THE QUALITY ASSURANCE JOURNAL, VOL.
2, 55–60 (1997)
EU and FDA GMP Regulations:
Overview and Comparison
The increasing emphasis on global
supply of drug products, as well as
starting materials and investigational
materials, along with international
agreements between regulatory
authorities, requires Quality
Professionals to be versed in the GMP
requirements of other nations. In
particular, knowledge of both EU and
US GMPs is becoming a necessary
aspect of doing business in today’s
market. The foundations of the EU and
US GMP systems, an overview
comparison of drug product GMP
regulations and a summary of the
status of regulations is presented.
INTRODUCTION
In 1989, the European Council delegated to the
Commission the task of adopting measures to
strengthen the control of manufacture of medicinal
products by means of a directive and guidelines on
good manufacturing practice. The Commission
used the Community Guide to Good Manufactur-
John G. Grazal
Specialist Microbiologist
(American Academy of
Microbiology), Senior Manager,
International Compliance Group,
Zeneca Pharmaceuticals, Zeneca
Inc., Wilmington, Delaware, USA
David S. Earl
Qualified Person (as defined by
Article 23 of EC Directive 75/319),
Quality Assurance Manager,
Quality Assurance Dept., Zeneca
Pharmaceuticals, Macclesfield, UK
CCC/1087-8378/97/020055–06 $17.50
© 1997 John Wiley & Sons, Ltd.
ing Practice, prepared by a working party of
Community pharmaceutical inspectors, as the basis
for the Directives 91/356 and 91/412/EEC which
established the principles and guidelines for good
manufacturing practice for medicinal products for
human and veterinary use, respectively. There is no
difference in GMPs between the two directives and
subsequent reference will be to 91/356/EEC. The
GMP principles are interpreted with reference to
detailed guidelines published by the European
Commission in the Guide to Good Manufacturing
Practice for Medicinal Products (GMP Guide), con-
tained within Volume IV of the Rules Governing
Medicinal Products in the European Community
(1).
The US first promulgated GMP regulations in 1963.
These were updated in 1971, and a major revision
was written in 1978 which, notwithstanding several
clarifying revisions, remains in effect today. The
GMP requirements for human drugs are contained
in regulations 21 Code of Federal Regulations
(CFR) Parts 210 and 211 (2). These laws are binding
regulations which are to be considered minimum
standards below which products are deemed adul-
terated. The regulations apply to both human and
veterinary drug products. FDA enforces current
good manufacturing practices (CGMP) based on
the CGMP provision in the Food Drug and Cos-
metic (FD & C) Act. This provision states that a
drug is deemed adulterated if the methods used in,
or the facilities used for drug product manufacture,
processing, packing, or holding do not conform to
or are not operated or administered in conformity
with CGMP. If a practice is not specified in the
regulations, FDA must prove that the practice is
CGMP.
EC GMP DIRECTIVES AND US
REGULATIONS
The EC GMP Directives contain the principles and
guidelines for medicinal drug manufacture. These
laws are made up of 16 articles which lay down the
legal framework that member states and manu-
facturers must comply with. EC Directive
91/356/EEC contains three chapters. Chapter 1
(Articles 1–5) General Provisions, requires repeat
56
Table 1. EU Principles and Guidelines of GMP
Quality management
Personnel
Premises and equipment
Documentation
Production
Quality control
Work contracted out
Complaints and product recall
Self inspection
inspections by member states, establishes the GMP
Guide as the means of interpretation of the princi-
ples and guidelines, requires importers of product
from third countries to ensure equivalent standards
of manufacture to those in EC Rules Volume IV, and
states that manufacturers shall ensure compliance
with the marketing authorization. Chapter 2 (Arti-
cles 6–14) promulgates the principles and guide-
lines of GMP for medicinal products for human use
(Table 1). Chapter 3 (Articles 15 and 16) The Final
Provisions, directs member states to implement the
directives into national law. It is the principles
outlined in EC Directive 91/356 which provide the
legal basis for GMP in the EU. EC member states
were expected to bring into force the laws, regula-
tions and necessary administrative provisions to
comply with the Directive no later than 1 January
1992. The UK Medicines Act was updated by
Statutory Instrument 2846 on 11 December 1992.
Other member states followed later and made
compliance with the principles of GMP statutory.
The difference in timings can be attributed to the
definition of an EC Directive which is a mechanism
for providing a framework for national legislation
by setting out broad principles and criteria for
regulating a particular subject. Directives are bind-
ing but leave the method of achieving the outcome,
within specified time limits, to the individual
states.
The US GMP regulations are contained in the CFR
Title 21, Food and Drugs, Parts 210 and 211. Part
210 provides the framework for the regulations
along with some definitions. Part 211 states the
requirements (Table 2). These GMP regulations are
Federal Law. The CFR contains the rules published
in the Federal Register by the Executive depart-
ments and agencies of the US Federal Government.
The document is divided into 50 titles representing
broad areas subject to Federal regulation. Title 21,
covering food and drugs, is updated annually in
April. By law, all proposed regulations must be
published in the Federal Register to allow a
minimum of 30 days for public review and com-
ment before becoming final. The publication of a
John G. Grazal and David S. Earl
Table 2. US CMP Regulations for Finished
Pharmaceuticals
General provisions
Organization and personnel
Buildings and facilities
Equipment
Control of components and drug product
containers and closures
Production and process controls
Packaging and labelling control
Holding and distribution
Laboratory controls
Records and reports
Returned and salvaged drug products
final food or drug regulation in the Federal Register
is accompanied by a summary of each type of
comment submitted on the proposal along with the
FDA Commissioner’s conclusions. The Commis-
sioner’s rationale (preamble) for accepting or reject-
ing a comment represents FDA’s position on spe-
cific GMP requirements and serves as an invaluable
reference when interpreting Title 21 Parts 210 and
211.
Failure to comply with any of the GMP regulations
in 21 CFR renders the drug adulterated under the
FD & C Act. With that, the drug and the individuals
responsible for the failure to comply shall be subject
to regulatory action.
EC AND US GMP GUIDELINES
The stated purpose of guideline information for
both the EU and the US is very similar. Both
represent current acceptable practice by providing
detailed guidance which interprets and expands on
the principles or regulations. Guideline require-
ments are used by the regulatory authorities in both
the EU and the US when assessing applications
(Manufacturing and Marketing Authorizations,
New Drug Applications (NDAs), Abbreviated new
Drug Applications (ANDAs)) as well as a basis for
inspections of manufacturers. The regulatory
authorities allow implementation of alternate meth-
ods to those stated in guideline documents provid-
ing equivalent assurance is established. The risk in
adopting alternate methods lies in justifying and
documenting equivalence to the authorities. In
short, guidelines list principles and practices which
are acceptable; they do not list the principles and
practices that must, in all instances, be used to
comply with law. Neither the EC Guide or the FDA
guidance documents carry the legal sanction of the
principles or regulations. Volume IV of The Rules
and Guidance Governing Medicinal Products In The
EU and FDA GMP Regulations 57

Table 3. EU GMP Guide Chapters and Annexes

Chapters Annexes
1. Quality management 1. Sterile medicinal products
2. Personnel 2. Biological medicinal products for human use
3. Premises and equipment 3. Radiopharmaceuticals
4. Documentation 4. Veterinary medicinal products other than immunologicals
5. Production 5. Immunological veterinary medicinal products
6. Quality Control 6. Medicinal gasses
7. Contract manufacture and analysis 7. Herbal medicinal products
8. Complaints/product recall 8. Sampling of starting and packaging materials
9. Self-inspection 9. Liquids, creams and ointments
10. Pressurized metered dose aerosol preparations for inhalation
11. Computerized systems
12. Ionizing radiation in the manufacture of medicinal products
13. Investigational medicinal products
14. Products derived from human blood or human plasma

Table 4. Examples of FDA Guidance Documents

Guidelines Inspection guides
Validation Pharmaceutical QC laboratories
Bacterial endotoxin testing using LAL Lyophilization of parenterals
Stability High purity water systems
Aseptic processing Validation of cleaning processes
Clinical Supplies Microbiological QC laboratories
Repackaging Bulk pharmaceutical chemicals

European Community titled Good Manufacturing Prac-
tice for Medicinal Products contains the nine Chapters
and 13 Annexes which make up the GMP Guide.
The chapter titles and the annexes are listed in Table
3. Examples of FDA GMP guidance documents are
listed in Table 4.
Additional sources of current GMPs (CGMPs) can
be found in international guidelines such as the
World Health Organization (WHO) GMP Guide-
lines, International Conference on Harmonization
of Technical Requirements for Registration of Phar-
maceuticals for Human Use (ICH) Guidelines,
International Organization for Standards (ISO)
standards, and Pharmaceutical Inspection Co-
operation Scheme (PICS) Guidelines. Common
practices within the industry, license reviews, and
crisis management control are also sources of
CGMPs.
REGULATION OVERVIEW AND
COMPARISON
The subject areas of both the US and EU GMP
regulations are very similar. The US regulations are
lengthier and more prescriptive by incorporating
detail which, in the EU scheme, is included in the
Guide to GMP. An overview comparison keying on
the EU GMP Principles and Guidelines is
presented.
Article 6 of the EU Principles requires an effective
quality assurance system involving management’s
active participation. Article 11 outlines the responsi-
bilities of the quality control department. It is useful
to review both Articles together. The terms quality
control department (EU), and quality control unit
(US) do not discriminate between laboratory con-
trol and the responsibilities of the group most often
referred to in industry as Quality Assurance (QA).
Nevertheless, concepts such as batch record review,
ensuring conformity to specifications, adequate
laboratory facilities, and a reserve sample pro-
gramme are common to both sets of regulations. EU
regulations require a reserve (retained) sample of
starting materials be held for at least 2 years after
the release of the product. The US require a reserve
sample of the active ingredient to be retained for 1
year after the expiration date of the last lot of drug
product containing the active ingredient. The US
regulations emphasize written procedures, in many
cases detailing minimum requirements. The EU
regulations leave the detail of written procedures to
the GMP Guide.
58
Both sets of regulations allow the use of outside
laboratories to carry out the quality control func-
tions necessary for examination and testing of
materials. The thrust of the regulations is that
adequate laboratory facilities be available to the
quality function, not that the facilities be owned
and operated by the drug product manufacturer.
However, the drug product manufacturer is ulti-
mately responsible for ensuring the contract labo-
ratory operates to GMP.
“Intaken
the EU legal action can be
against the Heads of
Production and Quality Control
and the Qualified Persons...
”
The regulations in both the EU and the US assign
the responsibility for quality manufacturing
practices to senior management. In the US,
products are deemed adulterated based on either
laboratory examination of drug products or on the
basis of objectionable conditions observed during
manufacturing or holding of the drug products.
The latter means of determining product
adulteration results from an FDA conclusion that
the product(s) were not manufactured in
accordance with CGMP. When products have been
found to be adulterated, FDA has both
administrative and legal options it can exercise.
Administrative actions include issuing Warning
Letters and withholding approval of applications.
The legal actions in the US include product seizure,
debarment of individuals from working in the
pharmaceutical industry, court injunctions and
prosecution. Where product is manufactured
outside the US and been found to be adulterated,
FDA has taken administrative actions and in some
cases barred import of the drug products into the
US. In the EU, besides the powers European
inspectors have to seize and detain medicinal
products from the manufacturing facility, legal
action can be taken against the persons named on
the Manufacturers License. These are the Heads of
Production and Quality Control and the Qualified
Persons (QP).
Article 7 of the EU Principles discusses personnel
requirements. Organizational charts and job
descriptions are required. There are no similar
requirements for these documents in the US
regulations. Education, experience, and training as
the foundation for qualified personnel is integral to
both sets of regulations, although the detail in the
EU is again covered in the Guide. There is a
statutory requirement for initial and ongoing
John G. Grazal and David S. Earl
training, including GMP training, in both sets of
regulations. Health, hygiene, and clothing for
personnel is also addressed in the regulations.
Uniquely, CFR Part 211.34 addresses the use of
consultants requiring them to be qualified and
mandating the drug product manufacturer to
maintain records containing the name, address,
qualifications and the type of service performed by
these individuals.
Article 8 addresses premises and equipment.
Chapter 3 of the Guide provides the detail. The CFR
Part 211 Subparts C and D cover facilities and
equipment in similar detail to the Principles and
Guide. The design, construction and operation
features of buildings and equipment must be such
as to minimize the potential for contamination and
quality problems. 211 CFR Subpart C goes into a
fair amount of detail on requirements for separate
or defined areas for various operations including
aseptic processing. Both sets of regulations require
buildings and equipment to be maintained.
Equipment surfaces that come into contact with
product must not be ‘reactive, additive or
absorptive’(2). Maintenance and cleaning activities
are detailed in the CFR while similar requirements
are in the EU GMP Guide.
Premises and equipment critical to product quality
must be subject to appropriate qualification
according to Article 8, Item 3. While the wording is
less clear, FDA point to 21 CFR Part 211.68a, in
particular the requirement that equipment be
‘checked according to a written program designed
to assure proper performance’(2) as the regulation
requiring equipment qualification or validation.
Separate facilities for penicillin production are
addressed in the US regulations and the EU GMP
Guide.
CFR 211.72 on sterile filtration covers many of the
same details outlined in Annex 1 of the GMP Guide.
This section of the CFR should be read in
conjunction with the FDA Guideline On Sterile
Drug Products Produced By Aseptic Processing
1987, where specific good practices relating to
sterile filtration are detailed.
Article 9 on documentation coupled with Chapter 4
of the GMP Guide provides a comprehensive and
detailed set of requirements related to
documentation. CFR 211 Subpart J, Records and
Reports, details the US requirements. The similarity
in content and detail between the documentation
requirements should provide firms on both sides of
the Atlantic with adequate instruction to meet
FDA’s inspectional emphasis on documentation.
EU and FDA GMP Regulations
Based on the number of FDA 483 observations
related to documentation deficiencies, this does not
appear to be the case.
Both EU and US regulations require that documents
be available for inspection purposes. The use of
electronic storage for documents is recognized
provided the system has been validated.
Article 10 on production covers process validation
and revalidation requirements. CFR Part 211 is
scant in the area of process validation. This appears
at odds with both the US industry and FDA’s
emphasis on validation. Clearly, process validation
CGMPs have evolved without benefit of detailed
regulation in this area. It must be remembered that
the last major revision of 21 CFR was in 1978.
Validation GMPs have progressed significantly
since that time. A draft revision to 21CFR Parts 210
and 211, published by FDA in 1996 includes more
specific validation requirements which have drawn
negative comment from industry. Whilst time limits
are discussed in Part 211.111 and apply to all drug
products, the European approach to this process
control is reserved for the GMP Guide Sterile
Products Annex.
Article 11 was discussed in the context of
QA/QC.
Article 12 is devoted to work contracted out. The
requirement for a written contract defining
responsibilities between each party is unique to the
European regulations. The EU provisions around
inspections and subcontracting are GMP practices
in the US. However, these requirements along with
QP responsibilities (not recognized in the US) are
not part of the GMP regulations. It is noteworthy
that in the US, the quality control unit of a contract
facility is required to approve or reject drug
products produced by the contractor but the final
release to market is to be performed by the owner
of the drug product. In the EU, this distinction is
not made provided the release is done by a QP. All
holders of Manufacturers Licenses within the EU
are required to have the services of a QP as defined
in EC Directive 75/319. No batch of medicinal
product may be released to the market within the
EU unless a nominated QP has certified that it has
been manufactured and checked in compliance
with the laws in force.
Article 13 on complaints and product recall outlines
the requirements in these areas. Written procedures,
investigations, and alerting the regulatory
authorities are common to both systems. Recalls are
voluntary in both the US and the EU. Both sets of
59
regulations refer the reader to further
guidance/regulation on the conduct of recalls.
“Firms have been cited on FDA
Form 483 for not having an
internal audit plan...
”
Article 14 on Self Inspections does not have an
equivalent in the US GMP regulations. While it is
certainly CGMP to perform internal auditing, and
the FDA expectation is that firms do so, there is no
legal requirement in the US regulations. Firms have
been cited on FDA Form 483 observations for not
having an internal audit plan or for failing to carry
out scheduled audits.
STATUS OF GMP REGULATIONS IN THE
EU AND US
The draft revision of CFR Parts 210 and 211
mentioned above was published in a 6 May 1996
submission to the Federal Register. The Agency has
stated that the reason for the proposed revisions to
the regulations is to clarify requirements in certain
areas of GMP that have been the subject of recent
enforcement actions. Industry has commented that
the proposed regulations impose substantial new
requirements that do not contribute to the quality
or safety of drug products. FDA is reviewing the
industry comments and is expected to issue a final
revision in 1998.
Currently there are no statutory GMP regulations
for active pharmaceutical ingredients (APIs) in
either the EU or the US. While the FDA has an
active inspection programme for APIs and uses
CFR Parts 210 and 211, these regulations are used as
guidelines only. APIs manufactured for use in drug
products for the US market are required to conform
to GMP since the Food, Drug and Cosmetic Act
makes no distinction between drug substances and
drug products, but there are no formal regulations.
A similar situation exists in the EU, although there
is no formal inspection programme for APIs. FDA
released a draft guidance ‘Manufacture, Processing,
or Holding of Active Pharmaceutical Ingredients’ in
October 1996. FDA is reviewing industry comment
to this proposal and the final revision is expected in
1998.
A legal GMP framework (regulations and guide-
lines) has been proposed in the EU for starting
materials. This would establish both routine and
60
‘for cause’ inspections for selected starting materi-
als including all active agents and certain exci-
pients. These listed starting materials would be
required to be manufactured in accordance with the
regulations and guidelines. Inspections of third
country starting material manufacturers is also
called for.
Investigational materials or clinical supplies must
conform with the drug product CFRs for manu-
facture and/or distribution in the US. In the EU,
these materials are not currently subject to statutory
requirements. While the EU principles and guide-
lines, along with the detailed guidelines are rele-
vant to the manufacture of investigational materi-
als, it is Annex 13 in the GMP Guide which
provides the framework for common standards in
the area of investigational materials.
CONCLUSIONS
Pharmaceutical manufacture and regulation is
clearly an international business. With the increas-
ing emphasis on harmonization efforts and stan-
John G. Grazal and David S. Earl
dard setting along with mutual recognition agree-
ments, knowledge of foreign regulations is a
necessity for both understanding the future direc-
tion of these efforts as well as for international
supply of drug products. This paper presented
some background information and an overview of
drug GMP regulations and guidelines in the EU
and the US. The laws and principles relating to
GMP are fundamentally similar between the EU
and the US. It is the detailed guidelines and their
application where the differences arise, and even
here there is much that is similar. As with any
overview, there is much detail which is not covered.
The intent of this article is to introduce the reader to
the regulations and provide a starting point for
further investigations.
REFERENCES
1. Commission of the European Communities. The Rules Govern-
ing Medicinal Products in the EC. Vol. IV. Good Manufacturing
Practice for Medicinal Products. Luxembourg: Office for Official
Publications of the EC, 1992. ISBN 92-826-3180-X.
2. Food and Drug Administration, Department of Health and
Human Services. 21CFR 210, 211. Washington: Office of the
Federal Register National Archives and Records Administra-
tion, 1997.