A Comparison of EU and US GMPs

(We’ve much to learn from those “across the pond”)

Martin L. Jeiven, MS, RPh

President
Jeiven Pharmaceutical Consulting, Inc.
Reliable Guidance
The Essential Worldwide
Principle of GMPs
Product Quality depends on:

 Quality, Safety, and

Effectiveness must be
designed and built into
the product;
 Quality cannot be tested
into the product; and
 Each step in a manufacturing process must be
controlled to maximize the probability that the finished
product will meet all its quality and design
specifications.
Brief GMP History

 1957: First GMPs issued as a government

regulation (by the Canadian Specifications
Board for drug supplied to the Canadian
military)
 1963/1978: US FDA GMPs
 1967: WHO GMPs
 1968/1973: UK GMPs
 1984: GMPs in more than 25 countries
US vs. EU GMPs: Overview
 In most aspects, both
are similar in content
and focus on Quality
 There are a number of
important differences
 There is considerably
more detail in the EU
GMPs
 FDA has been criticized
for lack of detail in
validation, internal
audits, the different
roles of QA and QC,
etc.
US vs. EU GMPs: Overview (cont’d)

 FDA’s response to the criticism: the GMPs

are minimum requirements, and industry’s
responsibility is to remain current by
incorporating into their procedures information
from guidances, inspectional guidelines,
Warning Letters, FDA presentations, etc.
 Most countries within the EU update their GMPs
every 1-5 years; the US GMPs are substantially
the same as the 1978 Final Rule
The EU GMPs stress:
 The expectations of Quality Management
and the role of the QP
 The expectation for, and extensiveness of,
validation
 The need for self-inspection (=internal audits)
 Training and assessment of competence
 The role of contract manufacture and
analysis
EU Countries (2005)
Austria Czech Rep Portugal
Denmark Hungary Netherlands
Sweden Slovenia Germany
UK Cyprus Finland
Belgium Estonia France
Italy Latvia Greece
Ireland Malta Luxembourg
Spain Poland
Slovakia Iceland – Non EU country
Lithuania Norway – Non EU country
International GMP Lexicon
ADR Adverse Reaction
CA Competent Authority
CRO Contract Research Organization
CT Clinical Trial
CTA Clinical Trial Application
CTD Clinical Trial Directive
CTM Clinical Trial Material
EC European Community
EC Ethics Committee
EEA European Economic Area
 International GMP Lexicon (cont’d)
EEC European Economic Community
EMEA European Medicines Evaluation Agency
EU European Union
EUDRACT European Clinical Trials Database
GCP Good Clinical Practice
GMP Good Manufacturing Practice
HPFBI Health Product and Food Inspection
Branch (Canada)
ICH International Conference of Harmonization
IMP Investigational Materials Product
International GMP Lexicon (cont’d)
IMPD Investigational Materials Product
Dossier
MCA Medicines Control Agency
MRA Mutual Recognition Agreement
MS Member State
PI Pharmaceutical Inspectorate
PIC Pharmaceutical Inspection Convention
PIC/S Pharmaceutical Inspection
Cooperation Scheme
PSF Product Specification File
QP Qualified Person
WHO World Health Organization
International GMPs:
 GMPs are in effect in 104
countries
 They may be regulations (as
in the US, Japan or Korea),
directives (as in the EU),
guides (as in the UK), codes
(as in Australia), or WHO
code (as in many Southeast
Asia countries)
 The intent is the same: strict
adherence to consistently
assure product quality
 FDA and EU Inspections
 “FDA inspectors inspect for compliance; EU
inspectors inspect for adequate science”.

 An FDA inspector may spend 80-90% of the time

reviewing documentation related to manufacturing
and testing, looking for evidence of compliance
and the absence of fraud; the EU inspector will
spend 80-90% of the time interviewing staff and
management, walking the facility to observe
manufacturing and testing, and assessing the
soundness of the operation.
GMP Inspections in the EU
 The key document controlling
GMP inspections in the EU is the
Commission Directive
2003/94/EC (8 October 2003).
 It represents a proposal by the EU
Commission designed to ensure
freedom of movement of goods,
personnel, finances, and services
within the EU. Once approved by the European Parliament,
implementation requires that each member state incorporate the
directive into its own national legislation within three years of
original passage.
EU GMPs
Chapter 1 – Quality Management
Principle
The holder of a Manufacturing Authorization
must manufacture medicinal products so as to
ensure that they are fit for their intended use,
comply with the requirements of the Marketing
Authorization and do not place patients at risk
due to inadequate safety, quality or efficacy. The
attainment of this Quality objective is the
responsibility of Senior Management, and
requires the participation and commitment by
staff in many different departments and at all
levels within the company, by the company’s
suppliers and by the distributors.
EU GMPs
Chapter 1 – Quality Management (cont’d)
Principle (cont’d)
To achieve the Quality objectives reliably, there
must be a comprehensively designed and
correctly implemented system of QA incorporating
GMP and it should be fully documented and its
effectiveness monitored. All parts of the QA
system should be adequately resourced with
competent personnel, and suitable and sufficient
premises, equipment and facilities.
Quality Management and the
Qualified Person (QP)
 In the US, FDA holds Senior Management
directly and personally responsible for
compliance to GMPs
 In Europe, the QP is directly and legally
responsible for ensuring that a
pharmaceutical product complies with the
GMP commitments made by the company in
its application to market products (or test
clinically).
 Quality Management and the
Qualified Person (QP) (cont’d)
 QP qualifications include: university degree
from a member state, minimum of 4 years
theoretical/practical studies in pharmacy,
veterinary medicine, chemistry or biology;
minimum of 2 years working in the industry, and
(in some countries), passage of an examination.
EU GMPs
Chapter 1 – Quality Management (cont’d)
Principle (cont’d)
• The basic concepts of QA, GMPs and QC
are inter-related and fundamental to the
production and control of medicinal
products.
EU GMPs
Chapter 2 – Personnel
Principle
The establishment and
maintenance of a satisfactory system of and the
correct manufacture of
medicinal products relies
upon people. There must be sufficient qualified
personnel to carry out all the tasks. Individual
responsibilities should be clearly understood and
recorded. All personnel should be aware of the
principles of GMP that affect them, and receive
initial and continuing training relevant to their needs.
EU GMPs
Chapter 3 – Premises and Equipment
Principle
Premises and equipment must be
located, designed, constructed,
adapted and maintained to suit the
operations to be carried out. Their layout and design
must aim to minimize the risk of errors and permit
effective cleaning and maintenance in order to avoid
cross-contamination, build up of dust or dirt and, in
general, any adverse effect on the quality of products.
EU GMPs
Chapter 4 - Documentation
Principle
Good documentation constitutes
an essential part of the QA
system. Clearly written
Documentation prevents errors
from spoken communication and
permits tracing or batch history. Specifications,
manufacturing formulas and instructions,
procedures, and records must be free from errors
and available in writing. The legibility of
documents is of paramount importance.
EU GMPs
Chapter 5 – Production
Validation
 Validation studies should
reinforce GMPs, and be
conducted in accordance
with defined procedures.
Results and conclusions
should be recorded.
 When any new manufacturing formula or method of
preparation is adopted, steps should be taken to
demonstrate its suitability for routine processing.
The defined process, using the materials and
equipment specified, should be shown to yield a
product consistently of the required Quality.
 EU GMPs
Chapter 5 – Production (cont’d)
Validation (cont’d)
 Significant amendments to the manufacturing
process, including any change in equipment or
materials, which may affect product quality
and/or the reproducibility of the process should
be validated.
 Processes and procedures should undergo
periodic critical re-validation to ensure that
they remain capable of achieving the intended
results.
EU GMPs
Chapter 6 – Quality Control
Principle
QC is concerned with sampling, specifications
and testing as well as the organization,
documentation and release procedures which
ensure that the necessary and relevant tests
are carried out, and that materials are not released for use,
nor products released for sale or supply, until their Quality
has been judged satisfactory. QC is not confined to
laboratory operations, but must be involved in all decisions
which may concern the quality of the product. The
independence of QC from Production is considered
fundamental.
EU GMPs
Chapter 7 – Contract Manufacture and Analysis

Principle
Contract manufacture and analysis must be
correctly defined, agreed and controlled in order
to avoid misunderstandings which could result in
a product or work of unsatisfactory quality.
There must be a written contract between the
Contract Giver and the Contract Acceptor which
clearly establishes the duties of each party. The
contract must clearly state the way in which the
QP releasing each batch of product for sale (or
clinical use) exercises his full responsibility.
EU GMPs
Chapter 8 – Complaints and Product Recall
Principle
All complaints and other
information concerning
potentially defective products
must be reviewed carefully
according to written procedures.
In order to provide for all
contingencies, a system should
be designed to recall, if
necessary, promptly and
effectively products known or
suspected to be defective from
the market (for the clinic).
 EU GMPs
Chapter 9 – Self Inspection
Principle
 Self inspections should be conducted in order to
monitor the implementation and compliance with
GMP principles and to propose necessary
corrective measures.
 Personnel matters, premises, equipment,
documentation, production, QC, distribution of
the medicinal products, arrangements for
dealing with complaints and recalls, and self
inspections, should be examined at intervals
following a pre-arranged programme in order to
verify their conformity with the principles of QA.
EU GMPs
Chapter 9 – Self Inspection (cont’d)
 Self inspections should be conducted in an
independent and detailed way by designated
competent person(s) from the company.
Independent audits by external experts may
also be useful.
 All self inspections should be recorded.
Reports should contain all the observations
made during the inspections and, where
applicable, proposals for corrective
measures. Statements on the actions
subsequently taken should also be recorded.
EU GMPs
The “Orange Guide”
This publication from the Medicines Control
Agency includes the main pharmaceutical
Regulations, Directives, and guidances,
including the GMPs, which manufacturers and
wholesales are expected to follow when
manufacturing and distributing medicinal
products in the EU. The latest edition is 2002
and includes key annexes, UK’s Code of
Practice for QPs, and notes on mutual
recognition agreements.
Certification by a Qualified Person
and Batch Release – Annex 16
Principle
Each batch of finished product must be certified by
a QP within the EC/EEA or for export.
The purpose of controlling the batch release in this
way is:
 To ensure that the batch has been manufactured and
checked in accordance with the requirements of its
marketing authorization, the principles and guidelines of
EC GMP or the GMP of a third country recognized as
equivalent under an MRA and any other relevant legal
requirement before it is placed on the market
Certification by a Qualified Person and
Batch Release – Annex 16 (cont’d)
Routine duties of a Qualified Person
Before certifying a batch prior to release, the QP
doing so should ensure, with reference to the
guidance above, that at least the following
requirements have been met:
 The batch and its manufacture comply with
the provisions of the marketing authorization
(including the authorization required for
importation where relevant);
Certification by a Qualified Person and
Batch Release – Annex 16 (cont’d)
Routine duties of a Qualified Person
 All the necessary checks and tests have been
performed, including any additional sampling,
inspection, tests or checks initiated because of
deviations or planned changes;
 All necessary production and QC documentation has
been completed and endorsed by the staff authorized to
do so;
 All audits have been carried out as required by the QA
system;
 The QP should in addition take into account any other
factors of which he is aware which are relevant to the
quality of the batch.
Certification by a Qualified Person and
Batch Release – Annex 16 (cont’d)
Routine duties of a Qualified Person
A QP who confirms the compliance of an
intermediate stage of manufacture, has the same
obligations as above in relation to that stage unless
specified otherwise in the agreement between the
QPs
A QP should maintain his knowledge and
experience up to date in the light of technical and
scientific progress and changes in quality
management relevant to the products which he is
required to certify.
Certification by a Qualified Person and
Batch Release – Annex 16 (cont’d)
Routine duties of a Qualified Person
If a QP is called upon to certify a batch of a product
type with which he is unfamiliar, he should first
ensure that he has gained the relevant knowledge
and experience necessary to fulfill this duty.
Certification by a Qualified Person and
Batch Release – Annex 16 (cont’d)
Routine duties of a Qualified Person
 Manufacture has been carried out in accordance with GMP
or, in the case of a batch imported from a third country, in
accordance with GMP standards at least equivalent to EC
GMP;
 The principal manufacturing and testing processes have
been validated; with documented production conditions and
manufacturing records;
 Deviations or planned changes in production or QC have
been authorized by the responsible person(s). Any
changes requiring variation to the marketing or
manufacturing authorization have been authorized by the
relevant authority
Harmonization of API GMPs

FDA and many of the EU member states

have routinely conducted inspections of API
manufacturers since 1979. Following the
death of 87 children in Haiti from
contaminated acetaminophen liquid, and
realizing that there was a lack of clear GMP
regulations and guidelines for API
manufacture, ICH enacted an international
set of GMPs governing the manufacture,
testing, and distribution of APIs: the ICH-Q7A
guideline has been adopted as law in the US,
EU, Japan, and other countries.
Self-Inspection
The role of self-inspection is not
discussed, or required, in the US
GMPs; however this plays a major
role in the European and WHO GMPs.
The European GMPs describe self-inspections in the
following way:
Self-inspections should be conducted in order to
monitor the implementation and compliance with
GMP principles and to propose necessary
corrective measures.
Self-Inspection (cont’d)

Personnel matters, premises, equipment,

documentation, production, QC, distribution of
the medicinal products, arrangements for
dealing with complaints and recalls, and self-
inspection, should be examined at intervals
following a pre-arranged program in order to
verify their conformity with the principles of QA.
Self-Inspection (cont’d)
While this is deemed in the US to be the
function of internal audit programs, such audit
programs are “off limits” to FDA inspectors
and are not routinely reviewed for adequacy
of self-inspection, or for adequacy of the
follow-up actions that might be necessitated
from such a self inspection. Without
question, the role of self-inspection is vital
to assure final product quality and to
attempt to attain continuous improvement
in the workplace.
Self-Inspection (cont’d)
Self-inspections should be conducted in an
independent and detailed way by designated
competent person(s) from the company.
Independent audits by external experts may
also be useful. All self inspections should be
recorded. Reports should contain all the
observations made during the inspections
and, where applicable, proposals for
corrective measures. Statements on the
actions subsequently taken should also be
recorded.
 The Clinical Trials Directive

Directive 2001/20/EC (GCP Directive)

This directive has GMP implications with
respect to manufacturing, packaging,
labeling, storage, distribution, returns,
destruction and importation into the EU of
IMPs.
Clinical Trial Authorization (CTA)

Article 9(2) of Directive 2001/20/EC requires that a

request for authorisation to conduct the clinical trial
be made to the Competent Authority (=QP) in each
member state in which the sponsor plans to carry
out the trial. CTA must be approved by the QP
before a trial can start.
 CTA comprises the Clinical Trial Dossier (CTD)
and Investigational Materials Product Dossier
(IMPD)
GMP Considerations Before a
Clinical Trial is Initiated
 Technical Agreements are in place.
 Manufacturing and assembly activities have
been, and will be, conducted in accordance
with EU GMPs.
 CTA is approved, and the QP has access to its
contents.
 PSF contains all the necessary documents and is
accessible to the QP.
 Comparators are sourced from qualified vendors.
 Shipment conditions are appropriate, and will be recorded.
 Testing requirements for the IMP are clear.
Annex 13 - GMP Manufacturing of
Investigational Medicinal Products
 Documentation
• Manufacturing
• Packaging materials
• Comparator products
• Blinding operations
• Randomization codes
• Packaging
• Labeling
 Quality Control
 Product Release
 Shipping
 Complaints
 Recalls & Returns
 Distribution
IMP(=CTM) Certification by a Qualified
Person and Batch Release – Annex 16

Principle
 Each batch of finished IMP must be certified by a QP
within the EC/EEA or for export.
 Controlling the release ensures that IMPs have been
manufactured to the requirements of its marketing
authorization, the principles and guidelines of EC
GMPs or the GMPs of a third country recognized as
equivalent under a MRA and any other relevant legal
requirements.
 Responsibility of the
QP for GMP Compliance
Annex 16 (section 5) gives guidance when
different sites and different QPs are involved in
different stages of the process.
The general principle is that the QP who is
responsible for certifying the final packaged
product may take personal responsibility for all
stages or may take account of the confirmation of
earlier stages by the relevant QP responsible for
those stages.
Certification by a QP and IMP
Batch Release – Annex 16
Routine duties of a Qualified Person
 Checks and tests have been performed, including any
additional sampling, inspection, tests or checks initiated
because of deviations or planned changes;
 Production and QC documentation has been completed
and endorsed by the staff authorized;
 Audits have been carried out as required by QA
The Role of Qualified Person for CTM
 The responsibilities of the Clinical Trials QP are
generally the same as existing arrangements for
marketed products. For example:
• Batch certification is recorded in a register
• QPs are required to maintain their knowledge and
experience
• QPs are required to have the knowledge relevant to
the product type they are certifying
 Personally responsible/liable for their decisions.
 CTM can be released by the ‘local’ country QP if
delivered directly to an individual MS
PSF Responsibility of the QP for
CTM (cont’d)
 The QP needs to know the contents of each
study file, where they are kept and who is
contact at the appropriate sites.
 There will need to be a rigorous change control
system in place to ensure that the QP knows
about the changes and certifies each batch
against current data.
Responsibility of the QP for Comparator
Products used in Clinical Trials
 For comparator products sourced in the EU, or
with a MA in the EU, QP certification is limited to
ensuring that the product is used according to
the MA conduct the trial and is blinded,
packaged and labeled, stored and distributed
appropriately.
 IMP from non-EU sources must be certified as
manufactured under EU GMPs
 Use of non-EU sourced comparators in EU trials
will be a challenge
 Importation of IMPs
 Importation of IMP into the EU
requires the importer to have a
Manufacturer’s License and to
name a QP on that license.
 The license will include the product types (e.g.:
tablets, injectables, etc.) that the company can
import
 There are variations between member states.
 Some MSs will conduct testing of IMP as part of
their release.
 Other MSs, including the UK, leave it to the QP to
decide
International GMPs: Future
Directions
An important future direction for GMP inspections in
developed countries is risk assessment.
 Canadian inspections in the early 1970s: first attempt to
establish a risk-based approach to GMP compliance
 Canadian HPFBI classifies both drug products and GMP
non-compliance observations found under their “Risk
Classification of GMP Observations” scheme. They also
categorize critical products.
 Australian inspectors take a similar approach.
 FDA is pursuing risk-based inspections as one of its
initiatives.
International GMPs: Future
Directions (cont’d)
Training Validation, or competency testing
of personnel, appears to be the next area to
be officially addressed. Going beyond US
GMPs [211.25(a)], the UK is now requiring
technical staff to be certified as meeting
National Vocational Qualification (NVQ)
standards
QUESTIONS?

THANK YOU!