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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5335_Библиотеки_им_академика_М_И_Перельмана.pdf
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
This PIC/S GMP standard is organized into nine Chapters and
20 Annexes. Chapter 1 deals with the Pharmaceutical Quality System of the manufacturer, including the need to conduct Product
Quality Review and Quality Risk Management. Chapter 2 deals
with Personnel, Chapter 3 deals with Premises and Equipment, and
their design, construction, maintenance and cleaning, while Chapter 4 on Documentation has provisions concerning Standard Operating Procedures (SOPs) and records such as the Batch Production
Records, Batch Packaging Records, Analytical Records, and Distribution Records, that are required to be kept by the manufacturer.
Chapter 5 covers Production (including Packaging) and it deals
with the control of production and packaging processes including
the need to conduct process validation studies, whilst Chapter 6
is concerned with the Quality Control (QC) of starting materials,
intermediate products, packaging materials and finished products
and the need to use validated test methods. Chapters 7 covers outsourced activities, including contract manufacture and contract
testing (analysis) whilst Chapter 8 deals with the handling of complaints and product recalls. Chapter 9 is about self-inspection or
internal quality audit. Each of these chapters will be elaborated for
a better understanding of why they have been incorporated into
the PIC/S GMP standard.
In addition to the nine chapters, the PIC/S GMP Standard also
has 20 Annexes which stipulate additional requirements for various types of medicinal products and GMP-related matters. These
Annexes are referred to by the inspectors when they inspect specific
categories of manufacturers, e.g., facilities producing sterile products, biologicals, radiopharmaceuticals, herbal products and other
pharmaceutical dosage forms.
Compliance of Pharmaceutical Manufacturers to Good Manufacturing Practice Standards
5.3. How is an On-site GMP Inspection Conducted?
In the conduct of an on-site GMP inspection of a pharmaceutical
facility, the inspector is often guided by the flow of the manufacturing processes, rather than by the 9 Chapters and 20 Annexes of the
PIC/S GMP standard. Appended below is a typical manufacturing
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Typical manufacturing flow
flow at a pharmaceutical production facility. At the manufacturing
facility, the inputs are the starting materials, comprising the active
pharmaceutical ingredients (APIs), excipients, and the packaging
materials. During production and packaging of a pharmaceutical
dosage form, such as tablets, the processes include weighing, mixing,
granulation, drying, compression, coating, packaging, labeling, with
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
QC testing carried out at the dierent manufacturing stages, as well
as before batch release. The outputs of the entire manufacturing
process are the finished pharmaceutical dosage forms such as tablets,
capsules, creams, ointments, liquids, eye drops and injections. Thus,
a pharmaceutical inspector often finds it convenient and practical
to begin his on-site GMP inspection at the Warehouse, followed by
the Weighing Room, Production Areas and Packaging Room, and
the QC Laboratories such as the Chemistry Laboratory and Microbiology Laboratory. Last but not least, there is also a Document Audit
covering the review of SOPs, Records, Reports and Specifications,
before the conclusion of the on-site inspection. However, it must be
emphasized that an experienced inspector can choose to commence
an on-site GMP assessment of a pharmaceutical manufacturing
facility at any point in the manufacturing flow. The inspector is not
obliged to start his inspection from the warehouse.
However, as it is practical and convenient for the inspector to conduct an on-site GMP inspection following the manufacturing flow,
this chapter will start with the warehouse where the starting materials are stored.
5.3.1. Why is the Warehouse Inspected?
The objective of inspecting the warehouse is to assess that:
— all starting materials such as the APIs, packaging materials and
pharmaceutical excipients have approved specifications, and these
starting materials are purchased from pre-qualified suppliers;
— approved written procedures are in place for managing receipt,
quarantine and sampling of starting materials for quality
Compliance of Pharmaceutical Manufacturers to Good Manufacturing Practice Standards
assessments, release of these
starting materials upon successful assessments, as well as
for managing rejected materials and products; and
— the environment of the ware-
house has control programs
(e.g., temperature and relative
humidity monitoring and
pest control programs) in
place, which can preserve the
quality of materials and products stored at the warehouse(s).
The GMP requirements for the warehouse are covered
under the PIC/S Guide to GMP for Medicinal Products Chapter 3 (Premises: Storage Areas) and Chapter
5 (Production: Starting Materials). After inspecting
the warehouse, the inspectors will audit the weighing
(or dispensing) room.
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Temperature and
relative humidity
5.3.2. Why is the Weighing (or Dispensing)
monitoring
Room Inspected?
The objective of inspecting the weighing room is to assess that:
— calibrated, accurate and reliable weighing balances are used;
— the weighed materials are of correct identity, quantity and quality;
— authorized personnel wear appropriate personal protective
equipment (PPE); and
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
— the weighing room is environmentally controlled to prevent
cross-contamination.
Thus, the items covered by the inspector when he audits the weighing room will include calibration of the weighing balances, labeling of starting materials, wearing of proper PPE by the operators,
installation of eective dust extraction system and maintenance of
the weighing room. Inspection of the weighing or dispensing room
is covered under the PIC/S Guide to GMP for Medicinal Products
Chapter 5 (Production: Dispensing).
Weighing (dispensing) process
After inspecting the weighing room, the inspector will move on to
audit the production processes. In the case of tablet manufacturing,
the production processes will comprise mixing (or blending), granulation, drying, tablet compression and coating. These processes are
carried out at the production areas.
Compliance of Pharmaceutical Manufacturers to Good Manufacturing Practice Standards
5.3.3. Why are the Production Areas Inspected?
The objective of inspecting the production areas where the mixing/
blending, granulation, drying, tablet compression and coating processes are carried out, is to assess that the:
• production premises are designed to prevent cross-contamination;
• production equipment is eectively cleaned and regularly
maintained;
• personnel control programs are in place, e.g.:
— access is restricted only to authorized personnel;
— authorized personnel wear appropriate gowns and PPE;
• starting materials of correct identity, quantity and quality are
used for production; and
147
Mixing (blending) process
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
• process controls are in place, e.g.:
— critical processes are validated (and re-validated periodically)
— in-process QC programs are in place, and
— comprehensive batch production records are kept.
The production areas are covered under the PIC/S Guide to GMP for
Medicinal Products Chapter 5. The items covered during the inspection of the production areas include the:
• Production Rooms
— Design and construction
— Partition, segregation, air-handling and containment
measures
— Connecting pipe work are made of stainless steel and drain-
age has no backflow
— Change room is appropriately designed and fitted with air
shower
— Cleaning and maintenance are carried out regularly with
proper records kept
— Environmental and microbiological monitoring programs
• Production Equipment
— Design and construction
— Cleaning, maintenance, calibration and usage records
— Status labeling of equipment
• Production Process Control
— Labeling and control of weighed materials
— Gowning of production personnel
— Batch production records
— Process deviation and investigation
— Process validation, revalidation and change controls
Compliance of Pharmaceutical Manufacturers to Good Manufacturing Practice Standards
149
Granule drying process
Tablet compression
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Tablet coating
• Personnel
— Wearing appropriate PPE and avoiding jewelry and applica-
tion of cosmetic products
After inspecting the production areas, the inspector will proceed
to audit the packaging process taking place at the packaging room.
5.3.4. Why are the Packaging Areas Inspected?
The objective of inspecting the packaging areas is to assess that:
— there is proper design, construction, maintenance, cleaning and
environmental monitoring of the packaging rooms to prevent
cross-contamination and mix-ups;
Compliance of Pharmaceutical Manufacturers to Good Manufacturing Practice Standards
— there is also regular maintenance, cleaning and status labeling
of the packaging equipment to prevent cross-contamination
and mix-ups;
— the packaging process is validated, and line clearances are per-
formed and batch packaging records are kept; and
— there is eective control of labels to prevent mix-ups and appro-
priate temperature and relative humidity control to maintain
quality of packaged products.
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Packaging process
The items covered during the audit of the packaging areas
include the:
• Packaging Rooms
— Design and construction
— Cleaning, maintenance and calibration of weighing and
monitoring equipment
— Environmental and microbiological monitoring
• Packaging Equipment
— Cleaning, maintenance, calibration and usage records
— Status labeling of equipment