GMP & cGMP

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GMP – history

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.

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 GMP – history

We can choose it by looking:

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GMP – history

We can not choose it by looking:

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 GMP – history

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

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GMP – history
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).

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 GMP – history

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.

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GMP – history

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

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 GMP – history

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.

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GMP – history

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.

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 GMP – history

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.

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GMP – history

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

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 GMP – history

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

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

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

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GMP – definition

• 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.

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 GMP – definition

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.

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GMP – definition

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

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:

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.

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GMP – definition

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

Maintaining GMP is a continuous (cyclic) process:

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 GMP – definition

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

Maintaining GMP is a continuous (cyclic) process:

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GMP – structure

GMP Great Mountain of Paper it is a systematic collection of guidelines

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 GMP – structure

Where can we find the Good Manufacturing Practices?

Photocopies
Bookshop

Library

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GMP – structure

http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm
(internet website of the European community) ® All rights reserved

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 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.

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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.

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 GMP – structure

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.

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GMP – structure

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 use
Replacement 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.

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 GMP – structure

2011: GMP vol. 4 restyling in structure

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GMP – structure
• 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
2011: new structure Basic requirements for active substances used as starting materials
• Part III - GMP related documents
(three parts)
Site Master File
Q9 Quality Risk Management
Q10 Note for Guidance on Pharmaceutical Quality System
MRA Batch Certificate
• Annexes
• Glossary

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 GMP – structure
• 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)
2011: new structure • Annex 12 Use of Ionising Radiation in the Manufacture of Medicinal
(18 annexes) 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
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GMP – structure

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.

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 GMP – structure

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GMP – structure

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.

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 GMP – structure

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 ?

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GMP – structure

Latest entries:
ENTRY IN FORCE
Annex 15 – qualification & validation September 2001
Annex 16 – certification by QP & batch January 2002
release
Annex 17 – parametric release January 2001
Annex 19 – reference & retention January 2006
samples

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 GMP – structure

Latest revisions:
ENTRY IN FORCE
INTRODUCTION December 2010
CHAPTER 1 – Quality Management Revision February 2008, in force 1 July 2008
CHAPTER 4 - Documentation Revision January 2011, in force 30 June 2011
CHAPTER 6 – Quality control Revision October 2005, in force 1 June 2006
CHAPTER 8 – Complaints and product Revision December 2005, in force 1 February 2006
recall
BASIC REQUIREMENTS FOR ACTIVE Revision February 2010, in force 31 July 2010
SUBSTANCES USED AS STARTING
MATERIALS (part II)

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GMP – structure

Latest revisions:
ENTRY IN FORCE
Annex 1 – sterile medicinal products Revision 25 November 2008, in force 1 March 2009
& 1 March 2010 for freeze dried
Annex 3 - radiopharmaceuticals Revision September 2008, in force 1 March 2009
Annex 6 – medicinal gases Revision 3 February 2010, in force 31 July 2010
Annex 11 – computerized Systems Revision January 2011, in force 30 June 2011
Annex 13 – investigational medicinal Revision 3 February 2010 , in force 31 July 2010
products
Annex 14 – products derived from Revision May 2011, in force 30 November 2011
human blood or human plasma

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 GMP – updates

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

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GMP – updates

Basic design for capping (by Bayer Healthcare)

filling stoppering conveyance conveyance capping

Class B Class D/ contr. environment

Class A Class A Grade A Tunnel, LAF LAF/ grade B
air supply air supply air supply

filling stoppering conveyance conveyance capping

Class B Class D/ contr. environment

Class A Class A Class A Tunnel, grade A Grade A
air supply air supply
+ RABS
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 GMP guidelines
• GMP as per Schedule “M”
www.cdsco.nic.in
• GMP as per WHO
www.who.int
• GMP as per MCA now known as MHRA
www.mca.gov.uk
• GMP as per TGA
www.tga.gov.au
• GMP as per US FDA
www.fda.gov
• GMP as per ICH guidelines
www.ich.org

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GMP
• GMP in solid dosage forms
• GMP in semisolid dosage forms
• GMP in Liquid orals
• GMP in Parenterals Production
• GMP in Ayurvedic medicines
• GMP in Bio technological products
• GMP in Nutraceuticals and cosmeceuticals
• GMP in Homeopathic medicines

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 GMP
• Good Manufacturing Practice
• Good Management Practice
• Get More Profit
• Give more Production
• GMP Training with out tears

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GMP
• All past GMPs are history….It is
looking like in rear view mirror and
driving

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 Ten Principles of GMP
1. Design and construct the facilities and equipments
properly
2. Follow written procedures and Instructions
3. Document work
4. Validate work
5. Monitor facilities and equipment
6. Write step by step operating procedures and work on
instructions
7. Design ,develop and demonstrate job competence
8. Protect against contamination
9. Control components and product related processes
10. Conduct planned and periodic audits

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Beyond GMP
• Reduce pollution - Zero discharge
• Adaptation of environment friendly methods
• Consideration for better and healthier life tomorrow
• Consideration of ethics in life
• One should begin with end in mind otherwise it will be
the beginning of the end

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 Cost of effective GMP

• In fact Cost benefits – positive cost benefits of GMP/QA

• Good plant layout, Smooth work flows, Efficient

documentation systems, well controlled process, good
stores lay outs and stores records- These are Good
manufacturing practices

• Reduction in work in process and inventory holding costs

• Avoidance of cost of Quality failure ( cost of waste, of

rework, of recall, of consumer compensation and of loss
of company reputation)

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List of important documents in GMP

• Policies
• SOP
• Specifications
• MFR (Master Formula Record)
• BMR
• Manuals
• Master plans/ files
• Validation protocols
• Forms and Formats
• Records

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 10 attributes of a good document
1. Accurate
2. Clear
3. Complete
4. Consistent
5. Indelible
6. Legible
7. Timely
8. Direct
9. Authentic
10. Authorized
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Certifying agencies
• ICH. www.ich.org

• WHO. www.who.int

• US FDA. www.fda.gov

• EU/EMEA. www.emea.europa.eu

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How do GMPs of different countries
compare?
At a high level, GMPs of various nations are very
similar; most require things like:
Equipment and facilities being properly
designed, maintained, and cleaned
Standard Operating Procedures (SOPs) be
written and approved
An independent Quality unit (like Quality
Control and/or Quality Assurance)
Well trained personnel and management

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cGMP For Finished Pharmaceuticals

1. General Provision
2. Organization & Personnel
3. Building & Facilities
4. Equipment
5. Control of Components & Drug Product Containers
& Closures
6. Production & Process Control
7. Packaging & Labeling Control
8. Handling & Distribution
9. Laboratory Control
10. Records & Reports
11. Returned & Salvaged Drugs

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 Organization & Personnel
1. Responsibilities of quality control unit.

2. Personnel qualifications.

3. Personnel responsibilities.

4. Consultants.

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Building & Facilities

1. Design and construction features.
2. Lighting.
3. Ventilation, air filtration, air heating and cooling.
4. Plumbing.
5. Sewage and refuse.
6. Washing and toilet facilities.
7. Sanitation.
8. Maintenance .

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 Equipment
1. Equipment design, size, and location.
2. Equipment construction.
3. Equipment cleaning and maintenance.
4. Automatic, mechanical, and electronic equipment.
5. Filters.

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Control of Components & Drug

Product Containers & Closures
1. General requirements.
2. Receipt & storage of untested components, drug product
containers, and closures.
3. Testing and approval or rejection of components, drug
product containers, and closures.
4. Use of approved components, drug product containers, and
closures.
5. Retesting of approved components, drug product containers,
and closures.
6. Rejected components, drug product containers, and closures.
7. Drug product containers and closures.

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 Production & Process Control
1. Written procedures;
2. Charge-in of components.
3. Calculation of yield.
4. Equipment identification.
5. Sampling and testing of in-process materials and
drug products.
6. Time limitations on production.
7. Control of microbiological contamination.
8. Reprocessing.

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Packaging & Labeling Control

1. Materials examination and usage criteria.
2. Labeling issuance.
3. Packaging and labeling operations.
4. Tamper-evident packaging requirements for over-the-counter
(OTC) human drug products.
5. Drug product inspection.
6. Expiration dating.

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 Handling & Distribution

1. Warehousing procedures.

2. Distribution procedures.

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Laboratory Control
1. General requirements.
2. Testing and release for distribution.
3. Stability testing.
4. Special testing requirements.
5. Reserve samples.
6. Laboratory animals.
7. Penicillin contamination.

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 Records & Reports
1. General requirements.
2. Equipment cleaning and use log.
3. Component, drug product container, closure, and labeling
records.
4. Master production and control records.
5. Batch production and control records.
6. Production record review.
7. Laboratory records.
8. Distribution records.
9. Complaint files.

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Returned & Salvaged Drug

Products

1. Returned drug products.

2. Drug product salvaging.

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