PQS when applied to sterile medicinal products
4. Personnel
Guidance on the requirements for specific training, knowledge and skills. Also gives guidance to the qualification of personnel
5. Premises
General guidance regarding the specific needs for premises design and also guidance on the qualification of premises including the use of barrier technology
6. Equipment
General guidance on the design and operation of equipment
7. Utilities
Guidance with regards to the special requirements of utilities such as water, air and vacuum
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16. Annex 1 Format Section Number General overview
8. Production and specific technologies
Discusses the approaches to be taken with regards to aseptic and terminal sterilisation processes. Also discusses different technologies such as single use, lyophilisation and BFS / FFS where specific requirements may be required. Discusses approaches to sterilization of products, equipment and packaging components
9. Viable and non viable environmental and process monitoring
This section differs from guidance given in section 5 in that the guidance here applies to ongoing routine monitoring with regards to the setting of alert limits and reviewing trend data
The section also gives guidance on the requirements of Aseptic Process Simulation
10. Quality control
Give guidance on some of the specific Quality Control requirements relating to sterile medicinal products
11. Glossary
Explanation of specific terminology
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17. Introduction of QRM Principles
Scope
Introduction of QRM Principles
This Annex provides general guidance that should be used for all sterile medicinal products and sterile active substances, via adaption, using the principles of Quality Risk Management (QRM)
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18. Scope
The intent.. is to provide guidance for sterile medicinal products. However some of the principles and guidance, such as contamination control strategy, room qualification, classification, monitoring and 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 of microbial, particulate and pyrogen contamination, to reduce it as far as possible, is considered important.
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19. Quality Risk Management Contamination control strategy
Principle
Quality Risk Management
Contamination control strategy
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20. Integration of effective risk management systems
PQS
Emphasis on:
Integration of effective risk management systems
Robust investigations & Root cause determination
Iterative nature of risk assessments to identify, assess, eliminate (where applicable) and control contamination risks to prevent contamination, to monitor and detect contamination, and to establish process requirements and acceptance criteria for all elements of a sterile manufacturing process.
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21. Personnel Max number of personnel – determined based on QRM
More emphasis on training requirements
Visual assessment of gowning
Personnel Monitoring - immediately after completion of a critical intervention and upon each exit from the cleanroom
System for disqualification of personnel from entry into cleanrooms
Clarified requirements for gowning – e.g. Goggles
Temperature & RH controls
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22. Emphasis on importance of design
Premises
Emphasis on importance of design
Clarification on requirements for airflow velocities
Minimise entry to Grade A
Interface of Grade C with Grade B
Materials likely to generate fibres – should not be permitted in clean areas
The use of separate changing rooms for entering and leaving clean areas is generally desirable.
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23. Cascade – personnel changing airlocks
Premises
Cascade – personnel changing airlocks
Material transfer – use of QRM principles
Visualisation of airflow
Design of facilities – permit observation of activities
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24. Gloves / Sleeves – good mechanical and chemical resistance.
Barrier Technologies
Isolators
RABs
Background environment – Grade D or higher dependant on design, method for decontamination
Gloves / Sleeves – good mechanical and chemical resistance.
Routine integrity testing at start / end of batch & defined intervals e.g. after interventions that may affect integrity
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25. Clean room and Clean air device qualification
Annex 15
5um – no longer expected for qualification. In line with ISO revision
Clarification on sampling requirements
Defined link between viable monitoring and qualification
Removed reference to average values and clarify when using a reduced exposure time
Defined intervals for requalification
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26. Disinfectant efficacy studies
Disinfection
Disinfectant efficacy studies
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27. Direct / Indirect contact surfaces – Sterile
Equipment
Maintenance activities inside Clean areas – precautions such as additional disinfection and additional Environmental Monitoring should be considered
Direct / Indirect contact surfaces – Sterile
Unplanned maintenance – Impact assessment
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28. Dedicated section for utilities
Water systems – additional detail to be included regarding WFI produced by non-distillation methods
Steam
Compressed gasses
Cooling systems
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29. Production and Specified Technologies
Terminally sterilised products
Aseptically preparation – use of RABs, SIP etc. Minimise aseptic manipulations. Defined max duration for processes.
Container closure integrity
Capping
Visual inspection – QRM for classification – take account of impact to patient and route of administration. Ongoing assessment of trends
VI Qualification - worst case scenarios (e.g. inspection time, line speed, component size, fatigue at the end of shift)
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30. Sterilisation Emphasis on Terminal sterilisation or heat treatment
Emphasis on QRM principles
Clarification on expectations:
- Moist heat
- Dry heat
- Irradiation
- ETO
- Filtration
Reference to parametric
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31. VHP - Decontamination
VHP – not sterilisation. Organisms killed through an oxidative action. Method of providing surface decontamination
Fragile process - Poor penetrating ability and so there are limitations on what can be effectively sterilised
No set of standard exposure conditions exist to guide in the determination of resistance of BIs produced for this process
Clumping of spores can lead to failures
There is no standard condition for VHP, unlike steam, dry heat or EtO
Variances in the vapour or airflow rate between isolators
Variances in the turbulence between isolators
Variances in temperature and humidity between isolators
VHP failure due to very minor occlusion
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32. Pre-Use Post Sterilisation Integrity Test
The integrity of the sterilized filter assembly should be verified by testing before use, in case of damage and loss of integrity caused by processing, and should be verified by on line testing immediately after use by an appropriate method such as a bubble point, diffusive flow, water intrusion or pressure hold test. It is recognised that for small batch sizes, this may not be possible; in these cases an alternative approach may be taken as long as a formal risk assessment has been performed and compliance is achieved.
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33. Production Processes Form fill seal Blow fill seal Lyophilisation
Closed systems
Single use systems
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34. Viable & non-viable environmental and process monitoring
Incorporation of process simulations
Clarification on expectations
Non-viable 5um included for monitoring
Application of QRM
Introduction of rapid microbial methods
Process simulations – additional clarity on expectations. Target - Zero growth / recovery
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35. Specifications for starting materials Bioburden testing
Quality Control
Specifications for starting materials
Bioburden testing
Sterility testing
Growth promotion of media
Impact of decontamination of samples
Rapid Microbiological Methods
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36. Thank You greg.mcgurk@hpra.ie