Overview and Introduction

Annex 1 Revision

Paul Moody, Inspector

Pharmig

Current Hot Topics in Pharmaceutical Microbiology, Dublin

May 30th, 2018

Scope

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• History

• Process of Revision

• Rationale for Revision

• Stakeholders

• Current status

• Key Points

Annex 1 - History, Process &

Rationale for Revision

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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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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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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Stakeholders

Regulatory Stakeholders

EU – 28 member states

PICS – 54 Agencies (Human & Vet)

WHO – 194 members

Relevant to the whole world

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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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Annex 1 Working Group

UK Japan Germany Ireland

Poland Switzerland Australia US

Singapore Canada Taiwan

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Annex 1 - Current Status

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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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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Annex 1 - Key Points / Changes

Annex 1 – Format

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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

Annex 1 Format

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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

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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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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Principle

• Quality Risk Management

• Contamination control strategy

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PQS

• Emphasis on:

1. Integration of effective risk management systems

2. Robust investigations & Root cause determination

3. 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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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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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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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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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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Clean room and Clean air device qualification

• Annex 15

• 5um – no longer expected for qualification. In line with ISO 14644 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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Disinfection

• Disinfectant efficacy studies

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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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Utilities

• 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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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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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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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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Production Processes

• Form fill seal

• Blow fill seal

• Lyophilisation

• Closed systems

• Single use systems

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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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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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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 17 May 2018 35

Thank You compliance@hpra.ie