Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5978_Библиотеки_им_академика_М_И_Перельмана
.pdf
245
11
Good Manufacturing Practice (GMP)
11.1 Chapter Introduction
The previous chapters examined the considerable eorts that go into establishing
that medical products as developed are safe and eective. However, this alone will
not assure the safety of public health. It is equally important to address the manu-
facturing operations to ensure that the manufactured product displays a high level
of purity and consistency. Fundamental to this, are the principles of Good Manufac-
turing Practice (GMP), which have been developed by regulatory authorities. These
are based on the essential principles of quality assurance systems in general, but
with specic focus given to manufacturing operations and particular requirements
that may be required to assure the quality of drugs and devices. Thus, while the
requirements of general quality systems are expressed in very generic terms, GMP
principles tend to be stated as more detailed and specic requirements that reect
the particular product or operation to which they apply.
11.2 Drug GMP Regulations and Guidance
Drug GMPs have been developed as a combination of regulations and guidance.
Specic regulations havebeen issued to dene GMP legal requirements for the man-
ufacture of nished drug products, whereas guidance was initially used to establish
requirements for the earlier stage of active pharmaceutical ingredient (API) man-
ufacture. In general, the level of control is expected to increase as manufacturing
operations progress to the nal stages in the process. This is particularly evident
in the case for API manufacture, as illustrated in Figure 11.1. A similar approach
is also witnessed in terms of regulatory control. In Europe, most regulatory vigi-
lance is targeted at the manufacture and release of drug products, as this provides
the regulators with the most eective means of controlling the quality of the prod-
uct that gets released to the market. However,manufacturers and importers of active
pharmaceutical ingredients (APIs) are also required to register and may be subject
to risk-based GMP inspections by regulatory authorities. For example, should reg-
ulators identify problems that may be attributed to an API ingredient, a targeted
Medical Product Regulatory Aairs: Pharmaceuticals, Diagnostics, Medical Devices,
Second Edition. John J. Tobin and Gary Walsh.
© 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.
246 11 Good Manufacturing Practice (GMP)
Type of
manufacturing
Application of ICH GMP guide to indicated steps (shown in grey) of
API manufacturing
Chemical
manufacturing
Production of
the API Starting
Material
Introduction of
the API
Starting
Material into
process
Production of
Intermediate(s)
Isolation
and
purification
Physical
processing,
and
packaging
API derived from
animal sources
Collection of
organ, fluid, or
tissue
Cutting,
mixing, and/or
initial
processing
Introduction of
the API Starting
Material into
process
Isolation
and
purification
Physical
processing,
and
packaging
API extracted from
plant sources
Collection of
plants
Cutting and
initial
extraction(s)
Introduction of
the API Starting
Material into
process
Isolation
and
purification
Physical
processing,
and
packaging
Herbal extracts
used as API
Collection of
plants
Cutting and
initial
extraction
Further
extraction
Physical
processing,
and
packaging
API consisting of
comminuted or
powdered herbs
Collection of
plants and/or
cultivation and
harvesting
Cutting/
comminuting
Physical
processing,
and
packaging
Biotechnology:
fermentation/
cell culture
Establishment
of master cell
bank and
working cell
bank
Maintenance
of working cell
bank
Cell culture
and/or
fermentation
Isolation
and
purification
Physical
processing,
and
packaging
‘Classical’
Fermentation to
produce an API
Establishment
of cell bank
Maintenance
of the cell
bank
Introduction of
the cells into
fermentation
Isolation
and
purification
Physical
processing,
and
packaging
Increasing GMP requirements
Figure 11.1 Applicability of GMP requirements to API manufacture.
inspection of the API manufacturer is likely to ensue. This strategy is illustrated in
Figure 11.2. Under the US FDC Act, manufacturers of APIs come under the same
regulatory controls as manufacturersof nished pharmaceutical productsas the def-
inition of a drug include components of drug products.
The core European Union regulatory framework relating to drug GMPs is framed
by a combination of regulations, directives and a GMP guideline;
● Directive 2001/83/EC, Article 46 and Regulation (EU) 2019/6, Article 93 estab-
lish the requirement that human and veterinary medicinal products and APIs are
manufactured in accordance with GMP.
● Regulation No. 1252/2014 lays down the principles and guidelines of GMP for
active substances for medicinal products for human use, including active sub-
stances intended for export.
● Directive 2003/94/EC lays down the principles and guidelines of GMP in respect
of medicinal products for human use and investigational medicinal products for
human use.
● Directive 91/412/EEC lays down the principles and guidelines of GMP for
veterinary medicinal products.
● GMP guidelines (volume 4 of ‘The rules governing medicinal products in the
European Union’), provides interpretation of these principles and guidelines.
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
11.2 Drug GMP Regulations and Guidance 247
GMP Regulations
Apply
Inspection by
Regulatory
Authorities
Possible
GMP
Regulations
Apply
Manufacturer
Licensing/
Importer
Licensing/
Manufacturer
Registration
+
Mandatory
Inspection by
regulatory
authorities
Distributor
Licensing/
Registration
Active pharmaceutical ingredients
(APIs) manufacture
Pharmaceutical product
manufacture
Pharmaceutical product
packaging, labelling
Other Ingredients (Excipients)
Operate in accordance with ISO 9000
Standards for Quality Assurance
Manufacture to Pharmacopeial
Standards of purity
Pharmaceutical product
warehousing and distribution
I
N
C
R
E
A
S
I
N
G
C
O
N
T
R
O
L
S
Figure 11.2 Regulatory strategy for pharmaceutical manufacture in Europe.
The core US regulations are contained in Title 21 of the Code of Federal
Regulations (21 CFR), in particular in:
● Part 210, current GMP in Manufacturing, Processing, Packing, or Holding of
Drugs, General Requirements.
● Part 211, current GMP for Finished Pharmaceuticals.
Supplementary requirements for specic types of drug products are contained in
other Parts of Titles 9 and 21 of the Code of Federal Regulations, as summarised in
Table 11.1.
ICH Q7 guideline provides globally harmonised principles of GMP for APIs.
The topics addressed by European GMP regulations and guidance are shown in
Figure 11.3. The core requirements are set down in the articles of the directives,
whereas detailed guidance on specic aspects is appended as annexes. The annexes
together with guidance on the core GMP requirements may be found in The
Rules Governing Medicinal Products in the European Union, Volume 4, Medicinal
Products for Human and Veterinary Use: GMP. The topics covered by the basic US
regulations for drug GMP’s are shown in Figure 11.4, while the headings of the ICH
guideline for API GMP’s are shown in Figure 11.5. Although the terminology and
sequence of topics may appear dierent, the essential principles are the same in all
cases. As will become apparent, many of these measures are directed at ensuring
that the purity and authenticity of drug products are guaranteed and represent
specic embodiments of the general principles of quality assurance systems that
were discussed earlier in Chapter 2.
248 11 Good Manufacturing Practice (GMP)
Table 11.1 US current Good Manufacturing Practice (cGMP) regulations for specific types
of drug products.
CFR No. Subject Matter
9 CFR Veterinary biologics
Part 108 Facility requirements for licensed establishments
Part 109 Sterilization and pasteurization at licensed establishments
Part 113 Standard requirements
Part 114 Production requirements for biological products
21 CFR Drugs and human biologics
Part 212 current Good Manufacturing Practice for Positron Emission Tomography drugs
Part 225 current Good Manufacturing Practice for Medicated Feeds
Part 226 current Good Manufacturing Practice for Type A Medicated Articles
Part 250 special requirements for specic human drugs
Part 600 Biologic Products General
Part 606 current Good Manufacturing Practice for Blood and Blood Components.
Part 610 General Biological Product Standards
Part 630 Requirements for blood and blood components intended for transfusion or for
further manufacturing use
Part 640 Additional Standards for Human Blood and Blood Products
Part 660 Additional Standards for Diagnostic Substances for Laboratory Tests
Part 680 Additional Standards for Miscellaneous Products
11.3 Essential GMP Requirements
11.3.1 Quality Assurance System
At its core, each manufacturer must have a quality assurance system appropriate to
the manufacture of pharmaceutical products. Essential elements that such a system
should address are summarised in Figure 11.6.
11.3.2 Personnel
Previously Chapter 2 examined the importanceof the organisation, training and edu-
cational qualications of personal as core elements of quality systems in general.
Personal hygiene is a specic additional aspect that must be addressed to prevent
contamination of drugs. Training and practices must be adopted so as to achieve:
● high standards of personal hygiene,
● the correct use of appropriate clothing such as gowns, hairnets or masks,
● a prohibition of eating, drinking, chewing, smoking or storage of food drinks or
personal items in manufacturing areas
● restrictions on personnel with infectious diseases or other relevant conditions
from working on the products and
● the avoidance of direct contact with the product.
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
11.3 Essential GMP Requirements 249
Core Regulatory Requirements (Articles)
1. Pharmaceutical Quality System – maintain an eective pharmaceutical QA system.
2. Personnel – organisation, responsibilities, training, qualications, hygiene.
3. Premises and equipment – suitability, layout, maintenance, qualication and
validation.
4. Documentation – procedures, specications, retention of records, electronic data.
5. Production – follow procedures, record deviations, prevent mix-up, validate processes.
6. Quality control – responsibility, review test results and production records, retain
samples.
7. Outsourced Activities – contract clearly dening responsibilities, subject to GMP
inspections.
8. Complaints and product recall – complaints and recall procedures.
9. Self-inspection – regular internal auditing and follow-up corrective actions.
Guidance Annexes
Annex 1. Manufacture of sterile medicinal products.
Annex 2. Manufacture of Biological active substances and Medicinal Products for
Human Use.
Annex 3. Manufacture of Radio Pharmaceuticals.
Annex 4. Manufacture of Veterinary Medicinal Products other than Immunologicals.
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 Products derived from Human Blood or Human Plasma.
Annex 15. Qualication and validation.
Annex 16. Certication by a Qualied person and Batch Release.
Annex 17. Parametric Release.
Annex 19. Reference and Retention Samples.
Figure 11.3 Basic topics addressed by the EU GMP Directives for medicinal products.
11.3.3 Premises and Equipment
The careful planning of the layout and construction of premises is another GMP
requirement that is key to reducing the risk of contamination or product mix-up.
Ideally, the layout should be designed so as to allow the production to take place in
areas connected in a logical order, corresponding to the sequence of the operations
and the requisite levels of cleanliness. The design should minimise the movement of
personnel or equipment through the production areas. Areas where raw materials
are weighed or charged into reactors should be physically separated from other
production areas so as to reduce potential cross-contamination by dusts generated
during such operations. The manufacture of certain critical products such as peni-
cillins, or highlycytotoxic drugs may require dedicatedfacilities to eliminate allrisks
of cross-contamination. Consideration must be given to providing heating, ventila-
tion and air conditioning (HVAC) systems that are in keeping with the operations
250 11 Good Manufacturing Practice (GMP)
Subpart A--General Provisions
Sec. 211.1 Scope.
Sec. 211.3 Denitions.
Subpart B--Organization and Personnel
Sec. 211.22 Responsibilities of quality control unit.
Sec. 211.25 Personnel qualications.
Sec. 211.28 Personnel responsibilities.
Sec. 211.34 Consultants.
Subpart C--Buildings and Facilities
Sec. 211.42 Design and construction features.
Sec. 211.44 Lighting.
Sec. 211.46 Ventilation, air ltration, air heating and cooling.
Sec. 211.48 Plumbing.
Sec. 211.50 Sewage and refuse.
Sec. 211.52 Washing and toilet facilities.
Sec. 211.56 Sanitation.
Sec. 211.58 Maintenance.
Subpart D--Equipment
Sec. 211.63 Equipment design, size, and location.
Sec. 211.65 Equipment construction.
Sec. 211.67 Equipment cleaning and maintenance.
Sec. 211.68 Automatic, mechanical, and electronic equipment.
Sec. 211.72 Filters.
Subpart E--Control of Components and Drug Product Containers and Closures
Sec. 211.80 General requirements.
Sec. 211.82 Receipt and storage of untested components,drugproduct containers, and
closures.
Sec. 211.84 Testing and approval or rejection ofcomponents, drug product containers,
and closures.
Sec. 211.86 Use of approved components, drug product containers, and closures.
Sec. 211.87 Retesting of approved components, drugproduct containers, and closures.
Sec. 211.89 Rejected components, drug product containers, and closures.
Sec. 211.94 Drug product containers and closures.
Subpart F--Production and Process Controls
Sec. 211.100 Written procedures; deviations.
Sec. 211.101 Charge-in of components.
Sec. 211.103 Calculation of yield.
Sec. 211.105 Equipment identication.
Sec. 211.110 Sampling and testing of in-process materials and drug products.
Sec. 211.111 Time limitations on production.
Sec. 211.113 Control of microbiological contamination.
Sec. 211.115 Reprocessing.
Figure 11.4 Core GMP regulations as set out in Title 21 of the US Code of Federal
Regulations, Part 211 (21 CFR 211).
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
11.3 Essential GMP Requirements 251
Subpart G--Packaging and Labelling Control
Sec. 211.122 Materials examination and usage criteria.
Sec. 211.125 Labelling issuance.
Sec. 211.130 Packaging and labeling operations.
Sec. 211.132 Tamper-evident packaging requirements for over-the-counter (OTC)
human drug products.
Sec. 211.134 Drug product inspection.
Sec. 211.137 Expiration dating.
Subpart H--Holding and Distribution
Sec. 211.142 Warehousing procedures.
Sec. 211.150 Distribution procedures.
Subpart I--Laboratory Controls
Sec. 211.160 General requirements.
Sec. 211.165 Testing and release for distribution.
Sec. 211.166 Stability testing.
Sec. 211.167 Special testing requirements.
Sec. 211.170 Reserve samples.
Sec. 211.173 Laboratory animals.
Sec. 211.176 Penicillin contamination.
Subpart J--Records and Reports
Sec. 211.180 General requirements.
Sec. 211.182 Equipment cleaning and use log.
Sec. 211.184 Component, drug product container, closure, and labeling records.
Sec. 211.186 Master production and control records.
Sec. 211.188 Batch production and control records.
Sec. 211.192 Production record review.
Sec. 211.194 Laboratory records.
Sec. 211.196 Distribution records.
Sec. 211.198 Complaint les.
Subpart K--Returned and Salvaged Drug Products
Sec. 211.204 Returned drug products.
Sec. 211.208 Drug product salvaging.
Figure 11.4 (Continued)
undertaken in a particular area.Such measures should be complemented by surfaces
on oors, walls and ceilings that facilitate cleaning – hard smooth surfaces with
minimal recesses. In general, such measures may be appropriate for the nal stages
in a manufacturing process (such as packaging) where the highest levels of hygiene
are expected. A pest control programme must be applied throughout the facility.
There must be adequate storage space to allow clear segregation between raw mate-
rials, intermediates or nished products that are approved, and those that are on
hold pending QC approval, or that have been rejected. Quality Control laboratories,
personnel lockers, toilets, and canteen facilities should be kept separate from the
production areas. A schematic diagram of a facility layout is shown in Figure 11.7.
The manufacture of sterile products requires special measures in terms of facil-
ities and arrangements to ensure that the products can be handled with minimal
252 11 Good Manufacturing Practice (GMP)
1. Introduction
1.1 Objective
1.2 Regulatory Applicability
1.3 Scope
2. Quality Management
2.1 Principles
2.2 Responsibilities of the Quality Unit(s)
2.3 Responsibility for Production Activities
2.4 Internal Audits (Self-Inspection)
2.5 Product Quality Review
3. Personnel
3.1 Personnel Qualications
3.2 Personnel Hygiene
3.3 Consultants
4. Buildings and Facilities
4.1 Design and Construction
4.2 Utilities
4.3 Water
4.4 Containment
4.5 Lighting
4.6 Sewage and Refuse
4.7 Sanitation and Maintenance
5. Process Equipment
5.1 Design and Construction
5.2 Equipment Maintenance and Cleaning
5.3 Calibration
5.4 Computerized Systems
6. Documentation and Records
6.1 Documentation System and Specications
6.2 Equipment Cleaning and Use Record
6.3 Records of Raw Materials, Intermediates, API Labelling and Packaging Materials
6.4 Master Production Instructions (Master Production and Control Records)
6.5 Batch Production Records (Batch Production and Control Records)
6.6 Laboratory Control Records
6.7 Batch Production Record Review
7. Materials Management
7.1 General Controls
7.2 Receipt and Quarantine
7.3 Sampling and Testing of Incoming Production Materials
7.4 Storage
7.5 Re-evaluation
8. Production and In-Process Controls
8.1 Production Operations
8.2 Time Limits
8.3 In-process Sampling and Controls
8.4 Blending Batches of Intermediates or APIs
8.5 Contamination Control
9. Packaging and Identication Labelling of APIs and Intermediates
9.1 General
9.2 Packaging Materials
9.3 Label Issuance and Control
9.4 Packaging and Labelling Operations
Figure 11.5 Headings of ICH GMP guideline for Active Pharmaceutical Ingredients (API)
manufacture.
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
11.3 Essential GMP Requirements 253
10. Storage and Distribution
10.1 Warehousing Procedures
10.2 Distribution Procedures
11. Laboratory Controls
11.1 General Controls
11.2 Testing of Intermediates and APIs
11.3 Validation of Analytical Procedures
11.4 Certicates of Analysis
11.5 Stability Monitoring of APIs
11.6 Expiry and Retest Dating
11.7 Reserve/Retention Samples
12. Validation
12.1 Validation Policy
12.2 Validation Documentation
12.3 Qualication
12.4 Approaches to Process Validation
12.5 Process Validation Program
12.6 Periodic Review of Validated Systems
12.7 Cleaning Validation
12.8 Validation of Analytical Methods
13. Change Control
14. Rejection and Reuse of Materials
14.1 Rejection
14.2 Reprocessing
14.3 Reworking
14.4 Recovery of Materials and Solvents
14.5 Returns
15. Complaints and Recalls
16. Contract Manufacturers (including Laboratories)
17. Agents, Brokers, Traders, Distributors, Repackers, and Relabellers
17.1 Applicability
17.2 Traceability of Distributed APIs and Intermediates
17.3 Quality Management
17.4 Repackaging, Relabelling and Holding of APIs and Intermediates
17.5 Stability
17.6 Transfer of Information
17.7 Handling of Complaints and Recalls
17.8 Handling of Returns
18. Specic Guidance for APIs Manufactured by Cell Culture/Fermentation
18.1 General
18.2 Cell Bank Maintenance and Recordkeeping
18.3 Cell Culture/Fermentation
18.4 Harvesting, Isolation, and Purication
18.5 Viral Removal/Inactivation Steps
19. APIs for Use in Clinical Trials
19.1 General
19.2 Quality
19.3 Equipment and Facilities
19.4 Control of Raw Materials
19.5 Production
19.6 Validation
19.7 Changes
19.8 Laboratory Controls
19.9 Documentation
20. Glossary
Figure 11.5 (Continued)
254 11 Good Manufacturing Practice (GMP)
1. Pharmaceutical products are designed and developed in a way that takes account of the
requirements of Good Manufacturing Practice and Good Laboratory Practice.
2. Production and control operations are clearly specied and Good Manufacturing
Practice adopted.
3. Managerial responsibilities are clearly specied.
4. Arrangements are made for the manufacture, supply and use of the correct starting and
packaging materials.
5. All necessary controls on intermediate products, and any other in-process controls and
validations are carried out.
6. The nished product is correctly processed and checked, according to the dened
procedures.
7. Pharmaceutical products are not sold or supplied before a qualied person has certied
that each production batch has been produced and controlled in accordance with the
requirements of the Marketing Authorisation and any other regulations relevant to the
production, control and release of medicinal products.
8. Satisfactory arrangements exist to ensure, as far as possible, that the pharmaceutical
products are stored, distributed and subsequently handled so that quality is maintained
throughout their shelf life.
9. There is a procedure for Self-Inspection and/or quality audit, which regularly appraises
the eectiveness and applicability of the Quality Assurance system.
Figure 11.6 Pharmaceutical quality assurance system principles.
Raw materials
reception
Raw materials
hold area
Approved raw
materials
storage
Raw materials
weighing
Product
manufacturing
Product
packaging
Product
labelling
Finished product
hold area
Approved finished
product storage
Quality control
laboratories
Product hold
area
Personnel Lockers, Canteens, Toilet Facilities, Administration, Visitor Reception
Reject area
Figure 11.7 Schematic layout of a drug manufacturing facility.
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
Соседние файлы в папке Библиотека им академика М.И. Перельмана