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TitleEU cGMP Audit Checklist
Tags Industries Production And Manufacturing Wellness Quality Assurance
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Total Pages52
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EU cGMP AUDIT CHECKLIST

DATE: ____________ CLIENT NAME: ____________________________ AUDITORS: __________________________

SITE ADDRESS: ________________________________ __________________________

TYPE of ACTIVITY (cGMP or PAI): ____________________ __________________________

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Introduction The pharmaceutical industry of the European Union maintains high standards of quality assurance
in the development, manufacture and control of medicinal products. A system of marketing
authorisations ensures that all medicinal products are assessed by a competent authority to
ensure compliance with contemporary requirements of safety, quality and efficacy. A system of
manufacturing authorisations ensures that all products authorised on the European market are
manufactured only by authorised manufacturers, whose activities are regularly inspected by the
competent authorities. Manufacturing authorisations are required by all pharmaceutical
manufacturers in the European Community whether the products are sold within or outside of the
Community.

Two directives laying down principles and guidelines of good manufacturing practice (GMP) for
medicinal products were adopted by the Commission. Directive 2003/94/EC applies to medicinal
products for human use and Directive 91/412/EEC for veterinary use. Detailed guidelines in
accordance with those principles are published in the Guide to Good Manufacturing Practice,
which will be used in assessing applications for manufacturing authorisations and as a basis for
inspection of manufacturers of medicinal products.

The principles of GMP and the detailed guidelines are applicable to all operations which require
the authorisation referred to in Article 40 of Directive 2001/83/EC and in Article 44 of
Directive 2001/82/EC, as amended by Directives 2004/27/EC and 2004/28/EC, respectively.
They are also relevant for all other large scale pharmaceutical manufacturing processes, such as
that undertaken in hospitals, and for the preparation of products for use in clinical trials.
All Member States and the industry agreed that the GMP requirements applicable to the
manufacture of veterinary medicinal products are the same as those applicable to the
manufacture of medicinal products for human use. Certain detailed adjustments to the GMP
guidelines are set out in two annexes specific to veterinary medicinal products and to
immunological veterinary medicinal products.

The Guide is presented in two parts of basic requirements and specific annexes. Part I covers
GMP principles for the manufacture of medicinal products. Part II covers GMP for active
substances used as starting materials.

Chapters of Part I on “basic requirements” are headed by principles as defined in Directives
2003/94/EC and 91/412/EEC. Chapter 1 on Quality Management outlines the fundamental concept
of quality assurance as applied to the manufacture of medicinal products. Thereafter, each
chapter has a principle outlining the quality assurance objectives of that chapter and a text which

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provides sufficient detail for manufacturers to be made aware of the essential matters to be
considered when implementing the principle.

Part II was newly established on the basis of a guideline developed on the level of ICH and
published as ICH Q7a on “active pharmaceutical ingredients”, which was implemented as GMP
Annex 18 for voluntary application in 2001. According to the revised Article 47 and Article 51,
respectively, of the Directive 2001/83/EC and Directive 2001/82/EC, as amended, detailed
guidelines on the principles of GMP for active substances used as starting materials shall be
adopted and published by the Commission. The former Annex 18 has been replaced by the new
Part II of the GMP Guide, which has an extended application both for the human and the
veterinary sector.

In addition to the general matters of Good Manufacturing Practice outlined in Parts I and II, a
series of annexes providing detail about specific areas of activity is included. For some
manufacturing processes, different annexes will apply simultaneously (e.g. annex on sterile
preparations and on radiopharmaceuticals and/or on biological medicinal products).

A glossary of some terms used in the Guide has been incorporated after the annexes.
The Guide is not intended to cover security aspects for the personnel engaged in manufacture.
This may be particularly important in the manufacture of certain medicinal products such as
highly active, biological and radioactive medicinal products. However, those aspects are governed
by other provisions of Community or national law.

Throughout the Guide it is assumed that the requirements of the Marketing Authorisation
relating to the safety, quality and efficacy of the products are systematically incorporated into
all the manufacturing, control and release for sale arrangements of the holder of the
Manufacturing Authorisation.

The manufacture of medicinal products has for many years taken place in accordance with
guidelines for Good Manufacturing Practice and the manufacture of medicinal products is not
governed by CEN/ISO standards. Harmonised standards as adopted by the European
standardisation organisations CEN/ISO may be used at industry’s discretion as a tool for
implementing a quality system in the pharmaceutical sector. The CEN/ISO standards have been
considered but the terminology of these standards has not been implemented in this third edition
of the Guide.

It is recognised that there are acceptable methods, other than those described in the Guide,
which are capable of achieving the principles of Quality Assurance. The Guide is not intended to
place any restraint upon the development of any new concepts or new technologies which have
been validated and which provide a level of Quality Assurance at least equivalent to those set out
in this Guide. It will be regularly revised.

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6.0 Quality Control

6.8 Any Quality Control documentation relating to a batch record should be retained for one year after the
expiry date of the batch and at least 5 years after the certification referred to in Article 51(3) of Directive
2001/83/EC.

6.9 For some kinds of data (e.g. analytical tests results, yields, environmental controls) it is recommended that
records are kept in a manner permitting trend evaluation.

6.10 In addition to the information which is part of the batch record, other original data such as laboratory
notebooks and/or records should be retained and readily available.

Sampling

6.11 The sample taking should be done in accordance with approved written procedures that describe:

• the method of sampling;
• the equipment to be used;
• the amount of the sample to be taken;
• instructions for any required sub-division of the sample;
• the type and condition of the sample container to be used;
• the identification of containers sampled;
• any special precautions to be observed, especially with regard to the sampling of sterile or noxious
materials;

• the storage conditions;
• instructions for the cleaning and storage of sampling equipment.

6.12 Reference samples should be representative of the batch of materials or products from which they are
taken. Other samples may also be taken to monitor the most stressed part of a process (e.g. beginning or end of
a process).

6.13 Sample containers should bear a label indicating the contents, with the batch number, the date of
sampling and the containers from which samples have been drawn.

6.14 Further guidance on reference and retention samples is given in Annex 19.

Testing

6.15 Analytical methods should be validated. All testing operations described in the marketing authorisation
should be carried out according to the approved methods.

6.16 The results obtained should be recorded and checked to make sure that they are consistent with each
other. Any calculations should be critically examined.

6.17 The tests performed should be recorded and the records should include at least the following data:
a. name of the material or product and, where applicable, dosage form;
b. batch number and, where appropriate, the manufacturer and/or supplier;
c. references to the relevant specifications and testing procedures;
d. test results, including observations and calculations, and reference to any certificates of analysis;
e. dates of testing;
f. initials of the persons who performed the testing;

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Annex 15:
Qualification &

Validation
and reuse should be validated. Cleaning intervals and methods should be determined.

39 For cleaning procedures for products and processes which are similar, it is considered acceptable to select a
representative range of similar products and processes. A single validation study utilising a “worst case”
approach can be carried out which takes account of the critical issues.

40 Typically three consecutive applications of the cleaning procedure should be performed and shown to be
successful in order to prove that the method is validated.

41 “Test until clean” is not considered an appropriate alternative to cleaning validation.

42 Products which simulate the physicochemical properties of the substances to be removed may exceptionally
be used instead of the substances themselves, where such substances are either toxic or hazardous.

Change Control

• Does the Sponsor adhere to the following principle?

43 Written procedures should be in place to describe the actions to be taken if a change is proposed to a
starting material, product component, process equipment, process environment (or site), method of production
or testing or any other change that may affect product quality or reproducibility of the process. Change control
procedures should ensure that sufficient supporting data are generated to demonstrate that the revised
process will result in a product of the desired quality, consistent with the approved specifications.

44 All changes that may affect product quality or reproducibility of the process should be formally requested,
documented and accepted. The likely impact of the change of facilities, systems and equipment on the product
should be evaluated, including risk analysis. The need for, and the extent of, re-qualification and re-validation
should be determined.

Revalidation

• Does the Sponsor adhere to the following principle?

45 Facilities, systems, equipment and processes, including cleaning, should be periodically evaluated to confirm
that they remain valid. Where no significant changes have been made to the validated status, a review with
evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need
for revalidation.

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Other Annexes

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

ANNEX 12 USE OF IONISING RADIATION IN THE MANUFACTURE OF MEDICINAL PRODUCTS

ANNEX 13 MANUFACTURE OF INVESTIGATIONAL MEDICINAL PRODUCTS

ANNEX 14 MANUFACTURE OF MEDICINAL PRODUCTS DERIVED FROM HUMAN BLOOD OR PLASMA

ANNEX 15 QUALIFICATION AND VALIDATION

ANNEX 16 CERTIFICATION BY A QUALIFIED PERSON AND BATCH RELEASE

ANNEX 17 PARAMETRIC RELEASE

ANNEX 18 GOOD MANUFACTURING PRACTICE FOR ACTIVE PHARMACEUTICAL INGREDIENTS

ANNEX 19 REFERENCE AND RETENTION SAMPLES

GLOSSARY OF TERMS USED IN THE EU GUIDE TO GMP

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