Annex 1 Revision

Greg McGurk, GMP Manager (acting)

GMP Conference

7 February 2017

Dublin

History

First issued in 1989

Number of revisions since then 1996, 2003, 2005,

2007 and 2009, but not full revisions

2012 first proposal to revise

Proposal Re-issued in 2014

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Rationale for Revision

Needed “Tidying up”

Introducing principles of Quality Risk Management

New technologies:

• Reinforcing the need of manufacturers to keep up with current technologies

• Single use closed systems

• Disposable systems

• Innovative technologies

• Some ambiguities

Micro data averages

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Annex 1 update

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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 update

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Section Number General overview

7. Utilities Guidance with regards to the special requirements of utilities such as water, air

and vacuum

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

Annex 1 updates – 1. Scope

• New section to link to other annexes and chapters

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Annex 1 update – 2. PQS

Reinforce the existing requirements of EU GMP

EU Directive 2003/94 Article 5

EU Directive 2001/83 Article 23

Chapter 3

Chapter 5 (5.10)

QRM application, alternative at least as good as the stated objective

RCA & Product Impact Assessment

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Annex 1 update – 5. Personnel

Goggles (face coverings)

Training/knowledge

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Annex 1 update – 6. Premises 7. Equipment

Design

QRM application

Again reinforcing the need to keep the operators away from the product using current technology

Restricted Access Barrier Technology

Isolators

Cleanroom qualification: ISO 14644; 5.0 µm

Disinfection – Efficacy

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Annex 1 update – 8. Utilities

General services such as compressed air

WFI by RO - Possibility that this could then be moved to a separate section of the

GMPs

Biofilms

Cooling systems

Steam

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Annex 1 update – 9. Production and Specific technologies

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Blow Fill Seal

Form Fill Seal

Sterilisation Process & Controls

Aseptic Preparation

Finishing

Filtration – Pre-Use Post Sterilisation Integrity Test

Lyophilisation

Closed Systems

Single Use Technology

Annex 1 update – 10. Environmental Monitoring

Keep all monitoring in one place

To include Non Viable Particulates

To include all viable monitoring except the sterility test

To include process simulations

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Annex 1 update – 10. Environmental Monitoring

Reinforce the development of the “system” by risk assessment – process inputs, processes, operations / activities

Setting of appropriate operational limits

Emphasis on determination of adverse trends and evaluation of trend data

5.0 µm particles

Remove reference to averaged values for results

Rapid microbial methods

Aseptic Process Simulations – Zero growth, CAPA strategy

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Annex 1 update

• 11. Quality Control

• 12. Glossary

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Annex 1 update - Progress

Public Consultation phase – Estimated – Q2 2017

IWG & PICs review – Feb 2017

Container closure integrity & Pre-use post sterilisation integrity

Comments received back

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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Questions