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 (Text with EEA relevance)
Date: 2003-10-08
Institutions: European Commission
Subjects: marketing standard, pharmaceutical legislation, pharmaceutical product, product quality

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Official Journal of the European Union

14.10.2003

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

(Text with EEA relevance)

THE COMMISSION OF THE EUROPEAN COMMUNITIES,

Having regard to the Treaty establishing the European
Community,

Having regard to Directive 2001/83/EC of the European Parlia-
ment and of the Council of 6 November 2001 on the Commu-
nity code relating to medicinal products for human use (1), as
last amended by Commission Directive 2003/63/EC (2), and in
particular Article 47 thereof,

Whereas:

(1)

(2)

(3)

(4)

(5)

(6)

All medicinal products for human use manufactured or
imported into the Community,
including medicinal
products intended for export, are to be manufactured in
accordance with the principles and guidelines of good
manufacturing practice.

Those principles and guidelines are set out in Commis-
sion Directive 91/356/EEC of 13 June 1991 laying down
the principles and guidelines of good manufacturing
practice for medicinal products for human use (3).

Article 13(3) of Directive 2001/20/EC of the European
Parliament and of the Council of 4 April 2001 on the
approximation of the laws, regulations and administra-
tive provisions of the Member States relating to the
implementation of good clinical practice in the conduct
of clinical trials on medicinal products for human use (4)
requires that detailed guidance be drawn up, in accor-
dance with the guidelines on good manufacturing prac-
tice, on the elements to be taken into account when
evaluating investigational medicinal products for human
use with the object of releasing batches within the
Community.

It is therefore necessary to extend and adapt the provi-
sions of Directive 91/356/EEC to cover good manufac-
turing practice of investigational medicinal products.

Since most of the provisions of Directive 91/356/EEC
need to be adjusted, for the sake of clarity that Directive
should be replaced.

In order to ensure conformity with the principles and
guidelines of good manufacturing practice, it is necessary
to lay down detailed provisions on inspections by the
competent authorities and on certain obligations of the
manufacturer.

(1) OJ L 311, 28.11.2001, p. 67.
(2) OJ L 159, 27.6.2003, p. 46.
(3) OJ L 193, 17.7.1991, p. 30.
(4) OJ L 121, 1.5.2001, p. 34.

(7)

(8)

(9)

All manufacturers should operate an effective quality
management system of their manufacturing operations,
which requires the implementation of a pharmaceutical
quality assurance system.

Principles and guidelines of good manufacturing practice
should be set out in relation to quality management,
personnel, premises and equipment, documentation,
production, quality control, contracting out, complaints
and product recall, and self-inspection.

In order to protect the human beings involved in clinical
trials and to ensure
investigational medicinal
products can be traced, specific provisions on the label-
ling of those products are necessary.

that

(10)

The measures provided for in this Directive are in accor-
dance with the opinion of the Standing Committee on
Medicinal Products for Human Use, set up under Article
121 of Directive 2001/83/EC,

HAS ADOPTED THIS DIRECTIVE:

Article 1

Scope

This Directive lays down the principles and guidelines of good
manufacturing practice in respect of medicinal products for
human use whose manufacture requires
the authorisation
referred to in Article 40 of Directive 2001/83/EC and in
respect of investigational medicinal products for human use
whose manufacture requires the authorisation referred to in
Article 13 of Directive 2001/20/EC.

Article 2

Definitions

For the purposes of this Directive, the following definitions
shall apply:

1.

2.

3.

‘medicinal product’ means any product as defined in Article
1(2) of Directive 2001/83/EC;

‘investigational medicinal product’ means any product as
defined in Article 2(d) of Directive 2001/20/EC;

‘manufacturer’ means any person engaged in activities for
which the authorisation referred to in Article 40(1) and (3)
of Directive 2001/83/EC or the authorisation referred to in
Article 13(1) of Directive 2001/20/EC is required;

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4.

5.

6.

‘qualified person’ means the person referred to in Article 48
of Directive 2001/83/EC or in Article 13(2) of Directive
2001/20/EC;

‘pharmaceutical quality assurance’ means the total sum of
the organised arrangements made with the object of
ensuring that medicinal products or investigational medic-
inal products are of the quality required for their intended
use;

‘good manufacturing practice’ means the part of quality
assurance which ensures that products are consistently
produced and controlled in accordance with the quality
standards appropriate to their intended use;

7.

‘blinding’ means the deliberate disguising of the identity of
an investigational medicinal product in accordance with the
instructions of the sponsor;

8.

‘unblinding’ means the disclosure of the identity of a blinded
product.

Article 3

Inspections

By means of

1.
the repeated inspections referred to in
Article 111(1) of Directive 2001/83/EC and by means of the
inspections referred to in Article 15(1) of Directive 2001/20/
EC, the Member States shall ensure that manufacturers respect
the principles and guidelines of good manufacturing practice
laid down by this Directive. Member States shall also take into
account
the compilation, published by the Commission, of
Community procedures on inspections and exchange of infor-
mation.

For the interpretation of the principles and guidelines of
2.
the manufacturers and the
good manufacturing practice,
the detailed
competent authorities shall
guidelines referred to in the second paragraph of Article 47 of
Directive 2001/83/EC, published by the Commission in the
‘Guide to good manufacturing practice for medicinal products
and for investigational medicinal products’.

take into account

Article 4

Conformity with good manufacturing practice

1.
The manufacturer shall ensure that manufacturing opera-
tions are carried out in accordance with good manufacturing
practice and with the manufacturing authorisation. This provi-
sion shall also apply to medicinal products intended only for
export.

For medicinal products and investigational medicinal
2.
products imported from third countries,
the importer shall
ensure that the products have been manufactured in accor-
dance with standards which are at least equivalent to the good
manufacturing practice standards laid down by the Commu-
nity.

In addition, an importer of medicinal products shall ensure that
such products have been manufactured by manufacturers duly
authorised to do so. An importer of investigational medicinal
products shall ensure that such products have been manufac-
tured by a manufacturer notified to the competent authorities
and accepted by them for that purpose.

Article 5

Compliance with marketing authorisation

The manufacturer shall ensure that all manufacturing
1.
to a marketing
operations for medicinal products subject
authorisation are carried out in accordance with the informa-
tion provided in the application for marketing authorisation as
accepted by the competent authorities.

In the case of investigational medicinal products, the manufac-
turer shall ensure that all manufacturing operations are carried
out
in accordance with the information provided by the
sponsor pursuant to Article 9(2) of Directive 2001/20/EC as
accepted by the competent authorities.

2.
The manufacturer shall regularly review his manufac-
turing methods in the light of scientific and technical progress
and the development of the investigational medicinal product.

If a variation to the marketing authorisation dossier or an
amendment to the request referred to in Article 9(2) of Direc-
tive 2001/20/EC is necessary, the application for modification
shall be submitted to the competent authorities.

Article 6

Quality assurance system

The manufacturer shall establish and implement an effective
pharmaceutical quality assurance system, involving the active
participation of the management and personnel of the different
departments.

Article 7

Personnel

At each manufacturing site, the manufacturer shall have a
1.
sufficient number of competent and appropriately qualified
personnel at his disposal to achieve the pharmaceutical quality
assurance objective.

The duties of

2.
the managerial and supervisory staff,
including the qualified persons, responsible for implementing
and operating good manufacturing practice, shall be defined in
job descriptions. Their hierarchical
shall be
defined in an organisation chart. Organisation charts and job
descriptions shall be approved in accordance with the manufac-
turer's internal procedures.

relationships

The staff referred to in paragraph 2 shall be given suffi-

3.
cient authority to discharge their responsibility correctly.

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The personnel shall receive initial and ongoing training,
4.
the effectiveness of which shall be verified, covering in parti-
cular the theory and application of the concept of quality assur-
ance and good manufacturing practice, and, where appropriate,
the particular requirements for the manufacture of investiga-
tional medicinal products.

Hygiene programmes adapted to the activities to be
5.
carried out
and observed. These
established
programmes shall, in particular, include procedures relating to
health, hygiene practice and clothing of personnel.

shall be

Article 8

Premises and equipment

Premises and manufacturing equipment shall be located,
the

1.
designed, constructed, adapted and maintained to suit
intended operations.

2.
Premises and manufacturing equipment shall be laid out,
designed and operated in such a way as to minimise the risk of
error and to permit effective cleaning and maintenance in order
to avoid contamination, cross contamination and, in general,
any adverse effect on the quality of the product.

3.
Premises and equipment to be used for manufacturing
operations, which are critical to the quality of the products,
shall be subjected to appropriate qualification and validation.

Article 9

Documentation

The manufacturer shall establish and maintain a docu-
1.
mentation system based upon specifications, manufacturing
formulae and processing and packaging instructions, proce-
dures and records covering the various manufacturing opera-
tions performed. Documents shall be clear, free from error and
kept up to date. Pre-established procedures for general manu-
facturing operations and conditions shall be kept available,
together with specific documents for the manufacture of each
batch. That set of documents shall enable the history of the
manufacture of each batch and the changes introduced during
the development of an investigational medicinal product to be
traced.

For a medicinal product, the batch documentation shall be
retained for at least one year after the expiry date of the
batches to which it relates or at least five years after the certifi-
cation referred to in Article 51(3) of Directive 2001/83/EC,
whichever is the longer period.

records are retained as required for marketing authorisation in
accordance with the Annex I
if
required for a subsequent marketing authorisation.

to Directive 2001/83/EC,

2. When electronic, photographic or other data processing
systems are used instead of written documents, the manufac-
turer shall first validate the systems by showing that the data
will be appropriately stored during the anticipated period of
storage. Data stored by those systems shall be made readily
available in legible form and shall be provided to the compe-
tent authorities at their request. The electronically stored data
shall be protected, by methods such as duplication or back-up
and transfer on to another storage system, against
loss or
damage of data, and audit trails shall be maintained.

Article 10

Production

The different production operations shall be carried out
1.
in accordance with pre-established instructions and procedures
and in accordance with good manufacturing practice. Adequate
and sufficient resources shall be made available for the in-
process controls. All process deviations and product defects
shall be documented and thoroughly investigated.

2.
Appropriate technical or organisational measures shall be
taken to avoid cross contamination and mix-ups. In the case of
investigational medicinal products, particular attention shall be
paid to the handling of products during and after any blinding
operation.

For medicinal products, any new manufacture or impor-
3.
tant modification of a manufacturing process of a medicinal
product shall be validated. Critical phases of manufacturing
processes shall be regularly re-validated.

4.
For investigational medicinal products, the manufacturing
process shall be validated in its entirety in so far as is appro-
priate, taking into account the stage of product development.
At least the critical process steps, such as sterilisation, shall be
validated. All steps in the design and development of the manu-
facturing process shall be fully documented.

Article 11

Quality control

1.
The manufacturer shall establish and maintain a quality
control system placed under the authority of a person who has
the requisite qualifications and is independent of production.

For an investigational medicinal product, the batch documenta-
tion shall be retained for at least five years after the completion
or formal discontinuation of the last clinical trial in which the
batch was used. The sponsor or marketing authorisation
if different, shall be responsible for ensuring that
holder,

That person shall have at his disposal, or shall have access to,
one or more quality control laboratories appropriately staffed
and equipped to carry out
the necessary examination and
testing of the starting materials and packaging materials and
the testing of intermediate and finished products.

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For medicinal products,

including those imported from
2.
third countries, contract laboratories may be used if authorised
in accordance with Article 12 of this Directive and point (b) of
Article 20 of Directive 2001/83/EC.

For investigational medicinal products, the sponsor shall ensure
that the contract laboratory complies with the content of the
request referred to in Article 9(2) of Directive 2001/20/EC, as
accepted by the competent authority. When the products are
imported from third countries, analytical control shall not be
mandatory.

3.
During the final control of the finished product before its
release for sale or distribution or for use in clinical trials, the
quality control system shall take into account, in addition to
analytical results, essential information such as the production
conditions, the results of in-process controls, the examination
of the manufacturing documents and the conformity of the
product to its specifications, including the final finished pack.

Samples of each batch of finished medicinal product shall

4.
be retained for at least one year after the expiry date.

For an investigational medicinal product, sufficient samples of
each batch of bulk formulated product and of key packaging
components used for each finished product batch shall be
retained for at
two years after completion or formal
discontinuation of the last clinical trial in which the batch was
used, whichever period is the longer.

least

Unless a longer period is required under the law of the Member
State of manufacture, samples of starting materials, other than
solvents, gases or water, used in the manufacturing process
shall be retained for at least two years after the release of
product. That period may be shortened if the period of stability
of the material, as indicated in the relevant specification,
is
shorter. All those samples shall be maintained at the disposal of
the competent authorities.

Other conditions may be defined, by agreement with the
competent authority, for the sampling and retaining of starting
materials and certain products manufactured individually or in
small quantities, or when their storage could raise special
problems.

Article 12

Work contracted out

1.
Any manufacturing operation or operation linked thereto
which is carried out under contract shall be the subject of a
written contract.

The contract shall clearly define the responsibilities of
2.
each party and shall define,
in particular, the observance of
good manufacturing practice to be followed by the contract-
acceptor and the manner in which the qualified person respon-
sible for certifying each batch is to discharge his responsibil-
ities.

3.
The contract-acceptor shall not subcontract any of the
work entrusted to him under the contract without written
authorisation from the contract-giver.

The contract-acceptor shall comply with the principles
4.
and guidelines of good manufacturing practice and shall submit
to inspections carried out by the competent authorities
pursuant to Article 111 of Directive 2001/83/EC and Article
15 of Directive 2001/20/EC.

Article 13

Complaints, product recall and emergency unblinding

1.
In the case of medicinal products, the manufacturer shall
implement a system for recording and reviewing complaints
together with an effective system for recalling, promptly and at
any time, medicinal products in the distribution network. Any
complaint concerning a defect shall be recorded and investi-
gated by the manufacturer. The manufacturer shall inform the
competent authority of any defect that could result in a recall
or abnormal restriction on supply and, in so far as is possible,
indicate the countries of destination.

Any recall shall be made in accordance with the requirements
referred to in Article 123 of Directive 2001/83/EC.

In the case of

in cooperation with the sponsor,

investigational medicinal products,

the
2.
manufacturer shall,
imple-
ment a system for recording and reviewing complaints together
with an effective system for recalling promptly and at any time
investigational medicinal products which have already entered
the distribution network. The manufacturer shall record and
investigate any complaint concerning a defect and shall inform
the competent authority of any defect that could result in a
recall or abnormal restriction on supply.

In the case of investigational medicinal products, all trial sites
shall be identified and, in so far as is possible, the countries of
destination shall be indicated.

In the case of an investigational medicinal product for which a
marketing authorisation has been issued, the manufacturer of
the investigational medicinal product shall, in cooperation with
the sponsor, inform the marketing authorisation holder of any
defect
that could be related to the authorised medicinal
product.

3.
The sponsor shall implement a procedure for the rapid
unblinding of blinded products, where this is necessary for a
prompt recall as referred to in paragraph 2. The sponsor shall
ensure that the procedure discloses the identity of the blinded
product only in so far as is necessary.

Article 14

Self-inspection

The manufacturer shall conduct repeated self-inspections as
part of the quality assurance system in order to monitor the
implementation and respect of good manufacturing practice
and to propose any necessary corrective measures. Records
shall be maintained of such self-inspections and any corrective
action subsequently taken.

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Article 15

Labelling

In the case of an investigational medicinal product, labelling
shall be such as to ensure protection of the subject and trace-
ability, to enable identification of the product and trial, and to
facilitate proper use of the investigational medicinal product.

Article 16

Repeal of Directive 91/356/EEC

Directive 91/356/EEC is repealed.

References to the repealed Directive shall be construed as refer-
ences to this Directive.

Article 17

Transposition

1. Member States shall bring into force the laws, regulations
and administrative provisions necessary to comply with this
Directive by 30 April 2004 at the latest. They shall forthwith
communicate to the Commission the text of the provisions and
correlation table between those provisions and the provisions
of this Directive.

When Member States adopt those provisions, they shall contain
a reference to this Directive or be accompanied by such a refer-
ence on the occasion of their official publication. The Member
States shall determine how such reference is to be made.

2. Member States shall communicate to the Commission the
text of the main provisions of national law which they adopt in
the field covered by this Directive.

Article 18

Entry into force

This Directive shall enter into force on the 20th day following
that of its publication in the Official Journal of the European
Union.

Article 19

Addressees

This Directive is addressed to the Member States.

Done at Brussels, 8 October 2003.

For the Commission

Erkki LIIKANEN

Member of the Commission