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REVISION OF EUDRALEX VOL. 4 - GMP Luisa Stoppa, Ph.D. Inspection and Certification Department Italian Medicines Agency Swedish Academy of Pharmaceutical Sciences SAPS Stockholm, November 8th, 2011. Agenda. GMP – history GMP – definition GMP - structure GMP – updates

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REVISION OF EUDRALEX VOL. 4 - GMP

Luisa Stoppa, Ph.D.

Inspection and Certification Department

Italian Medicines Agency

Swedish Academy of Pharmaceutical Sciences SAPS

Stockholm, November 8th, 2011

agenda
Agenda
  • GMP – history
  • GMP – definition
  • GMP - structure
  • GMP – updates
  • GMP – next updates
  • GMP – under discussion
agenda3
Agenda

GMP – history

GMP – definition

GMP - structure

GMP – updates

GMP – next updates

GMP – under discussion

gmp history
GMP – history

1

Why are we interested in GMP history?

F. Nietzsche once said: If you know the why of living, you can endure any how

Everyone should know the story of how the GMPs have come to be.

Most requirements were put in place as response to tragic circumstances and to prevent future tragedies.

gmp history5
GMP – history

1

We can choose it by looking:

gmp history6
GMP – history

1

We can not choose it by looking:

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GMP – history

1

We have to trust in the supply chain and in the manufacturer:

gmp history8
GMP – history

1

Disasters are the driving force for establishing rules.

Disasters are the basis to issue standards.

“SHOULD”

gmp history9
GMP – history

1

1937 – sulfanilamide

  • Sulfa drugs were introduced in 1935 as anti-infectives;
  • one company used diethylene glycol (a poisonous solvent) in an oral elixir of sulfanilamide;
  • 108 deaths, many of them children;
  • company was charged with misbranding (=inaccurate and false labeling it is illegal…..over the years the word has been replaced with the word adulterated).
gmp history10
GMP – history

1

1938 – in USA, Congress enforced the Federal Food, Drug and Cosmetic (FD&C) Act.

Companies were required to prove that their products were safe before marketing them.

gmp history11
GMP – history

1

1941 – kick-off of GMP

- Sulfathiazole tablets contaminated with phenobarbital (a sedative);

- 300 people died or were injured;

  • FDA enforced and revised manufacturing and quality control requirements, leading to what would later be called GMP;
  • During the second world war, batch certification by FDA became a requirement for certain drugs (i.e. 1941 for insulin; 1945 for penicillin).

1906 – certificate of purity signed by doctor

gmp history12
GMP – history

1

1960 – Thalidomide drug

  • Thalidomide was marketed in Europe as a sleeping pill and to treat morning sick-ness;
  • regulatory agencies that gave the permission to sell this drug, knew nothing of its side-effects: it was teratogenic;
  • it caused deformities in developing fetuses;
  • children whose mother took thalidomide in the first three months were born with deformed arms and legs;
  • an estimated 10 000 cases were linked to thalidomide use.
gmp history13
GMP – history

1

1960 – Thalidomide drug

  • The drug reviewer responsible for thalidomide application in USA was Frances Kelsey;
  • in 1962 President Kennedy awarded her the President’s Distinguished Federal Civilian Service Award, the highest honor a government employee may earn as a civilian.
gmp history14
GMP – history

1

1962 – Kefauver-Harris Drug Amendments

  • Two legislators (Kefauver and Harris) pushed more stringent legislation;
  • FDA’s regulation required companies to test not only to ensure that products were safe but that they were efficacious for their intended use (“proof of efficacy” law);
  • regulating clinical trials, the amendments required drugs to be tested in animals before people;
  • manufacturers were required to report unexpected harm (adverse events);
  • GMP for drugs (21 CFR parts 210 & 211) were made final in 1970.
gmp history15
GMP – history

1

1962 – World Health Assembly set out resolutions on drug safety and monitoring.

1968 – The Medicines Act (UK) (an Act of Parliament) governs the manufacture and supply of medicines. It introduced system for:

  • product licensing covering old (pre 1968) and new medicines;
  • licensing of manufacturing sites;
  • licensing of clinical trials.
gmp history16
GMP – history

1

1976 – Medical Device Amendments

  • 1972 and 1973 were reported some pacemaker failures;
  • 1975 incidents involving a contraceptive intrauterine device caused thousands of injuries (pelvic infections, infertility and some deaths) and the product was taken off the market;
  • a Medical Device Amendments required manufacturers to provide FDA with safety and effectiveness data before marketing medical devices.

President Gerarl Ford signs the Medical Device Amendments

gmp history17
GMP – history

1

1980 – Infant Formula Act (FDA)

  • 1978 manufacturer of infant formula re-formulated two of its soy-based products;
  • 1979 infants diagnoses with lack of chlorides (hypochloremic);
  • greater regulatory control over the formulation and production of nutritional for infant formula;
  • manufacturers are required to analyze each batch of formula for nutrient, code each container with a slot number, keep detailed records of production and analysis;
  • the food GMPs (21 CFR part 110) were finalized in the 1980s.
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GMP – history

1

Beyond 1980s

  • FDA began publishing a series of guidance documents that have had a major effect on interpretation of current good manufacturing practices;
  • such documents provide guidance only on principles and practices that are not legal requirements;
  • however, typically they reflect current agency thinking and expectations.
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GMP – history

1

We can learn from these lessons or can mankind educate itself only by disaster and tragedy?

(by sen. Paul Douglas on the acceptance of the Senate’s 1962 drug bill)

Quality / Safety / Efficacy requirements

agenda20
Agenda

GMP – history

GMP – definition

GMP - structure

GMP – updates

GMP – next updates

GMP – under discussion

gmp definition
GMP – definition

2

  • What GMPs are?
  • What GMPs are for?
  • Who is responsible to apply / to control GMP ?

Good Manufacturing Practices are a set of regulations, codes and guidelines for the manufacture of drug substances and drug products, in vivo and in vitro diagnostic products and food.

GMPs are promulgated by the Authority (EMA, FDA, TGA, Japan, …) and have the force of law.

GMPs require that manufacturers and packagers of drugs, medical devices, some food, and blood have to ensure that their products are safe, pure, and effective before marketing them.

gmp definition22
GMP – definition

2

GMP regulations require a quality approach to manufacturing in order to minimize or eliminate contamination, mix-ups, and errors and produce a “quality product”.  This protects the consumer from purchasing a product which is not effective or even dangerous.

Failure of firms to comply with GMP regulations can result in very serious consequences including recall, seizure, fines, and …. injures / death for patients.

Most GMP requirements are very general and open-ended, allowing each manufacturer to decide individually how to best implement the necessary controls….and meet the technological improvements.

gmp definition23
GMP – definition

2

This provides much flexibility, but also requires that the manufacturer has to apply the requirements in a manner which makes sense for each individual business.

GMP regulations address issues including record-keeping, personnel qualifications and training, sanitation, cleanliness, equipment verification, process validation, complaint handling, ….

Facilities that are in good condition, equipment that is properly maintained and calibrated, employees who are qualified and fully trained, and processes that are validated and reproducible, …. are a few examples of how cGMP requirements help to assure the safety and efficacy of drug products.

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GMP – definition

2

Good Manufacturing Practice ensures that drug products are manufactured batch upon batch, year upon year to the appropriate and consistent quality standards in a reproducible way and in accordance with regulatory requirements.

GMPs are also sometimes referred to as "cGMPs". The "c" stands for "current," reminding manufacturers that they must employ technologies and systems which are up-to-date in order to comply with the regulation.

Inspectors’ definition:

gmp definition25
GMP – definition

2

Maintaining GMP is everyone’s responsible (Regulatory Authorities & manufacturers).

Maintaining GMP is a continuous (cyclic) process:

gmp definition26
GMP – definition

2

Maintaining GMP is everyone’s responsible (Regulatory Authorities & manufacturers).

Maintaining GMP is a continuous (cyclic) process:

agenda27
Agenda

GMP – history

GMP – definition

GMP - structure

GMP – updates

GMP – next updates

GMP – under discussion

gmp structure
GMP – structure

3

GMP Great Mountain of Paper

it is a systematic collection of guidelines

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GMP – structure

3

Where can we find the Good Manufacturing Practices?

Photocopies

Bookshop

Library

gmp structure30
GMP – structure

3

http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm

(internet website of the European community)

gmp structure31
GMP – structure

3

EU Legislation - Eudralex

The body of European Union legislation in the pharmaceutical sector is compiled in Volume 1 and Volume 5 of the publication "The rules governing medicinal products in the European Union“:

Volume 1 - EU pharmaceutical legislation for medicinal products for human use

Volume 5 - EU pharmaceutical legislation for medicinal products for veterinary use

The basic legislation is supported by a series of guidelines that are also published in the following volumes of "The rules governing medicinal products in the European Union":

Volume 2 - Notice to applicants and regulatory guidelines for medicinal products for human use

Volume 3 - Scientific guidelines for medicinal products for human use

Volume 4 - Guidelines for good manufacturing practices for medicinal products for human and veterinary use

Volume 6 - Notice to applicants and regulatory guidelines for medicinal products for veterinary use

Volume 7 - Scientific guidelines for medicinal products for veterinary use

Volume 8 - Maximum residue limits

Volume 9 - Guidelines for pharmacovigilance for medicinal products for human and veterinary use

Volume 10 - Guidelines for clinical trial

Medicinal products for paediatric use, orphan, herbal medicinal products and advanced therapies are governed by specific rules.

gmp structure32
GMP – structure

EU Legislation - Eudralex

The body of European Union legislation in the pharmaceutical sector is compiled in Volume 1 and Volume 5 of the publication "The rules governing medicinal products in the European Union“:

Volume 1 - EU pharmaceutical legislation for medicinal products for human use

Volume 5 - EU pharmaceutical legislation for medicinal products for veterinary use

The basic legislation is supported by a series of guidelines that are also published in the following volumes of "The rules governing medicinal products in the European Union":

Volume 2 - Notice to applicants and regulatory guidelines for medicinal products for human use

Volume 3 - Scientific guidelines for medicinal products for human use

Volume 4 - Guidelines for good manufacturing practices for medicinal products for human and veterinary use

Volume 6 - Notice to applicants and regulatory guidelines for medicinal products for veterinary use

Volume 7 - Scientific guidelines for medicinal products for veterinary use

Volume 8 - Maximum residue limits

Volume 9 - Guidelines for pharmacovigilance for medicinal products for human and veterinary use

Volume 10 - Guidelines for clinical trial

Medicinal products for paediatric use, orphan, herbal medicinal products and advanced therapies are governed by specific rules.

3

gmp structure33
GMP – structure

3

Volume 1 of the publications "The rules governing medicinal products in the European Union" contains the body of European Union legislation in the pharmaceutical sector for medicinal products for human use.

Namely:

  • 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 (Consolidated version : 05/10/2009).
  • Directive 2011/62/EU of the European Parliament and of the Council  of  8 June 2011 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products.
gmp structure34
GMP – structure

3

Volume 4 of "The rules governing medicinal products in the European Union" contains guidance for the interpretation of the principles and guidelines of good manufacturing practices for medicinal products for human and veterinary use laid down in Commission Directives 91/356/EEC, as amended by Directive 2003/94/EC, and 91/412/EEC respectively.

  • Commission Directive 2003/94/EC, of 8 October 2003, laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human useReplacement of Commission Directive 91/356/EC of 13 June 1991 to cover good manufacturing practice of investigational medicinal products.
  • Commission Directive 91/412/EEC of 23 July 1991 laying down the principles and guidelines of good manufacturing practice for veterinary medicinal products.
gmp structure35
GMP – structure

3

2011: GMP vol. 4 restyling in structure

gmp structure36
GMP – structure

3

  • Introduction
  • Part I - Basic Requirements for Medicinal Products

Chapter 1 - Quality Management

Chapter 2 - Personnel

Chapter 3 - Premise and Equipment

Chapter 4 - Documentation

Chapter 5 - Production

Chapter 6 - Quality Control

Chapter 7 - Contract Manufacture and Analysis

Chapter 8 - Complaints and Product Recall

Chapter 9 - Self Inspection

  • Part II - Basic Requirements for Active Substances used as Starting Materials

Basic requirements for active substances used as starting materials

  • Part III - GMP related documents 

Site Master File

Q9 Quality Risk Management

Q10 Note for Guidance on Pharmaceutical Quality System

MRA Batch Certificate

  • Annexes
  • Glossary

2011: new structure

(three parts)

gmp structure37
Annex 1 Manufacture of Sterile Medicinal Products

Annex 2 Manufacture of Biological Medicinal Products for Human Use

Annex 3 Manufacture of Radiopharmaceuticals

Annex 4 Manufacture of Veterinary Medicinal Products other than Immunological Veterinary Medicinal Products

Annex 5 Manufacture of Immunological Veterinary Medicinal Products

Annex 6 Manufacture of Medicinal Gases

Annex 7 Manufacture of Herbal Medicinal Products

Annex 8 Sampling of Starting and Packaging Materials

Annex 9 Manufacture of Liquids, Creams and Ointments

Annex 10 Manufacture of Pressurised Metered Dose Aerosol Preparations for Inhalation

Annex 11 Computerised Systems (revision January 2011)

Annex 12 Use of Ionising Radiation in the Manufacture of Medicinal Products

Annex 13 Manufacture of Investigational Medicinal Products

Annex 14 Manufacture of Products derived from Human Blood or Human Plasma

Annex 15 Qualification and validation

Annex 16 Certification by a Qualified person and Batch Release

Annex 17 Parametric Release

Annex 19 Reference and Retention Samples

GMP – structure

3

2011: new structure

(18 annexes)

gmp structure38
GMP – structure

3

Discussion, still pending (future Part 4?):

Separate section for GMP on excipients:

The IPEC-PQG Excipients GMPs Guide proposes GMP appropriate for the manufacture of excipients and is a joint initiative between the International Pharmaceutical Excipients Council (IPEC), as IPEC-Americas and IPEC Europe and the Pharmaceutical Quality Group (PQG).  It incorporates the IPEC Good Manufacturing Practices Guide for Bulk Pharmaceutical Excipients, 2001 with the PQG’s PS 9100:2002 Pharmaceutical Excipients.

The Guide makes an essential contribution to the wider understanding of good manufacturing practice appropriate for the excipient supply industry.  Excipient manufacturers and their customers can be assured that excipients manufactured according to this Guide will meet internationally accepted good manufacturing practice principles.

gmp structure40
Part III

It is intended to host a collection of GMP related documents, which are not detailed guidelines on the principles of GMP laid down in Directives 2003/94/EC and 91/412/EC.

The aim of Part III is to clarify regulatory expectations and it should be viewed as a source of information on current best practices. Details on the applicability will be described separately in each document. It includes:

- the former annex 20 on ICH Q9 Quality Risk Mangement;

- ICH Q10 guideline on Pharmaceutical Quality System;

- Site master file (a guidance for manufacturers);

- EU Format for batch certification (in the framework of Mutual recognition agreements).

Note: GMP part II is the former annex 18 on API manufacture.

GMP – structure

3

gmp structure41
First edition of GMP was issued in year 1989

Some chapters and annexes have been revised and updated and others have been drafted as new

Latest entries ?

Latest revisions ?

GMP – structure

3

gmp structure42
GMP – structure

3

Latest entries:

gmp structure43
GMP – structure

3

Latest revisions:

gmp structure44
GMP – structure

3

Latest revisions:

agenda45
Agenda

GMP – history

GMP – definition

GMP - structure

GMP – updates

GMP – next updates

GMP – under discussion

slide46

GMP – updates

4

  • Details for:
  • Introduction / site master file December 2010
  • chapter 4 June 2011
  • annex 11 June 2011
  • annex 14 November 2011
  • annex 6 July 2010
  • annex 1 March 2009
gmp updates
Eudralex news: 7/02/2011Eudralex – Volume 4 Good mnaufacturing practice (GMP) Guidelines: Publication of a revised introduction and theSite Master FileGMP – updates

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gmp updates48
Eudralex news: 7/02/2011Eudralex – Volume 4 Good mnaufacturing practice (GMP) Guidelines: Publication of a revised introduction and theSite Master FileGMP – updates

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Introduction

In addition to the general matters of Good Manufacturing Practice outlined in Part I and II, a

series of annexes providing detail about specific areas of activity is included. For some

manufacturing processes, different annexes will apply simultaneously (e.g. annex on sterile

preparations and on radiopharmaceuticals and/or on biological medicinal products).

A glossary of some terms used in the Guide has been incorporated after the annexes. Part III is intended to host a collection of GMP related documents, which are not detailed guidelines on the principles of GMP laid down in Directives 2003/94/EC and 91/412/EC. The aim of Part III is to clarify regulatory expectations and it should be viewed as a source of information on current best practices.Details on the applicability will be described separately in each document.

gmp updates49
Eudralex news: 7/02/2011Eudralex – Volume 4 Good mnaufacturing practice (GMP) Guidelines: Publication of a revised introduction and theSite Master FileGMP – updates

4

gmp updates50
Eudralex news: 7/02/2011Eudralex – Volume 4 Good mnaufacturing practice (GMP) Guidelines: Publication of a revised introduction and theSite Master FileGMP – updates

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Site Master File

These notes are intended to provide guidance on the recommended content of the Site

Master File. A requirement for a Site Master File is referred to in Chapter 4 of the GMP

Guide.

The Site Master File is prepared by the pharmaceutical manufacturer and should contain specific information about the quality management policies and

activities of the site, the production and/or quality control of pharmaceutical

manufacturing operations carried out at the named site and any closely

integrated operations at adjacent and nearby buildings.

When submitted to a regulatory authority, the Site Master File should provide

clear information on the manufacturer’s GMP related activitiesthat can be

useful in general supervision and in the efficient planning and undertaking of

GMP inspections.

gmp updates51
Eudralex news: 7/02/2011Eudralex – Volume 4 Good mnaufacturing practice (GMP) Guidelines: Publication of a revised introduction and theSite Master FileGMP – updates

4

Site Master File

These Explanatory Notes apply for all kind of manufacturing operations such as

production, packaging and labelling, testing, relabeling and repackaging of all types of

medicinal products.

The outlines of this guide could also be used in the preparation of a Site Master File or corresponding document by Blood and Tissue Establishments and

manufacturers of Active Pharmaceutical Ingredients.

ANNEX: CONTENT OF SITE MASTER FILE

………….

………….

Structure of GMPs

gmp updates52
Eudralex news: 7/02/2011Eudralex – Volume 4 Good mnaufacturing practice (GMP) Guidelines: Publication of a revised introduction and theSite Master FileGMP – updates

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Content of Site Master File

gmp updates53
Eudralex news: 7/02/2011Eudralex – Volume 4 Good mnaufacturing practice (GMP) Guidelines: Publication of a revised introduction and theSite Master FileGMP – updates

4

Content of Site Master File

gmp updates54
Eudralex news: 7/02/2011Eudralex – Volume 4 Good mnaufacturing practice (GMP) Guidelines: Publication of a revised introduction and theSite Master FileGMP – updates

4

Content of Site Master File

gmp updates55
Eudralex news: 7/02/2011Eudralex – Volume 4 Good mnaufacturing practice (GMP) Guidelines: Publication of a revised introduction and theSite Master FileGMP – updates

4

Content of Site Master File

gmp updates56
Eudralex news: 7/02/2011Eudralex – Volume 4 Good mnaufacturing practice (GMP) Guidelines: Publication of a revised introduction and theSite Master FileGMP – updates

4

Content of Site Master File

gmp updates57
Eudralex news: 7/02/2011Eudralex – Volume 4 Good mnaufacturing practice (GMP) Guidelines: Publication of a revised introduction and theSite Master FileGMP – updates

4

Content of Site Master File

gmp updates58
Eudralex news: 12/01/2011

Today, DG SANCO launches the publication of revised GMP guidelines (chapter 4 on documentation and Annex 11 on computerised system).

The revised guidelines will come into operation on 30 June 2011.

GMP – updates

4

NOTE:

DG SANCO is the acronym for the Directorate General for Health and Consumer Affairs.

It is the public authorities in the EU member states have responsibility over the health of European citizens.

The 3 priority objectives are to:

- improve information and knowledge for the development of public health;

- enhance capability to respond to threats to health;

- promote health and prevent disease through addressing health determinants.

gmp updates60
Eudralex news: 12/01/2011EU published the revised GMP guidelines, chapter 4 (on documentation).

The chapter was completely reworked and a lot of details were adopted. A lot of changes address the growing use of electronic documentation and data recording. The chapter 4 has been mainly updated as a consequence of the new revised Annex 11 on computerized systems revised at the same time.

However, other general changes and further explanations were included in the new chapter 4 (for example with respect to style, language and revision histories).

Chapter 4 has completely changed and there are only a few identical paragraphs to the prior version from 2004. A synopsis table could show in detail where changes have been made.

GMP – updates

4

gmp updates61
Eudralex news: 12/01/2011EU published the revised GMP guidelines, chapter 4 (on documentation).

A synopsis table could show in detail where changes have been made.

GMP – updates

4

gmp updates62
Eudralex news: 12/01/2011EU published the revised GMP guidelines, chapter 4 (on documentation).

Changes:

it applies to various types of documents and media (paper-based, electronic or photographic media) and the term “written” means recorded or documented on media from which data may be rendered in a human readable form;

2. it also distinguishes between instructions (specifications; manufacturing formulae, processing, packaging and testing instructions; procedures; protocols; technical agreements) and records (records; certificate of analysis; reports). An inventory of documents should be maintained as part of Quality Management System; the SOPs and other working instructions should be written in an imperative mandatory style.

GMP – updates

4

gmp updates63
Eudralex news: 12/01/2011EU published the revised GMP guidelines, chapter 4 (on documentation).

Changes:

3. it mentions the Site Master File in accordance with new part III;

4. it includes a new section on “retention of documents” (batch documentation must be kept for one year after expiry of the batch or at least five years after certification of the batch by the qualified person, which ever is longer; for IMP, batch documentation must be kept for at least 5 years after the completion of the last clinical trial; other “critical” documentation should be retained while the Marketing Authorisation remains in force);

5. A formal “line clearance” has been introduced to show that equipment and work station are clear of previous products, materials, documents.

GMP – updates

4

gmp updates64
Eudralex news: 12/01/2011EU published the revised GMP guidelines, chapter 4 (on documentation).

Changes:

6. the list of documentation is increased: technology transfer, change controls, investigations into deviations and non conformances, internal quality/GMP compliance audits, supplier audits;

7. the emphasis on the logbook is increased: analytical testing, production equipment, areas where product has been processed;

8. the role of the Qualified Person is also explained in more detail. All records should be available to the QP for review when requested; appropriate records should routinely be provided to the QP for batch certification. However there is no obligation implemented that the QP is obliged to review and approve (sign) all GMP-relevant documents.

GMP – updates

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gmp updates65
Eudralex news: 12/01/2011EU published the revised GMP guidelines, Annex 11 (on computerised system).GMP – updates

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gmp updates66
Eudralex news: 12/01/2011EU published the revised GMP guidelines, Annex 11 (on computerised system).

The annex was revised because the importance of computer systems in the pharmaceutical manufacturing increased in the last decade. The complexity also increased as well.

The new version shows that the regulators prefer the risk based approach and endorse the implementation in most areas.

The new annex is really new and completely over-worked. It is very difficult to compare the prior version from 1997 with the new one. A synopsis table was draft for that aim to see differences faster and better.

GMP – updates

4

gmp updates67
Eudralex news: 12/01/2011EU published the revised GMP guidelines, Annex 11 (on computerised system).

The synopsis table

GMP – updates

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gmp updates68
Eudralex news: 12/01/2011EU published the revised GMP guidelines, Annex 11 (on computerised system).

Changes:

1. increased scope and key elements of the principle of annex 11:

- it applies to all forms computerised systems used as part of a GMP regulated activities (it includes also in-house developed spreadsheets and databases);

- the application should be validated; IT infrastructure should be qualified (for the first time there is a specific requirement for IT infrastructure qualification);

- when a computerised system replaces a manual process should be no resultant decrease in product quality, process control or quality assurance (from the previous version, there is an additional requirement of process control. It states the minimum quality of a computerised system should be as good as the manual system but in reality, the computerised system should be much better as the human factor is);

GMP – updates

4

gmp updates69
Eudralex news: 12/01/2011EU published the revised GMP guidelines, Annex 11 (on computerised system).

Changes:

2. risk management have to be applied throughout the Life Cycle of a computerised system dependent on patient safety, data integrity and product quality. The work done should be based on a justified and documented risk.

3. There still remains the requirement for closer cooperation between all involved with the system. Two new roles are mentioned: process owner (person responsible for the business process -a senior manager-) and system owner (person responsible for the availability and maintenance of a computerised system and the security of data- laboratory manager-).

GMP – updates

4

gmp updates70
Eudralex news: 12/01/2011EU published the revised GMP guidelines, Annex 11 (on computerised system).

Changes:

4. The chapter on Suppliers and Service providers has been expanded. When third parties are used to carry out any work on a computerised system there needs to be a formal agreement: clear statement of the responsibilities of the third party. Besides, IT departments should be considered analogous.

5. Validation section has been expanded from one to eight chapters. A life cycle should be used to validate a system and a manufacturer should be able to justify its approach based on risk assessment. The annex 11 does not mandate any validation approach but whichever one is selected for a specific system it needs to be justified and documented.

GMP – updates

4

gmp updates71
Eudralex news: 12/01/2011EU published the revised GMP guidelines, Annex 11 (on computerised system).

Changes:

6. The requirements for data integrity including audit trail, security, backup, migration and archiving of documents have been expanded. Audit trail are not mandatory on all system but should be based on risk assessment.

7. Chapters addressing business continuity and incident management have been added, and electronic signatures are now addressed for the first time in EU GMP regulations.

GMP – updates

4

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GMP – updates

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  • Annex 14 – entry in force 30 November 2011-

EU has revised annex 14 defining the requirements for drugs derived from human blood or plasma.

The new annex 14 also applies to stable derivatives of human blood or human plasma (e.g. albumin) incorporated into medical devices.

However it does not apply to blood components intended for transfusion.

The annex has been revised to implement contents of Directives 2002/98/EC which defines requirements for the collection and testing of human blood and blood components for all uses, including the manufacture of medicinal products.

The new annex 14 introduces some revised and new requirements for qualified person such as: steps like processing, storage and transportation which are done after the collection should be performed in an establishment with a manufacturing authorization under the responsibility of a QP.

gmp updates74
GMP – updates

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  • Annex 14 – entry in force 30 November 2011-

The new annex takes into account the fact that specific processing steps in relation to plasma for fractionation take place in a blood establishment without a manufacturing authorization. In this case the specific appointment of a qualified person may not be appropriate.

These steps should be carried out under the responsibility of a “responsibleperson”. In this case a contract is needed which clearly defines the responsibilities and requirements in order to ensure quality and safety.

The qualified person should ensure that audits are performed to confirm that the blood establishment complies with the contract and the requirements.

gmp updates76
GMP – updates

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  • Annex 6

The annex 6 has been revised as a consequence of the re-structuring of the GMP Guide and the need to review requirements of Part II of the Guide for the applicability to medicinal gases. In this occasion the annex has been also revised.

The annex states that bulk gases could be regarded as an active substances used as starting materials or bulk medicinal products as decided by national competent authorities.

Manufacture of active substance gases should comply with the basic requirements of the Part II while manufacture of medicinal gases should comply with the basic requirements of Part I.

gmp updates78
GMP – updates

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  • Annex 1

The changes are:

  • classification vs. monitoring of clean room and clean air device;
  • more detailed guidance (in accordance with FDA) on media simulations;
  • bioburden monitoring prior to sterilisation;
  • guidance on crimp/capping of vials.
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  • Annex 1: classification vs. monitoring

Clean room / clean air device classification is required to be performed according to EN ISO 14644-1. Probe-locations should be chosen in order to demonstrate the homogeneity across the room.

Monitoring, on the other hand, does not need to be performed according to EN ISO 14644-1. It can be performed for a reduced number of sampling points and sampling volumes.

A formal risk analysis study based on experiments and analysis of the monitoring data (over at least 6 months operation) should provide a basis for the determination of frequencies and limits. These limits and sample locations should be periodically reviewed for on-going validity of the risks initially considered.

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  • Annex 1: classification vs. monitoring

Particle counters with long tube lengths will no longer be acceptable for clean room classification, as they absorb too many particles (especially 5 mm particles).

Therefore, modern portable particle counters with short tubes or (even preferable when possible) those without tubes should be used for classification purposes.

The certificate of calibration of the particle counter should mention the tube length and nature of material (inox or polymer). When calibration of the particle counter is performed outside by an external laboratory, the particle counting system should be qualified on site with a comparative measurement with an isokinetic probe.

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  • Annex 1: media fill guidance

The number of containers used for media fills should be sufficient to enable a valid evaluation. For small batches, the number of containers for media fills should at least equal the size of the product batch. The target should be zero growth and the following should apply:

  • when filling <5,000 vials no contaminated units should be detected
  • When filling 5,000 to 10,000 units:

a) One (1) contaminated unit should result in an investigation, including consideration of a repeat media fill;

b) Two (2) contaminated units are considered cause for revalidation, following investigation.

  • When filling more than 10,000 units:

a) One (1) contaminated unit should result in an investigation;

b) Two (2) contaminated units are considered cause for revalidation, following investigation.

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  • Annex 1: bioburden monitoring

Bioburden should be performed on each batch both for aseptically filled products and terminally sterilised products;

in terminally sterilised products, when an overkill approach is used, bioburden can be monitored at suitable scheduled intervals;

for parametric release system, bioburden has to be performed on each batch and considered as an in-process test;

… the level of endotoxin should be monitored.

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  • Annex 1: crimp/ capping of vials

As the equipment used to crimp vial caps can generate a large quantities of non-viable particulates, the equipment should be located at a separate station equipped with adequate air extraction.

Vial capping is “as aseptic process” using sterilised caps or “as a clean process” performed outside the aseptic core.

When considered a “clean process” stoppered vials have to be protected by Grade A conditions in the aseptic area, and stoppered vials protected with a Grade A air supply until the cap has been crimped.

When required human intervention at the capping station, appropriate technology has to be used.

RABS and isolators may minimise direct human interventions.

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Basic design for capping(by Bayer Healthcare)

OLD

stoppering

capping

filling

conveyance

conveyance

Class B

Class D/ contr. environment

LAF/ grade B

air supply

Class A

Grade A

air supply

Tunnel, LAF

air supply

Class A

NEW

stoppering

capping

filling

conveyance

conveyance

Class B

Class D/ contr. environment

Grade A

air supply

+ RABS

Class A

Class A

Tunnel, grade A

air supply

Class A

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Agenda

GMP – history

GMP – definition

GMP - structure

GMP – updates

GMP – next updates

GMP – under discussion

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  • Eudralex news: 19/11/2010Today DG SANCO launches a public discussion of the revised chapter 5 of the GMP laying down the detailed guidelines for production.

Changes were proposed on the qualification of suppliers of starting material, the supply chain traceability for starting materials (API supply chain & control of starting material) and the testing of starting materials and pedigree concept.

Rapporteur: France and UK

Status: Final draft for agreement and consolidation at EMA September 2011 meeting. Review of impact of veterinary products (EMA November meeting) required before finalisation.

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  • Eudralex news: 9/11/2010

Today, DG SANCO launches a public consultation of the revised chapter 7 of the GMP laying down the detailed guidelines for outsourcing activities.

Following the ICH Q10 guideline on the Pharmaceutical Quality System, Chapter 7 of the GMP Guide has been revised to provide guidance on outsourced activities beyond the current scope of contract manufacture and analysis operations.

Rapporteur: Greece.

Status: Final draft agreed at EMA September 2011 meeting

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  • Eudralex news: 19/04/2010

Today, the unit in charge of pharmaceuticals launches a public consultation on Annex 2 of the GMP laying down the guidelines for the manufacture of biological medicinal substances and products for human use.

Annex 2 was proposed to be revised as a consequence of the restructuring of the GMP guide, the increased breadth of biological products to include several new product types such as transgenic derived products and the Advanced Therapy Medicinal Products, (ATMPs) together with associated new legislation. Significant changes have also been made as a result of the comments received from the first consultation.

Rapporteur: UK

Status: comments agreed with CAT, BWP and GMDP IWG and ready for transmission to EU Commission

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Eudralex news: 19/04/2010

Annex 2 of the GMP laying down the guidelines for the manufacture of biological medicinal substances and products for human use.

Incorporation of some principles of the following regulations:

Regulation (EC) No. 1394/2007 (amending Directive 2001/83/EC)

art. 5 - GMP: the Commission shall, after consulting the Agency, draw up guidelines in line with the principles of good manufacturing practice and specific to advanced therapy medicinal products.

art. 15 – traceability: the holder of a marketing authorisation for an advanced therapy medicinal product shall establish and maintain a system ensuring that the individual product and its starting and raw materials, including all substances coming into contact with the cells or tissues it may contain, can be traced through the sourcing, manufacturing, packaging, storage, transport and delivery to the hospital, institution or private practice where the product is used.

The marketing authorisation holder shall keep the data referred to in paragraph 1 for a minimum of 30 years after the expiry date of the product.

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Eudralex news: 19/04/2010

Annex 2 of the GMP laying down the guidelines for the manufacture of biological medicinal substances and products for human use.

The new annex is designed to meet the requirements of EC regulations:

Commission Directive 2009/120/EC amending Directive 2001/83/EC, regards advanced therapy medicinal products

It is provides further ATMP details i.e. somatic cell therapy/xenogeneic products has been combined with tissue engineered products.

Directive 2004/23/EC on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells

art. 6 - Accreditation, designation, authorisation or licensing of tissue establishments and tissue and cell preparation processes.

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Eudralex news: 19/04/2010

Annex 2 of the GMP laying down the guidelines for the manufacture of biological medicinal substances and products for human use.

Incorporation of some principles of the following regulations:

Commission Directive 2002/98/EC setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components

supply chain, traceability, …

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Eudralex news: 19/04/2010

Annex 2 of the GMP laying down the guidelines for the manufacture of biological medicinal substances and products for human use.

Changes:

The original Annex 2 has been re‑structured to become Part A (General Guidance), a new Part B (Specific Guidance on Selected Product Types)has been created to provide further guidance on selected product types (10 sections) and a Glossary has been added for technical terms or phrases used in the Annex.

Part A

A table providing illustrative guidance on the scope of the Annex, the table is based on that in Part II. The differences (e.g. start point of GMP) drew comments at the consultations but is based on the fact that Annexes in EU GMP have a different scope to Part II.

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Eudralex news: 19/04/2010

Annex 2 of the GMP laying down the guidelines for the manufacture of biological medicinal substances and products for human use.

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Table includes the start point of GMP where GMP principles are applicable. This is principally in the context of animal sourced products and seed/cell banks. These early-stage and upstream sites will in general not be inspected.

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Eudralex news: 19/04/2010

Annex 2 of the GMP laying down the guidelines for the manufacture of biological medicinal substances and products for human use.

Changes:

Text on the need, or otherwise, for the dedication of facilities, has been align to the extent possible with expectations in FDA’s revisions on the manufacture of live vaccines and spore forming organisms.

New text on considerations for batch certification of products with a short shelf life (RMM application)

Part B

A section on animal derived products was introduced as a result of the issues with heparin, however this section is not specific for heparin or China.

Glossary

There are nearly 3 pages of entries, where legal definitions of terms used in the Annex have been made.

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Agenda

GMP – history

GMP – definition

GMP - structure

GMP – updates

GMP – next updates

GMP – under discussion

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CHAPTER 1

CHAPTER 2

CHAPTER 3 & 5

Latest news from 63rd EMA GMDP IWG meeting (September 2011)

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Chapters 1 -Quality Management (crossing reference to ICH Q10)

Rapporteur: UK

Status: breakout session in November meeting to revise the role of Quality Unit

On 4 January 2010, EU has published a proposal for the revision of Chapter 1 in order to put the contents of ICH Q10 into European legislation.

The changes are very comprehensive: this is already clear from the title which was changed from “Quality Management” to “Quality Management System” in order to emphasize that the GMP requirements call for the detailed proof of a system for establishing, maintaining and further developing a quality managing system.

In addition, new sections were included into chapter 1 to incorporate the principles of ICH Q10:

- Process performance and product quality monitoring system;

- Management of outsourced activities and purchased materials;

- Management of review on the quality management system;

- Monitoring of internal and external factors impacting the quality Management system.

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Chapters 1 (crossing reference to ICH Q10)

Rapporteur: UK

Status: breakout session in November meeting to revise the role of Quality Unit

Also the principles ISO 9001 is now part of the GMP requirements:

- emphasis of the senior management's responsibility;

  • quality management manual.

There is also a detailed description of the requirement to establish a CAPA procedure in connection with the requirement of quality risk management and in compliance with ICH Q9; CAPA measures should be specified as the result of a risk assessment.

This section also include a note on the use of data management and statistical systems.

For the first time there is also a statement on design space in the EU GMP Guide.

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Chapters 1 (crossing reference to ICH Q10)

Rapporteur: UK

Status: breakout session in November meeting to revise the role of Quality Unit

What is of major importance is the section “outsourced activities and purchased materials”: these activities have to be described in detail and become part of QM system; the purchase of raw materials (active ingredients and excipients) also gets a special mention.

The responsibility of the pharmaceutical company is stressed; this is of great legal importance, e.g. in case of counterfeit raw material.

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Chapters 2 –Personnel(in order to integrate the principles of “Pharmaceutical Quality System” as described in the ICH Q10)

Rapporteur: UK

Status: breakout session in November meeting to revise the role of Quality Unit

The chapter 2 which consisted of 5 subchapter, has been extended by 2 new subchapters on “consultant” and “management of change in Product ownership”.

The chapter Consultant corresponds in the essence to the USA requirements from CFR Part 211.34

…..

Management of change in product ownership is identical with chapter 2.8 of ICH Q10……….it means that, in case product ownership changes (e.g. company buy-outs / company sales), a continuous chain of responsibility a to be kept up by the concerned firms and it should be guaranteed that the information necessary for this is transferred to the new owner.

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Chapters 3 & 5 – concerning dedicated facilities

Rapporteur: Germany, France

Status: SWP has to agree to develop toxicological tools as basis for a risk assessment for production of certain classes of drugs to identify and reduce risks; the impact on veterinary products (allergic reactions) has to be clarified (ref. RiskMAPP guide published by ISPE):

risk based approach for … the production of … certain antibiotics, certain hormones, certain cytotoxics, certain highly active drugs …in dedicated facilities

Dedicated facilities are currently mandatory for highly sensitising products (i.e. penicillines), biological preparations using live pathogenic microorganisms.

Working on campaign is acceptable for other products.

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Chapters 6 – quality control

Rapporteur: France

Status: new draft including the technical transfer of analytical methods consolidated in September 2011 meeting

Chapters 8 – complaints and product recall

Rapporteur: Ireland

Status: new drafting underway; a concept paper is agreed at September meeting

It was proposed to update it to reflect the need for Quality Risk Management Principles to be applied when investigating quality defect/complaint issues and when making decisions in relation to product recalls. It was also proposed to update it to more accurately reflect the wording of Dir 2003/94/EC on when a quality defect/complaint should be reported to the Competent authority.

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Annex 15 – qualification & validation

Rapporteur: UK

Status: awaiting finalisation of QWP guideline on process validation (continuous process verification following the FDA gudeline)

Annex 16 – certification by a QP and batch release

Rapporteur: Finland

Status: concept paper to be clarified on definition of Batch release / Batch certification / batch confirmation

Open questions: role in the complex supply chain, retained sampling location for imported products.

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Annex 17 – parametric release

Rapporteur: UK

Status: amended to “real time release testing”; awaiting finalisation of QWP consultation.

Annex 1 – sterile medicinal products

Rapporteur: tbc

Status: a concept paper for sterile filtration to be draft.

Annex 19 – reference & retention samples

Rapporteur: Denamrk

Status: survey for a common interpretation; discussion at EMA November meeting.

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  • EU guidance document – revision process to put in force updated chapters /annexes

3

4

7

6

5

8

9

10

Guidelines come into operation 6 months after their adoption

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EMA structure

Committees

Scientific evaluation on applications from pharmaceutical companies is carried out by six Scientific Committees.  These Committees normally meet on a monthly basis and are comprised of members nominated by the Member States. Assessments are based on purely scientific criteria and determine whether or not the medicines concerned meet the necessary quality, safety and efficacy requirements (in accordance with EU legislation, particularly Directive 2001/83/EC). These processes ensure that medicines have a positive risk-benefit balance in favour of patients/users of these products once they reach the marketplace.

Committee for Medicinal Products for Human Use (CHMP)

Committee for Medicinal Products for Veterinary Use (CVMP)

Committee for Orphan Medicinal Products (COMP)

Committee on Herbal Medicinal Products (HMPC)

Paediatric Committee (PDCO)

Committee for Advanced Therapies (CAT)

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EMA structure

Working parties and other groups

The Agency has a number of working parties and related groups, which can be consulted by the Agency's scientific committees on scientific issues relating to their particular field of expertise.

The groups are made up of members who have expertise in a particular scientific field, selected from the European expert list maintained by the Agency. Members are given tasks associated with the scientific evaluation of marketing authorization applications or drafting and revision of scientific guidance documents.

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EMA structure

i.e. The current CHMP standing working parties are:

Biologics Working Party

Patients' and Consumers' Working Party

Pharmacovigilance Working Party

Quality Working Party

Safety Working Party

Scientific Advice Working Party

GMP – updating process