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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5577_Библиотеки_им_академика_М_И_Перельмана.pdf
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
gloves, shoe covers and gowns to be worn by Clean Room operators
and, very importantly, a contamination control strategy.
Annex 2A – Manufacture of Advanced Therapy Medicinal
Products
Annex 2B – Manufacture of Biological Medicinal Substances and
Products
Annex 3 – Manufacture of Radiopharmaceuticals
Annex 2A describes specific GMP requirements for advanced therapy medicinal products, which are also known as cells, tissues and
gene therapy products in many jurisdictions outside of the European Union (EU). Annex 2B provides the GMP requirements for
the manufacture of biological medicinal substances and products,
while Annex 3 provides the GMP requirements for radiopharmaceuticals, which often have very short shelf-lives.
Annex 4 – Manufacture of (Non-Immunological) Veterina ry
Products
Annex 5 – Manufacture of (Immunological) Veterinary Products
Annex 6 – Manufacture of Medicinal Gases
Annex 7 – Manufacture of Herbal Medicinal Products
Annex 7 provides special considerations for the manufacture of
herbal medicinal products which contains natural herbal ingredients, and are often used in the practice of traditional medicines
of various ethnic groups, e.g., the Chinese Proprietary Medicines,
Indian Ayurvedic medicines, Malay and Indonesian Jamu, Japanese
Compliance of Pharmaceutical Manufacturers to Good Manufacturing Practice Standards
Kampo, Korean Hanyak and Western herbs. Many herbal and traditional medicines have a long history of use, dating back to hundreds
or even thousands of years ago. This helps provide some degree of
assurance as to their safety and ecacy. However, the quality of
herbal medicinal products is independent of history and traditional
use. Manufacturers of these products are still required to comply
with GMP standard. The manufacture and supply, science and regulation of traditional and herbal medicinal products are covered in
greater detail under Chapter 17.
Annex 8 – Sampling of Starting and Packaging Materials.
This Annex describes the sampling plans and special precautions to
be taken during the sampling of materials for QC testing.
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Annex 9 – Manufacture of Liquids, Creams and Ointments
Annex 10 – Manufacture of Inhalations
Annexes 9 and 10 describe the special GMP requirements for
these specific pharmaceutical dosage forms which are formulated
and manufactured as liquids, semi-solids and inhalation products
respectively.
Annex 11 – Computerized Systems
Computerized systems are increasingly being used in the manufacture of medicinal products in warehousing, production, packaging and QC, and this Annex describes the GMP requirements
for such computerized systems. The subject of computerized systems is discussed in greater detail under Chapter 8 on Good Documentation Practice and Pharmaceutical Data Integrity, as well as
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Chapter 25 on Industry 4.0 and Emerging Trends in Pharmaceutical Manufacturing.
Annex 12 – Use of Ionizing Radiation in Manufacturing
Ionizing radiation is used as a method of sterilization for certain
types of materials/medicinal products, and its validation is described
in this Annex.
Annex 13 – Manufacture of Investigational Medicinal Products
Investigational Medicinal Products are also called clinical trial products. There are special GMP considerations in their manufacture
for clinical trials, where the medicinal products are in the various
stages of clinical development, and where the batch sizes produced
are often much smaller than those of a commercial or approved
medicinal product.
Annex 14 – Manufacture of Blood Products
This Annex provides stringent GMP requirements for the manufacture of blood products such as Albumin Injection, Factor XIII and
Factor IX, in particular the need for viral inactivation and clearance
and screening of donors of the plasma which are used as starting
materials.
Annex 15 – Qualification and Process Validation
This Annex describes the GMP requirements for qualification of
manufacturing equipment and associated process validation to
ensure product homogeneity.
Compliance of Pharmaceutical Manufacturers to Good Manufacturing Practice Standards
Annex 16 – Qualified Person and Batch Release
A Qualified Person is a person with specialized knowledge in pharmaceutical laws and GMP standard. He is legally responsible for
the release of each and every batch of a medicinal product manufactured in the EU. This Annex is not applicable to non-EU PIC/S
members.
Annex 17 – Parametric Release
Parametric release is the release of injections, usually large-volume
parenteral products (>100 mL in volume), that are terminally sterilized by moist heat (i.e., autoclaving) without the need for the manufacturer to carry out the batch sterility test. Parametric release
is permitted if the autoclaving process is well-validated, and when
stringent pre- and post-sterilization controls have been put in place
by the manufacturer, with ocial approval granted by the drug regulatory authority.
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Annex 18 – Empty
Annex 18 is currently empty. It was previously designated for the
API GMP standard which has now been renamed PIC/S Guide to
GMP for Medicinal Products Part II.
Annex 19 – Reference and Retention Samples
There is an obligation for the manufacturer to keep reference and
retention samples for on-going stability testing and for potential
regulatory testing, when there are quality problems or when there
are conflicting test results for the product concerned.
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Annex 20 – Quality Risk Management
At present, this Annex is voluntary. This means that manufacturers
are not obliged to comply to Annex 20 as of now, but they can use
Annex 20 as a guidance to implement quality risk management,
which is a GMP requirement incorporated as a component of Pharmaceutical Quality System (PIC/S Guide to GMP for Medicinal
Products Chapter 1).
5.5. PIC/S Inspection System: A Risk-based Approach
As Singapore is a member of PIC/S, the GMP inspection system of
Singapore HSA follows the PIC/S framework. Essentially, a GMP
inspection may be divided into three main stages:
• Pre-inspection planning phase which can take up to a day or
even several days;
• Conduct of on-site inspection (2–4 man-days or up to 5–10 mandays); and
• Post-inspection follow-up (duration varies, depending on the
outcome of the inspection).
During the pre-inspection planning phase, HSA forms an inspection team, comprising a lead inspector and a co-inspector, who
will review the Site Master File submitted by the manufacturer
before proceeding with the on-site inspection. The on-site inspection will cover the warehouse, weighing room, production and
packaging areas, QC laboratory and documentation review. If there
are deficiencies or non-conformities, the inspection team will follow through with the manufacturer on the CAPAs that need to be
Compliance of Pharmaceutical Manufacturers to Good Manufacturing Practice Standards
taken by the manufacturer before the inspection is closed out. If
there are no deficiencies, the post-inspection follow-up activities will
include writing the inspection report, establishing the dates for the
next inspection, and issuance of the manufacturer’s license or GMP
certificates, where applicable. The frequency of a GMP inspection,
i.e., how often a manufacturer is inspected or re-inspected, follows
a risk-based system. Pharmaceutical manufacturers may be broadly
classified into three “risk” categories:
• Manufacturers of sterile products, e.g., injections, eye drops and
eye ointments (high-risk manufacturers);
• Manufacturers of non-sterile oral products, e.g., tablets, capsules, syrups and mixtures (medium-risk manufacturers); and
• Manufacturers of non-sterile external products, e.g., creams and
ointments (low-risk manufacturers).
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The risk factors considered in the determination of inspection frequency include the:
— category of manufacturer (whether sterile, oral or external);
— GMP compliance profile or track record (whether acceptable,
unacceptable or marginal);
— frequency of changes to key personnel, premises and equipment;
— history of product recalls;
— history of legal and regulatory contraventions;
— number of products manufactured at the facility; and
— potency and sensitivity of the products manufactured, e.g. ste-
roids, hormones and penicillin products.
Being a PIC/S member, the GMP standards used for inspection are
the PIC/S Guide to GMP for Medicinal Products (Part I) for Medicinal Products in finished dosage forms, and the PIC/S Guide to GMP
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
(Part II) for APIs. The types of GMP inspections may be categorized
into:
— pre-approval inspection (of a new manufacturing facility);
— routine inspection (of an existing manufacturing facility);
— follow-up inspection (subsequent to the inspection of a new or
existing manufacturing facility);
— voluntary inspection (for the purposes of granting a GMP Certif-
icate); and
— investigational or “for cause” inspection, which can arise from
customer complaints, product recalls, quality defects or from
whistleblowing.
Whether a GMP inspection is a pre-approval, routine, follow-up,
voluntary or investigational, an on-site inspection of the manufacturing facility covering key areas such as the warehouse, production and packaging areas, and the QC laboratories, is required. The
on-site inspection will also cover the computers and computerized
systems used in warehousing, production, packaging and QC. Pharmaceutical utilities such as HVAC system, steam, compressed air and
water purification systems are inspected too. The documentation
system, including the SOPs, manufacturing records and reports are
also inspected. The manufacturing personnel will be interviewed
throughout the inspection.
5.5.1. Whom can the GMP Inspector Interview?
An Inspector can interview any sta in the company who is connected with manufacturing and QC. He can interview the operators,
the supervisors, the head of production, the head of QC, the data
entry personnel and computer systems manager, the maintenance
Compliance of Pharmaceutical Manufacturers to Good Manufacturing Practice Standards
engineers and technicians, the human resource manager and even
the CEO of the company. But there are certain areas that are out of
bounds to the inspectors. The GMP inspector does not audit records
of finance and accounts or related business documents. These matters are none of his concerns and outside the ambit or scope of a
GMP inspection. Furthermore, a GMP inspector is not a subject
matter expert in finance or accounting. Such kinds of inspections,
if they are required to be conducted, are carried out by commercial
crime auditors, investigators from the accounting and corporate
regulatory agency, or the police.
5.5.2. Inspector and Manufacturer Working in Partnership:
Mutual Expectations
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Inspectors should work in collaboration with the manufacturers
which they regulate. Both parties, the regulator and regulated,
should strive for a successful outcome. A successful GMP inspection is one where the inspector and the manufacturer work in close
partnership, and where mutual expectations are clear. Such a partnership will lead to a win-win-win outcome — a win for the manufacturer, for the regulator and, most importantly, for the consumer.
Therefore, the GMP inspector should strive to make his expectations known clearly to the manufacturer which he inspects. The
following are some inspector’s expectations of a manufacturer:
5.5.2.1. Inspector’s Expectations of a Manufacturer
• The manufacturer should be audit-ready (or inspection-ready)
at all times. Being audit-ready means that the manufacturer is
confident that his facility is GMP-compliant at all times. This
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
in turn indicates that the manufacturing processes at the facility are under control, and as a corollary, the products manufactured are consistently of good quality. For manufacturers which
are repeatedly not audit-ready, e.g., if the inspector is repeatedly
informed that key personnel such as the head of production or
head of QC is often not available, or often on sick leave, then
something fishy is probably happening. Under such circumstances, the inspector may consider unannounced inspections
as the manufacturer appears to have something to hide and is
trying to avoid a scheduled or announced inspection.
• The manufacturer should always ensure that key representatives
are present during an inspection. However, there are still some
manufacturers who are not sure which manufacturing personnel should be present during an inspection. For such manufacturers, the inspector will make it very clear that there should
always be a leader, who is the head of QC/QA or head of production, who is the facilitator and coordinator. This focal person has to be present throughout the entire audit. There should
also be a scribe to keep notes of all questions asked and documents requested. The scribe should also be present throughout
the entire inspection. Supporting technical sta and line supervisors need not be present throughout the entire audit, but
should be available to provide specific answers and details when
required. The MD or CEO needs only to be present during the
Opening and Closing Meetings, if he is available. The inspector
does not encourage too many sta to stop their work and tag
along during an inspection. Very large groups are discouraged
as they give the impression that nobody has an overall picture.
Besides, they also disrupt normal manufacturing schedules, and
are prone to the provision of inconsistent answers. Some manufacturers may erroneously believe that a large group can serve
to intimidate or rue the inspectors, hoping that the harassed
Compliance of Pharmaceutical Manufacturers to Good Manufacturing Practice Standards
inspector will not ask too many questions. However, inspectors are typically very well-trained and they are not going to
be so easily rued. Inspectors are generally confident, assertive,
authoritative and trained to be persevering and probing in carrying out their duties.
• The inspector also expects the manufacturer to enforce rules
and procedures regardless of the status of the person entering
the manufacturing facility. GMP rules must be observed by each
and every one regardless of whether he is an operator, a supervisor, external contractor, service personnel, head of QC, head of
production, or even the MD or CEO.
• The inspector also expects the manufacturing personnel to
know his SOPs and work instructions.
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5.5.2.2. Manufacturer’s Expectations of an Inspector
Similarly, the manufacturer also has his expectations of the (GMP)
Inspector or the inspectorate where he comes from. Consistency of
inspections is one of the most common expectations of manufacturers
who have provided feedback that dierent inspectors assessed manufacturers dierently, thereby causing confusion and inconsistencies. As a
regulator, the Singapore HSA and other PIC/S Participating Authorities
have minimized inconsistency through several internal mechanisms:
• Form inspection team with at least two inspectors to provide
check and balance;
• Develop and implement a SOP for all inspectors on how a GMP
inspection is conducted, with the inspection process clearly
defined;
• Have an exit or closing meeting with the manufacturer to allow
discussion, agreement or disagreement of any observation;