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
275
12
Oversight and Vigilance
12.1 Chapter Introduction
The previous chapter outlined the Good Manufacturing Practices (GMP) principles
that a manufacturer must apply in order to meet the required standards of quality,
identity and purity. This chapter will look at the regulatory requirements regarding
oversight of manufacturing operations and product performance in the market-
place. The key objectives of these requirements are to ensure that only consistently
high-quality products are produced, and to facilitate early detection of problems in
the marketplace. Manufacturing operations are controlled via requirements for the
registration and licensing of manufacturers and the conduct of site inspections to
guarantee that appropriate GMP are applied. The most stringent regulatory controls
are applied to the manufacture of nished pharmaceutical products. Obligations as
regards market vigilance and other reporting duties, allow regulatory authorities to
be kept informed of potential issues in the marketplace and take appropriate action
where necessary.
12.2 Registration of Manufacturers and Other Entities
As a prelude for exercising regulatory oversight of manufacturing operations,
regulatory authorities must be made aware of the entities involved. Dierent
procedures and requirements apply, depending on the type of product and the
applicable regulatory regime.
12.3 Manufacturing Authorisation of Medicinal
Products in the EU
According to Article 40 of Directive 2001/83/EC (human medicinal products) and
Article 88 of Regulation (EU) 2019/6 (veterinary medicinal products), pharmaceuti-
cal companies may not manufacture, package or label medicinal products in the EU
without obtaining a manufacturing authorisation. The authorisation requirement
also applies to companies that import pharmaceuticals into the EU from non-EU
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.
276 12 Oversight and Vigilance
countries. A separate authorisation (licence) is required for each site where such
activities take place. A core prerequisite for granting a manufacturing (or importing)
authorisation is demonstrable compliance with EU GMP requirements. To obtain
a licence, an application form must be submitted to the Competent Authority of
the Member State in whose territory the site is located. The application must be
accompanied by documented information on the following:
● The products manufactured or controlled at the site,
● The identity and qualications of the person responsible for product release
(a ‘Qualied Person’) and
● A description of the facilities’ equipment and quality control arrangements at
the site.
EU regulations require that each facility have at their disposal at least one
‘Qualied Person’, who is responsible for review and release of nished medicinal
products. The regulations specify various combinations of education, training
and experience that may be presented in order for a person to be recognised as a
Qualied Person. Many Qualied Persons hold degrees in medicine, veterinary
science or pharmacy. Before releasing a batch, the Qualied Person must review all
the batch paperwork and QC test records to ensure that the product has been man-
ufactured and checked in accordance with GMP regulations and the requirements
of the marketing authorisation. For products manufactured outside the EU, product
release will be based on a review of paperwork supplied by the manufacturer
coupled with testing performed at the EU site, unless there is an agreement on
mutual recognition of GMP inspections conducted by non-EU states.
Information on the site facilities andoperations should be presented in the form of
a Site Master File. A Pharmaceutical Inspection Cooperation Scheme (PIC/S) com-
mittee has developed specic guidance on the preparation of a Site Master File. The
suggested content of a Site Master File is outlined in Figure 12.1. This content is
identical to the content outlined in the EU GMP guidelines. The purpose of the
Site Master File is to provide the Competent Authorities with a basic understand-
ing and outline of activities at the site so as to enable them to eectively plan GMP
inspections. The CompetentAuthoritymust conduct a GMP inspection as partof the
licensing process. The authorities are allowed 90 days to issue a licence. The licence
is specic for both the products and the activities handled at the site. Changes to
either must be authorised by the authorities. The time allowed to authorise a change
is 30 days, but this may be extended to 90 days, if justied, as may be the case where
the change necessitates a site inspection. It should be noted that the manufacture
or import of products for human clinical trials is subject to the same authorisa-
tion procedures. A central database of manufacturing authorisations (EudraGMP)
is maintained by the European Medicines Agency (EMA) and may be accessed by
the general public.
12.3.1 Wholesale Distribution of Medicinal Products
Sites that warehouse and engage in wholesale distribution of medicinal products are
also subject to similar authorisation procedures.
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
12.3 Manufacturing Authorisation of Medicinal Products in the EU 277
1. GENERAL INFORMATION ON THE MANUFACTURER
1.1 Contact information on the manufacturer
1.2 Authorised pharmaceutical manufacturing activities of the site.
1.3 Any other manufacturing activities carried out on the site
2. QUALITY MANAGEMENT SYSTEM OF THE MANUFACTURER
2.1 The quality management system of the manufacturer
2.2. Release procedure of nished products
2.3 Management of suppliers and contractors
2.4 Quality Risk Management (QRM)
2.5 Product Quality Reviews
3. PERSONNEL
4. PREMISES AND EQUIPMENT
4.1 Premises
4.2 Equipment
5. DOCUMENTATION
6. PRODUCTION
6.1. Type of products
6.2 Process validation
6.3 Material management and warehousing
7. QUALITY CONTROL (QC)
8. DISTRIBUTION, COMPLAINTS, PRODUCT DEFECTS AND RECALLS
8.1 Distribution (to the part under the responsibility of the manufacturer)
8.2 Complaints, product defects and recalls
9. SELF INSPECTIONS
Appendix 1 Copy of valid manufacturing authorisation
Appendix 2 List of dosage forms manufactured including theINN-namesorcommon name
(as available) of active pharmaceutical ingredients (API) used
Appendix 3 Copy of valid GMP Certicate
Appendix 4 List of contract manufacturers and laboratories including the addresses and
contact information, and ow-charts of the supply chains for these outsourced activities
Appendix 5 Organisational charts
Appendix 6 Lay outs of production areas including material and personnel
ows, general ow charts of manufacturing processes of each product type (dosage form)
Appendix 7 Schematic drawings of water systems
Appendix 8 List of major production and laboratory equipment
Figure 12.1 Contents of a Site Master File.
The sites must:
● Have suitable premises to properly store and preserve the products,
● Employ a designated Qualied Person with responsibility for ensuring that
activities are carried out in compliance with the regulations,
● Distribute authorised productsonly to other authorised distributors orappropriate
sales outlets (pharmacies, licensed merchants, medical practitioners, veterinari-
ans, retail outlets, as appropriate to the product category),
● Maintain records of distribution, and
● Maintain an emergency plan to facilitate eective recall of product from the
market.
The authorisation timelinesare the same as for manufacturing sites, and similarly,
Competent Authorities are required to inspect the sites prior to issuing a licence.
278 12 Oversight and Vigilance
12.3.2 Registration of Economic Operators for Medical Devices on the
EU market
As already described in Section 10.4.5, manufacturers, authorised representatives
and importers are obliged to register on the EUDAMED IT system when placing
medical devices on the EU market. This process will result in the issuing of a single
registration number (SRN) once the Competent Authority in the Member State
where they are established have veried their existence. This SRN is then used to
identify the actor when requesting the involvement of a Notied Body and to link
them to the UDI-DI for devices placed on the market. Similar to a ‘Qualied Person’
associated with the manufacture of medicines, the medical device regulations now
require that each medical device manufacturer must have available at least one
suitably Qualied Person responsible for regulatory compliance. Qualied Persons
will typically be the holders of third-level qualications in law, medicine, pharmacy,
engineering or another relevant scientic discipline, combined with a minimum of
one year’s professional experience in regulatory aairs or quality management in
the medical device or IVD sector. They are responsible for ensuring that devices are
checked in accordance with the quality system prior to release, that the technical
documentation is kept up to date and that obligations in relation to post-market
surveillance, reporting and clinical/performance investigations are fullled. Small
and micro manufacturers may engage the services of an outside consultant to
undertake these duties. Authorised representatives, who full legal obligations on
behalf of manufacturers that are not established in the EU are also required to
have a Qualied Person for regulatory compliance permanently at their disposal.
Distinct from drug manufacturers, there is no requirement to register individual
manufacturing sites, as the Competent Authoritiesare not legally obliged to conduct
inspections of such sites. Instead, such sites are likely to be inspected by Notied
Bodies as part of the process of certifying the quality system and specied devices.
12.4 Registration of Producers of Drugs and Devices
in the US
According to section510 of the Food Drug and Cosmetic Act, producers of drugs and
devices are required to register the name and address of each establishment with the
Food and Drug Administration (FDA). These include all US-based sites involved in
manufacturing, packaging, labelling, ortestingof drugs, drug components ordevices
as well as foreign-based manufacturers that export products to the US. Wholesale
distributors of drugs must also register, but device distributors are exempt from this
requirement unless they are importing devices from outside the US. In addition to
registering their establishment, the registrants are also required to submit product
listings accompanied by the product labelling.
Detailed regulations concerning the registration of establishments and product
listings are set out in 21 CFR Parts 207 (drugs), 607 (blood/blood products),
807 (devices) and 9 CFR Part 102 (veterinary biologics). Establishment registration
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
12.6 Inspections 279
and drug listing data are submitted electronically. Establishment registration
submissions contain details of the name and address of the establishment, all
the trade names used by the establishment and establishment ownership details.
Additionally, a foreign registrant must identify a US-based agent and should also
list known importers. Establishment registrations must be renewed annually.
Product listings may be submitted twice annually to cover any material changes
from the previous listing (new products, discontinued products, modications).
Registration is mainly an administrative exercise and will result in the issuance
of Establishment Registration Numbers and product listing codes. However, fees
apply to the registration of medical device and generic drug establishments and
range from $6,493 for a device establishment to $228,134 for a foreign generic
drug nished dosage form facility (scal year 2023). Unlike the manufacturing
authorisation process in Europe, establishment registration is not directly coupled
with a site inspection. However, registration means that the site will be included in
the database of sites that are subject to a biannual inspection regime to ensure that
they comply with GMP and other requirements.
12.5 Additional Licensing Requirements
Many sites will have to full obligations under relevant environmental and safety
legislation. Sites that handle chemicals or engage in operations that are potentially
dangerous to the environment will have to register with the relevant environmental
protection agency. Sites will be inspected to ensure that there are adequate, controls,
containment measures and emergencyresponse procedures in place toprevent dam-
age to the environment. Integrated pollution prevention and control licenses will be
issued, which specify the conditions and restrictions under which the facility may
operate. Sites that hold quantities of hazardous chemicals abovethreshold levels that
could result in major accidents due to explosion, re or toxic releases, must register
with the local authorities. They must prepare emergency plans that are integrated
with those of the local emergency services.
12.6 Inspections
The regulatory authorities must conduct regular GMP inspections of sites in their
territory that are subject to GMP regulations. The duration between inspections,
often in the order of two years, is primarily determined by a risk-based approach
(dependent upon the potential harm associated with a loss of pharmaceutical
quality). These are normally scheduled visits but could be unannounced if the cir-
cumstances so warrant. API manufacturing sites are included as part of the routine
inspection programme under US regulations. In Europe, the authorities may inspect
API manufacturing sites or licence holders’ premises where it is deemed necessary.
Foreign manufacturing sites must permit inspections by authorities from states
where the product is being marketed. However, in practice, such foreign inspections
280 12 Oversight and Vigilance
have been greatly reduced by the establishment of mutual recognition agreements
where the parties accept the validity of their respective GMP inspection regimes.
The European Commission negotiates such agreements collectively on behalf of the
Member States. GMP mutual recognition agreements have been concluded with
the USA, Canada, Australia, New Zeeland, Switzerland and Japan among others.
It has not been possible to include devices in the GMP agreement between Europe
and the US. Under US regulations biannual GMP inspections of device manufactur-
ers must be conducted to ensure compliance with the Quality System Regulation.
Traditionally, the FDA as the regulatory authority has been responsible for these,
although reform of the regulations now permits accredited third-party bodies to
inspect sites producing class II or lower devices. In Europe, regular inspections of
device manufacturing sites are conducted by Notied Bodies for the purposes of
certifying compliance with relevant ISO quality standards. The regulatory author-
ities (Competent Authorities) may visit occasionally for monitoring purposes or in
response to compliance issues that may have surfaced through market surveillance,
but there is no legal obligation on them to routinely conduct or certify inspections.
Consequently, European device manufacturers that export to the US may receive
FDA inspections, although usually not at the same frequency as would apply to
US-based manufacturers. However, through an International Medical Device Reg-
ulators Forum (IMDRF), the FDA, in conjunction with the regulatory authorities
from Canada, Australia, Japan and Brazil, has pioneered a Medical Device Single
Audit Program (MDSAP). This enables international inspection organisations that
would be recognised as Notied Bodies in the EU to be also accepted as bodies that
conduct inspections in accordance with the MDSAP that are recognisedby the FDA.
12.6.1 Inspection Techniques
Irrespective of the particular focus of an inspection or the auditing strategy adopted,
most audits will have two basic elements:
● A review of documentation and procedures to verify that they comply with the
relevant requirements
● Checks to ensure that the conditions and practices outlined in the documentation
are actually achieved
In the case of pharmaceutical sites, inspectors will have the opportunity to do
some of the documentation verication in advance of a site visit. Relevant informa-
tion will be available either as a Site Master File submitted with a manufacturing
authorisation application in Europe, or the chemistry manufacturing and control
section of a drug marketing application, which will have been forwarded to the local
eld oce, in the case of FDA inspections. Actual site audits commence with a
meeting where quality management and usually other senior managers, are briefed
as regards the general outline and schedule. The inspector may then opt for a quick
orientation tour or else proceed with document review. Having identied what is
supposed to happen, the second stage is to verify that this in fact takes place. This
may be accomplished by a combination of record reviews and inspection tours.
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
12.6 Inspections 281
Inspection tours are usually the most dicult part of an audit to ‘manage’ from
a manufacturer’s perspective, as the inspector will be observing actual operations
and conditions and will frequently talk to sta to check that they have sucient
knowledge of the task that they are undertaking and its impact on GMP. Inspectors
may also remove samples of materials for independent testing.
The nature of an inspection will vary depending on the purpose of the audit and
the type and size of the facility under scrutiny. Initial audits of a new facility will
usually take the longest, as inspectors will want to conduct a full inspection of all
aspects of the operation. Subsequent routine surveillance audits will tend to be
shorter as auditors may just cover selected elements. Usually, this would include
areas of concern from previous audits and in this regard, it is vital that any such
issues are rectied when preparing for the next audit. It is also wise to ensure that
any issues that may have arisen in the market are adequately addressed, as these are
likely to be checked next time around. Serious adverse events on the market may
trigger an immediate ‘for cause’ inspection if it raises doubts as to the eectiveness
of, or the commitment to the GMP system. It is worthwhile to note that if an
identied deciency can be corrected during the course of an audit, it is prudent to
do so as this underlines the site’s commitment to compliance.
Inspectors from dierent jurisdictions may adopt dierent inspection strategies.
The PIC/S provide training for inspectors with a view to achieving greater harmony
in the standards of inspection among their member authorities. They organise
conferences, which discuss various aspects of GMP and arrange multinational
inspection teams, which enable inspectors from dierent countries to learn from
each other. Direction is also available from the EMA who have compiled a set of
guidance documents relating to GMP inspections (‘Compilation of Union procedures
on inspections and exchange of information’). European inspections will tend to be
conducted as either general GMP inspections when monitoring for routine pur-
poses, or product or process-oriented inspections in response to specic compliance
issues (e.g. re-audits or product quality problems). Inspectors report ndings under
the same headings as used for European GMP regulations i.e.
● Quality Management
● Personnel
● Premises and Equipment
● Documentation
● Production
● Quality Control
● Contract Manufacture and Analysis
● Complaints and Product Recall
● Self Inspection
The full EU GMP report template document format is presented in Figure 12.2.
The FDA has developed a systemsapproach for audit purposes. Theyhavegrouped
the GMP requirements for pharmaceutical sites into six major systems. These are
outlined in Figure 12.3.A full GMP inspectionof a pharmaceutical site,which would
be conducted for a new site, or an existing site where there are serious concerns
282 12 Oversight and Vigilance
Figure 12.2 EU GMP report template. Source: European Medicines Agency, 2014/European
Medicines Agency.
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
12.6 Inspections 283
Figure 12.2 (Continued)
284 12 Oversight and Vigilance
Figure 12.2 (Continued)
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
Соседние файлы в папке Библиотека им академика М.И. Перельмана