Document Text Contents
Page 2
Rules and Guidance
for Pharmaceutical
Manufacturers and
Distributors 2007
Page 224
2 EU Guidance on Good Manufacturing Practice 205
I II I
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 (Q.P.) certifying the finished product batch is located.
8.2 In accordance with Section 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 retention samples
should be kept within the EEA.
8.3 Retention samples should be stored at the premises of an authorised man-
ufacturer 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 importation/packaging/testing/batch release, as appropri-
ate of a product, the responsibility for taking and storage of retention
samples should be defined in a written agreement(s) between the parties
concerned.
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 information leaflet, then one retention sample, per pack-
aging 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.
10 Reference and Retention Samples in the Case of Closedown
of a Manufacturer
10.1 Where a manufacturer closes down and the manufacturing authorisation is
surrendered, revoked, or ceases to exist, it is probable that many unexpired
batches of medicinal products manufactured 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.
Page 225
206 II GUIDANCE ON GOOD MANUFACTURING PRACTICE (GMP)
10.2 If the manufacturer is not in a position to make the necessary arrangements
this may be delegated to another manufacturer. The Marketing Authorisa-
tion 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 unexpired batch has been
placed on the market.
10.3 These requirements apply also in the event of the closedown of a manu-
facture located outside the EEA. In such instances, the importer has a
particular responsibility to ensure that satisfactory arrangements are put
in place and that the competent authority/authorities is/are consulted.
Page 448
INDEX 429
viruses, inactivation/removal 109
APIs produced by cell culture or fermentation
261
from plasma-derived medicinal products 174,
177
testing 176
see also Infectious disease
visitors 51, 104
W
warehouses, temperatures 358
warehousing procedures, APIs 242
washing
equipment 56
facilities, API manufacturing 224
personnel 91
waste disposal see Disposal of products
waste handling, immunological veterinary product
manufacture 118
water
API manufacturing 225
chemical sanitisation and flushing after 142
distilled, deionized 57
drinking, WHO guidelines 225
for injections 94
liquids, creams and ointments production
142
medicinal gas manufacture 130, 132
water sources, aseptic processing 95
water treatment plants, sterile product manufacture
94
weighing
calibration 57
cross-contamination prevention 54
starting materials 54
weighing rooms 54
wholesale dealer’s licence
appointment/duties of responsible person 355
documentation 379
Guidance Notes 7
imported products 380
information supplied with products 352
obligations 349, 378
“specials” 353
personnel required 352
requirement to deal with specified persons only
380
standard provisions (UK) 382
supply sources 351
UK legislation 378
wholesale distribution
EU guidance 341
see also Good Distribution Practice (GDP)
EU legislation 371
authorization 372
documentation 375
guidelines on good practice 375
homeopathic products 375
minimum requirements 373
public service obligations 374
restricted products 375
time frame for authorisation application
373
UK guidance 349
checking bona fides of supplier/products
360
continued supply 363
counterfeits 359
diverted medicines 360
maintenance of supply chain integrity 363
obligations of dealer 349
parallel distribution 361
product recall/withdrawal 366
relabelling/repackaging 362
responsible person see Responsible Person
(RP)
storage/transportation temperatures 357
see also Wholesale dealer’s licence
UK legislation 377
2005 Act and Regulations 377
dealing with specified persons only 380
requirement for responsible persons 381
standard provisions (Schedule 4) 382
wholesale dealer’s licence obligations 378
see also Wholesale dealer’s licence
wholesalers
Directive 92/25/EEC 342
GDP Inspectors’ role 5
manufacturer’s licence holder obligations
319
obligations, UK guidance 349
orders from, guidelines 343
provision of information to member states
347
quality system 342
see also Distributors
withdrawal of products
blood and plasma product batch 176
UK guidance 366
UK guidance and obligations 366
see also Recall of products
Page 449
430 INDEX
workshops, maintenance 56
World Health Organization, certificates
supporting quality of pharmaceutical
products 6
“worst case” approach
cleaning validation 184
definition 186
wristwatches, wearing 92
Y
yield
deviations from expected 70
expected, definition 270
manufacturing processes 61
Quality Control records 75
theoretical, definition 270
Rules and Guidance
for Pharmaceutical
Manufacturers and
Distributors 2007
Page 224
2 EU Guidance on Good Manufacturing Practice 205
I II I
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 (Q.P.) certifying the finished product batch is located.
8.2 In accordance with Section 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 retention samples
should be kept within the EEA.
8.3 Retention samples should be stored at the premises of an authorised man-
ufacturer 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 importation/packaging/testing/batch release, as appropri-
ate of a product, the responsibility for taking and storage of retention
samples should be defined in a written agreement(s) between the parties
concerned.
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 information leaflet, then one retention sample, per pack-
aging 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.
10 Reference and Retention Samples in the Case of Closedown
of a Manufacturer
10.1 Where a manufacturer closes down and the manufacturing authorisation is
surrendered, revoked, or ceases to exist, it is probable that many unexpired
batches of medicinal products manufactured 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.
Page 225
206 II GUIDANCE ON GOOD MANUFACTURING PRACTICE (GMP)
10.2 If the manufacturer is not in a position to make the necessary arrangements
this may be delegated to another manufacturer. The Marketing Authorisa-
tion 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 unexpired batch has been
placed on the market.
10.3 These requirements apply also in the event of the closedown of a manu-
facture located outside the EEA. In such instances, the importer has a
particular responsibility to ensure that satisfactory arrangements are put
in place and that the competent authority/authorities is/are consulted.
Page 448
INDEX 429
viruses, inactivation/removal 109
APIs produced by cell culture or fermentation
261
from plasma-derived medicinal products 174,
177
testing 176
see also Infectious disease
visitors 51, 104
W
warehouses, temperatures 358
warehousing procedures, APIs 242
washing
equipment 56
facilities, API manufacturing 224
personnel 91
waste disposal see Disposal of products
waste handling, immunological veterinary product
manufacture 118
water
API manufacturing 225
chemical sanitisation and flushing after 142
distilled, deionized 57
drinking, WHO guidelines 225
for injections 94
liquids, creams and ointments production
142
medicinal gas manufacture 130, 132
water sources, aseptic processing 95
water treatment plants, sterile product manufacture
94
weighing
calibration 57
cross-contamination prevention 54
starting materials 54
weighing rooms 54
wholesale dealer’s licence
appointment/duties of responsible person 355
documentation 379
Guidance Notes 7
imported products 380
information supplied with products 352
obligations 349, 378
“specials” 353
personnel required 352
requirement to deal with specified persons only
380
standard provisions (UK) 382
supply sources 351
UK legislation 378
wholesale distribution
EU guidance 341
see also Good Distribution Practice (GDP)
EU legislation 371
authorization 372
documentation 375
guidelines on good practice 375
homeopathic products 375
minimum requirements 373
public service obligations 374
restricted products 375
time frame for authorisation application
373
UK guidance 349
checking bona fides of supplier/products
360
continued supply 363
counterfeits 359
diverted medicines 360
maintenance of supply chain integrity 363
obligations of dealer 349
parallel distribution 361
product recall/withdrawal 366
relabelling/repackaging 362
responsible person see Responsible Person
(RP)
storage/transportation temperatures 357
see also Wholesale dealer’s licence
UK legislation 377
2005 Act and Regulations 377
dealing with specified persons only 380
requirement for responsible persons 381
standard provisions (Schedule 4) 382
wholesale dealer’s licence obligations 378
see also Wholesale dealer’s licence
wholesalers
Directive 92/25/EEC 342
GDP Inspectors’ role 5
manufacturer’s licence holder obligations
319
obligations, UK guidance 349
orders from, guidelines 343
provision of information to member states
347
quality system 342
see also Distributors
withdrawal of products
blood and plasma product batch 176
UK guidance 366
UK guidance and obligations 366
see also Recall of products
Page 449
430 INDEX
workshops, maintenance 56
World Health Organization, certificates
supporting quality of pharmaceutical
products 6
“worst case” approach
cleaning validation 184
definition 186
wristwatches, wearing 92
Y
yield
deviations from expected 70
expected, definition 270
manufacturing processes 61
Quality Control records 75
theoretical, definition 270
