1.
Scope
1.1 This Annex to the Guide to Good Manufacturing Practice for Medicinal
Products (“the GMP Guide”) gives guidance on the taking and holding of
reference samples of starting materials, packag-ing materials or finished
products and retention samples of finished products.
1.2 Specific requirements for investigational medicinal products are
given in Annex 13 to the Guide.
1.3 This annex also includes guidance on the taking of retention samples
for parallel imported/ distributed medicinal products.
2.
Principle
2.1 Samples are retained to fulfil two purposes; firstly to provide a
sample for analytical testing and secondly to provide a specimen of the fully finished
product. Samples may therefore fall into two categories:
Reference sample: a sample of a batch of starting material, packaging material or
finished product which is stored for
the purpose of being analysed should the need arise during the shelf life of
the batch concerned. Where stability permits, reference samples from critical
intermediate stages (e.g. those requiring analytical testing and release) or
intermediates, that are transported outside of the manufacturer’s control,
should be kept.
Retention sample: a sample of a fully packaged unit from a batch of finished product. It
is stored for identification
purposes. For example, presentation, packaging, labelling, patient information
leaflet, batch number, expiry date should the need arise during the shelf life
of the batch concerned. There may be exceptional circumstances where this
requirement can be met without retention of duplicate samples e.g. where small
amounts of a batch are packaged for different markets or in the production of
very expensive medicinal products.
For finished products, in many instances the reference and retention
samples will be presented identi-cally, i.e. as fully packaged units. In such
circumstances, reference and retention samples may be re-garded as interchangeable.
2.2 It is necessary for the manufacturer, importer or site of batch
release, as specified under sec-tion 7 and 8, to keep reference and/or
retention samples from each batch of finished product and, for the manufacturer
to keep a reference sample from a batch of starting material (subject to
certain excep-tions – see 3.2 below) and/or intermediate product. Each
packaging site should keep reference samples of each batch of primary and
printed packaging materials. Availability of printed materials as part of the
reference and/or retention sample of the finished product can be accepted.
2.3 The reference and/or retention samples serve as a record of the
batch of finished product or starting material and can be assessed in the event
of, for example, a dosage form quality complaint, a query relating to
compliance with the marketing authorisation, a labelling/packaging query or a
phar-macovigilance report.
2.4 Records of traceability of samples should be maintained and be
available for review by com-petent authorities.
3.
Duration
of Storage
3.1 Reference and retention samples from each batch of finished product
should be retained for at least one year after the expiry date. The reference
sample should be contained in its finished primary
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packaging or in packaging
composed of the same material as the primary container in which the prod-uct is
marketed (for veterinary medicinal products other than immunologicals, see also
Annex 4, para-graphs 8 & 9).
3.2 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. Packaging materials should be retained for the duration of the shelf
life of the finished product concerned.
4.
Size of
Reference and Retention Samples
4.1 The reference sample should be of sufficient size to permit the
carrying out, on, at least, two occasions, of the full analytical controls on
the batch in accordance with the Marketing Authorisation File which has been
assessed and approved by the relevant Competent Authority / Authorities. Where
it is necessary to do so, unopened packs should be used when carrying out each
set of analytical con-trols. Any proposed exception to this should be justified
to, and agreed with, the relevant competent authority.
4.2 Where applicable, national requirements relating to the size of
reference samples and, if nec-essary, retention samples, should be followed.
4.3 Reference samples should be representative of the batch of starting
material, intermediate product or finished product 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). Where a batch is packaged in two, or
more, distinct packaging operations, at least one retention sample should be
taken from each individual packaging operation. Any proposed exception to this
should be justified to, and agreed with, the relevant competent authority.
4.4 It should be ensured that all necessary analytical materials and
equipment are still available, or are readily obtainable, in order to carry out
all tests given in the specification until one year after ex-piry of the last
batch manufactured.
5.
Storage
Conditions
5.1 Storage of reference samples of finished products and active
substances should be in accor-dance with the current version of the Note for
Guidance on Declaration of Storage Conditions for Me-dicinal Products and
Active Substances.
5.2 Storage conditions should be in accordance with the marketing authorisation
(e.g. refriger-ated storage where relevant).
6.
Written
Agreements
6.1 Where the marketing authorisation holder is not the same legal
entity as the site(s) responsible for batch release within the EEA, the
responsibility for taking and storage of reference/retention sam-ples should be
defined in a written agreement between the two parties in accordance with
Chapter 7 of the EC Guide to Good Manufacturing Practice. This applies also
where any manufacturing or batch release activity is carried out at a site
other than that with overall responsibility for the batch on the EEA market and
the arrangements between each different site for the taking and keeping of
reference and retention samples should be defined in a written agreement.
6.2 The Qualified Person who
certifies a batch for sale should ensure that all relevant reference and
retention samples are accessible at all reasonable times. Where necessary, the
arrangements for such access should be defined in a written agreement.
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6. 3 Where more than one site is
involved in the manufacture of a finished product, the availability of written
agreements is key to controlling the taking and location of reference and
retention samples.
7.
Reference
Samples – General Points
7.1 Reference samples are for the purpose of analysis and, therefore,
should be conveniently available to a laboratory with validated methodology.
For starting materials used for medicinal prod-ucts manufactured within the
EEA, this is the original site of manufacture of the finished product. For
finished products manufactured within the EEA, this is the original site of
manufacture.
7.2 For
finished products manufactured by a manufacturer in a country outside the EEA;
7.2.1 where an operational Mutual Recognition Agreement (MRA) is in
place, the reference sam-ples may be taken and stored at the site of manufacture.
This should be covered in a written agreement (as referred to in section 6
above) between the importer/site of batch release and the manufacturer located
outside the EEA.
7.2.2 where an operational MRA is not in place, reference samples of
the finished medicinal prod-uct should be taken and stored at an authorised
manufacturer located within the EEA. These samples should be taken in
accordance with written agreement(s) between all of the parties concerned. The
samples should, preferably, be stored at the location where testing on
impor-tation has been performed.
7.2.3 reference samples of starting materials and packaging materials
should be kept at the original site at which they were used in the manufacture
of the medicinal product.
8.
Retention
Samples – General Points
8.1 A retention sample should represent a batch of finished products as
distributed in the EEA and may need to be examined in order to confirm
non-technical attributes for compliance with the market-ing authorisation or EU
legislation. Therefore, retention samples should in all cases be located within
the EEA. These should preferably be stored at the site where the Qualified
Person (QP) certifying the finished product batch is located.
8.2 In accordance with 8.1 above, where an operational MRA is in place
and reference samples are retained at a manufacturer located in a country
outside the EEA (section 7.2.2 above), separate re-tention samples should be
kept within the EEA.
8.3 Retention samples should be stored at the premises of an authorised
manufacturer in order to permit ready access by the Competent Authority.
8.4 Where more than one manufacturing site within the EEA is involved in
the manufacture im-portation/packaging/testing/batch release, as appropriate of
a product, the responsibility for taking and storage of retention samples
should be defined in a written agreement(s) between the parties con-cerned.
9.
Reference
and Retention Samples for Parallel Imported/Parallel Distributed Products.
9.1 Where the secondary packaging is not opened, only the packaging
material used needs to be retained, as there is no, or little, risk of product
mix up.
9.2 Where the secondary packaging is opened, for example, to replace the
carton or patient infor-mation leaflet, then one retention sample, per
packaging operation, containing the product should be taken, as there is a risk
of product mix-up during the assembly process. It is important to be able to
identify quickly who is responsible in the event of a mix-up (original
manufacturer or parallel import assembler), as it would affect the extent of
any resulting recall.
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10.1 Where a manufacturer closes down and the manufacturing authorisation
is surrendered, re-voked, or ceases to exist, it is probable that many
unexpired batches of medicinal products manufac-tured by that manufacturer
remain on the market. In order for those batches to remain on the market, the
manufacturer should make detailed arrangements for transfer of reference and
retention samples (and relevant GMP documentation) to an authorised storage
site. The manufacturer should satisfy the Competent Authority that the
arrangements for storage are satisfactory and that the samples can, if
necessary, be readily accessed and analysed.
10.2 If the manufacturer is not in a position to make the necessary
arrangements this may be dele-gated to another manufacturer. The Marketing
Authorisation holder (MAH) is responsible for such delegation and for the
provision of all necessary information to the Competent Authority. In addition,
the MAH should, in relation to the suitability of the proposed arrangements for
storage of reference and retention samples, consult with the competent authority
of each Member State in which any unex-pired batch has been placed on the
market.
10. 3 These requirements apply also in the event of the closedown of a
manufacture located outside the EEA. In such instances, the importer has a
particular responsibility to ensure that satisfactory ar-rangements are put in
place and that the competent authority/authorities is/are consulted.
