Download Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2007 Aka the Orange Guide PDF

TitleRules and Guidance for Pharmaceutical Manufacturers and Distributors 2007 Aka the Orange Guide
TagsPharmacovigilance Wellness
File Size1.6 MB
Total Pages449
Table of Contents
                            Cover
Table of Contents
Preface to the 2007 edition
	GMP Directive
	Changes to the Community Code
	UK legislation
	Changes to the EU Guide to GMP
	The “Orange Guide’’ 2007
Acknowledgements
Feedback
Introduction
SECTION I: MEDICINES AND HEALTHCARE PRODUCTS REGULATORY AGENCY (MHRA)
	1 MHRA: Licensing, Inspection and Enforcement for Human Medicines
		Overview of MHRA
		Inspectorate
		Licensing Office
		Defective Medicines Report Centre (DMRC)
		Enforcement and Intelligence Group
		Advice
SECTION II: GUIDANCE ON GOOD MANUFACTURING PRACTICE (GMP)
	The MHRA Index to the EU Guide to GMP
	2 EU Guidance on Good Manufacturing Practice
		PART I: Basic Requirements for Medicinal Products
			Introduction
			1 QUALITY MANAGEMENT
				Principle
				Quality Assurance
				Good Manufacturing Practice for Medicinal Products (GMP)
				Quality Control
				Product Quality Review
			2 PERSONNEL
				Principle
				General
				Key Personnel
				Training
				Personnel Hygiene
			3 PREMISES AND EQUIPMENT
				Principle
				Premises
				Equipment
			4 DOCUMENTATION
				Principle
				General
				Documents Required
				Manufacturing Formula and Processing Instructions
				Packaging Instructions
				Batch Processing Records
				Batch Packaging Records
				Procedures and Records
			5 PRODUCTION
				Principle
				General
				Prevention of Cross-contamination in Production
				Validation
				Starting Materials
				Processing Operations: intermediate and bulk products
				Packaging Materials
				Packaging Operations
				Finished Products
				Rejected, Recovered and Returned Materials
			6 QUALITY CONTROL
				Principle
				General
				Good Quality Control Laboratory Practice
			7 CONTRACT MANUFACTURE AND ANALYSIS
				Principle
				General
				The Contract Giver
				The Contract Acceptor
				The Contract
			8 COMPLAINTS AND PRODUCT RECALL
				Principle
				Complaints
				Recalls
			9 SELF INSPECTION
				Principle
			ANNEX 1 MANUFACTURE OF STERILE MEDICINAL PRODUCTS
				Principle
				General
				Isolator Technology
				Blow/Fill/Seal Technology
				Terminally Sterilised Products
				Aseptic Preparation
				Personnel
				Premises
				Equipment
				Sanitation
				Processing
				Sterilisation
				Sterilisation by Heat
				Moist Heat
				Dry Heat
				Sterilisation by Radiation
				Sterilisation with Ethylene Oxide
				Filtration of Medicinal Products which cannot be Sterilised in their Final Container
				Finishing of Sterile Products
				Quality Control
			ANNEX 2 MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE
				Scope
				Principle
				Personnel
				Premises and Equipment
				Animal Quarters and Care
				Documentation
				Production
				Quality Control
			ANNEX 3 MANUFACTURE OF RADIOPHARMACEUTICALS
				Principle
				Personnel
				Premises and Equipment
				Production
				Quality Control
				Distribution and Recalls
			ANNEX 4 MANUFACTURE OF VETERINARY MEDICINAL PRODUCTS OTHER THAN IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS
				Manufacture of Premixes for Medicated Feedingstuffs
				Manufacture of Ectoparasiticides
				Manufacture of Veterinary Medicinal Products Containing Penicillins
				Retention of Samples (point 1.4 viii and point 6.14)
				Sterile Veterinary Medicinal Products
			ANNEX 5 MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS
				Principle
				Personnel
				Premises
				Equipment
				Animals and Animal Houses
				Disinfection–Waste Disposal
				Production
				Starting Materials
				Quality control
			ANNEX 6 MANUFACTURE OF MEDICINAL GASES
				1 Principle
				2 Personnel
				3 Premises and Equipment
				4 Documentation
				5 Production
				6 Quality Control
				7 Storage and Release
				Glossary
			ANNEX 7 MANUFACTURE OF HERBAL MEDICINAL PRODUCTS
				Principle
				Premises
				Documentation
				Sampling
				Quality Control
			ANNEX 8 SAMPLING OF STARTING AND PACKAGING MATERIALS
				Principle
				Personnel
				Starting Materials
				Packaging Material
			ANNEX 9 MANUFACTURE OF LIQUIDS, CREAMS AND OINTMENTS
				Principle
				Premises and Equipment
				Production
			ANNEX 9 MANUFACTURE OF LIQUIDS, CREAMS AND OINTMENTS
				Principle
				Premises and Equipment
				Production
			ANNEX 10 MANUFACTURE OF PRESSURISED METERED DOSE AEROSOL PREPARATIONS FOR INHALATION
				Principle
				General
				Premises and Equipment
				Production and Quality Control
			ANNEX 11 COMPUTERISED SYSTEMS
				Principle
				Personnel
				Validation
				System
			ANNEX 12 USE OF IONISING RADIATION IN THE MANUFACTURE OF MEDICINAL PRODUCTS
				Introduction
				Responsibilities
				Dosimetry
				Validation of the Process
				Commissioning of the Plant
				Premises
				Processing
				Documentation
				Microbiological Monitoring
			ANNEX 13 MANUFACTURE OF INVESTIGATIONAL MEDICINAL PRODUCTS
				Principle
				Glossary
				Quality Management
				Personnel
				Premises and Equipment
				Documentation
				Production
				Quality Control
				Release of Batches
				Shipping
				Complaints
				Recalls and Returns
				Destruction
			ANNEX 14 MANUFACTURE OF MEDICINAL PRODUCTS DERIVED FROM HUMAN BLOOD OR PLASMA
				Principle
				Glossary
				Quality Management
				Premises and Equipment
				Blood and Plasma Collection
				Traceability and Post Collection Measures
				Production and Quality Control
				Retention of Samples
				Disposal of Rejected Blood, Plasma or Intermediates
			ANNEX 15 QUALIFICATION AND VALIDATION
				Principle
				Planning for Validation
				Documentation
				Qualification
				Process Validation
				Cleaning Validation
				Change Control
				Revalidation
				Glossary
			ANNEX 16 CERTIFICATION BY A QUALIFIED PERSON AND BATCH RELEASE
				1 Scope
				2 Principle
				3 Introduction
				4 General
				5 Batch Testing and Release of Products Manufactured in EC/EEA
				6 Batch Testing and Release of Products Imported from a Third Country
				7 Batch Testing and Release of Products Imported from a Third Country with which the EC has a Mutual Recognition Agreement (MRA)
				8 Routine Duties of a Qualified Person
				9 Glossary
			ANNEX 17 PARAMETRIC RELEASE
				1 Principle
				2 Parametric Release
				3 Parametric Release for Sterile Products
				4 Glossary
			ANNEX 18 GOOD MANUFACTURING PRACTICE FOR ACTIVE PHARMACEUTICAL INGREDIENTS
			ANNEX 19 REFERENCE AND RETENTION SAMPLES
				1 Scope
				2 Principle
				3 Duration of Storage
				4 Size of Reference and Retention Samples
				5 Storage Conditions
				6 Written Agreements
				7 Reference Samples – General Points
				8 Retention Samples – General Points
				9 Reference and Retention Samples for Parallel Imported/Parallel Distributed Products.
				10 Reference and Retention Samples in the Case of Closedown of a Manufacturer
			GLOSSARY OF TERMS USED IN THE EU GUIDE TO GMP
		PART II: Basic Requirements for Active Substances Used as Starting Materials
			1 Introduction
			2 Quality Management
			3 Personnel
			4 Buildings and Facilities
			5 Process Equipment
			6 Documentation and Records
			7 Materials Management
			8 Production and In-Process Controls
			9 Packaging and Identification Labelling of APIs and Intermediates
			10 Storage and Distribution
			11 Laboratory Controls
			12 Validation
			13 Change Control
			14 Rejection and Re-Use of Materials
			15 Complaints and Recalls
			16 Contract Manufacturers (including Laboratories)
			17 Agents, Brokers, Traders, Distributors, Repackers, and Relabellers
			18 Specific Guidance for APIs Manufactured by CellCulture/Fermentation
			19 APIs for Use in Clinical Trials
			20 Glossary to Part II
	3 UK Guidance on Manufacture
		Manufacturers’ Obligations
		Qualified Persons
		Code of Practice for Qualified Persons in the Pharmaceutical Industry
		Appendix 1: UK Statements on CPD
		Import from Third Countries
		Mutual Recognition Agreements on Good Manufacturing Practice (GMP) and Manufacturing Authorisation
		Content of the Fabricator’s/Manufacturer’s Batch Certificate for Drug/Medicinal Products Exported to Countries Under the Scope of a Mutual Recognition Agreement (MRA)
		UK Guidance on Certificates of Analysis
		GMP for Starting Materials
		Manufacture and Importation of Unlicensed Medicines for Human Use
SECTION III: LEGISLATION ON MANUFACTURE
	4 EU Legislation on Manufacture
		DIRECTIVE 2001/83/EC, AS AMENDED, TITLE IV, MANUFACTURE AND IMPORTATION
		DIRECTIVE 2003/94/EC, LAYING DOWN THE PRINCIPLES AND GUIDELINES OF GOOD MANUFACTURING PRACTICE FOR HUMAN MEDICINES
	5 UK Legislation on Manufacture
		The Medicines for Human Use (Manufacturing, Wholesale Dealing and Miscellaneous Amendments) Regulations 2005 (SI 2005 No. 2789)
		Schedule 1 of the Regulations
		Schedule 2 of the Regulations
		Schedule 3 of the Regulations
		Prescribed Conditions for Manufacturer’s Undertakings for Imported Products (SI 1977 No. 1038)
		Schedule
SECTION IV: GUIDANCE ON WHOLESALE DISTRIBUTION PRACTICE
	6 EU Guidance on Wholesale Distribution Practice
		GUIDELINES ON GOOD DISTRIBUTION PRACTICE OF MEDICINAL PRODUCTS FOR HUMAN USE (94/C 63/03)
			Introduction
			Principle
			Personnel
			Documentation
			Premises and equipment
			Deliveries to customers
			Returns
			Self inspections
			Provision of information to Member States in relation to wholesale activities
	7 UK Guidance on Wholesale Distribution Practice
		Wholesale Dealer’s Obligations
		Appointment and Duties of the Responsible Person
		Control and Monitoring of Storage and Transportation Temperatures
		Counterfeits/Ensuring Bona Fides
		Diverted Medicines
		Parallel Distribution
		Continued Supply
		Product Recall/Withdrawal
SECTION V: LEGISLATION ON WHOLESALE DISTRIBUTION
	8 EU Legislation on Wholesale Distribution
		DIRECTIVE 2001/83/EC, AS AMENDED, TITLE VII, WHOLESALE DISTRIBUTION
			Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use as amended by Directive 2004/27/EC.
			Title VII: Wholesale Distribution of Medicinal Products
	9 UK Legislation on Wholesale Distribution
		The Medicines for Human Use (Manufacturing, Wholesale Dealing and Miscellaneous Amendments) Regulations 2005 (SI 2005 No. 2789)
SECTION VI: GLOSSARY OF LEGISLATION
	Glossary of Legislation
		European Legislation
		Primary (UK) Legislation
		Secondary Legislation (UK Statutory Instruments)
SECTION VII: INDEX
	Index
                        
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

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