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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
• Packaging Process Control
— Control of labels and packaging materials, bulk and finished
products
— Batch packaging records
— Validation, revalidation and change controls
• Personnel
— Wearing appropriate PPE
The packaging areas are also covered under the PIC/S Guide to GMP
for Medicinal Products Chapter 5, the same chapter as for production areas. After inspecting the packaging rooms, the inspector will
proceed to audit the QC Laboratories which include the Chemistry
Laboratory and the Microbiology Laboratory.
5.3.5. Why are the QC Laboratories Inspected?
The objective of inspecting the QC Laboratories is to assess that:
— properly trained analysts are available and there is independent
authority for Head of QC and Head of Production;
— QC test methods approved by the national medicines regulatory
authority are robust, sensitive, accurate and reliable for testing
as evident from records of analytical method validation and
routine QC test results;
— approved written procedures are in place for maintenance,
calibration, status labeling and assuring integrity of QC test
equipment, e.g., high-performance liquid chromatography system,
gas chromatography system, dissolution testing apparatus;
and
Compliance of Pharmaceutical Manufacturers to Good Manufacturing Practice Standards
— approved written procedures are in place for receipt, storage,
security, record-keeping of test samples, reagents, and reference
standards.
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Quality control (QC) laboratory
The items and areas covered during the inspection of the QC Laboratories include the approved written procedures for handling:
— test samples (e.g., API, finished products, water, swabs)
— prepared reagents
— reference standards (primary and secondary)
— retained (or retention) samples for stability or regulatory testing
— approved test methods
— validation and calibration of analytical equipment
analytical validation reports
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
records and/or calibration certificates
electronic records and raw data
— failure investigation
— stability studies conducted by the manufacturer.
The QC Laboratories are covered under the PIC/S Guide to GMP for
Medicinal Products Chapter 6.
5.3.6. Why do GMP Inspectors Visit Other Miscellaneous Areas?
Other miscellaneous areas which the GMP inspector would visit
include ancillary premises such as the engineering or maintenance
workshop, the corridors and even the restrooms (or toilets). The
restrooms do give a clue or two about the housekeeping attitude of
the manufacturer and may provide some correlation with the overall GMP compliance of the manufacturing facility. In fact, there are
inspectors who like to start an on-site audit by visiting the restrooms
first (instead of the warehouse) to have a look at their overall conditions. If the restrooms are poorly maintained, it is likely that the
cleaning, maintenance and general housekeeping of the company
cannot be expected to be meticulous or great.
5.3.7. Why do GMP Inspectors Audit Outsourced Activities,
e.g., Contract Testing Laboratories?
Contract testing laboratories provide QC testing services to pharmaceutical manufacturers based on a written contract specifying clearly the roles and responsibilities of the contract giver and
contract acceptor, and for an agreed service fee. Contract testing
Compliance of Pharmaceutical Manufacturers to Good Manufacturing Practice Standards
laboratories are often located at a dierent address because they
are not part of the manufacturing company. Inspectors have the
authority to inspect such contract testing laboratories for compliance with QC requirements of the PIC/S Guide to GMP for Medicinal Products. Alternatively, the inspector could rely on the audit
report of the contract testing laboratory conducted by the national
accreditation authority. In Singapore, contract testing laboratories
are audited and accredited by SPRING Singapore under its Singapore Laboratory Accreditation Scheme (SINGLAS) based on the ISO
17025 standard. Thus, the GMP inspector can rely on the SINGLAS
report for certified contract testing laboratories engaged by licensed
manufacturers of medicinal products. Often, the inspector does not
need to carry out an on-site audit of certified outsourced or contract
testing laboratories, unless there are serious quality issues associated with medicinal products made by the licensed manufacturer.
The ISO 17025 certificate issued by SPRING Singapore under SINGLAS is acceptable to HSA’s inspectors. This arrangement is also
practiced by some other PIC/S Participating Authorities.
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5.3.8. Why is there a Need to Conduct Documentation Audit/Review?
A GMP inspection is incomplete without the documentation audit
or review of the “Great Mountains of Papers”, comprising the SOPs,
records, reports, specifications, protocols, registers and other manufacturing documents.
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
The objective of documentation audit is to assess whether legal
requirements under national laws for the licensing of the establishment and registration of medicinal products have been complied
with by the manufacturer. Documentation audit can also verify
whether the regulatory commitments submitted by the manufacturer to the national medicines regulatory authority to obtain market authorization have been fulfilled by the manufacturer. These
regulatory commitments include the composition of the finished
product and specifications of starting materials, the test methods
used and their validation status, the process validation and stability reports, and their protocols and acceptance criteria. During the
documentation audit, SOPs that include those on product quality
reviews, handling of complaints and recalls, and self-inspection are
also reviewed by the inspector. The inspector also verifies that the
manufacturing and QC test records are authentic, and there is no
falsification of data. In short, the documentation audit is performed
to confirm that the manufacturer conforms to legal requirements,
regulatory commitments as well as the PIC/S GMP standard.
The items covered during the documentation audit include the:
• Document control system
— SOP on preparation of SOPs
— SOP on document control
— Control of e-documents and records
• SOP and records on pest control
• SOP and records on temperature and relative humidity
monitoring
• Batch manufacturing records
• Stability testing program
Compliance of Pharmaceutical Manufacturers to Good Manufacturing Practice Standards
• Process validation protocols, acceptance criteria and validation
master plan
• GMP training program
• SOP on records of product quality review, handling of com-
plaints and recalls, and self-inspection programs
5.3.8.1. Assessing Product Quality Review
Product quality review comes under the PIC/S Guide to GMP for
Medicinal Products Chapter 1. The inspector will assess the product
quality review records to ensure that these reviews are conducted
annually by the manufacturer for all its authorized products,
covering:
— Quality of starting materials;
— Quality of finished products and critical in-process controls;
— Failed batches of products and investigations;
— Manufacturing and QC deviations, and their corrective actions
and preventive actions (CAPA) reports;
— Changes to manufacturing processes and analytical methods;
— Changes to market authorizations;
— Stability testing and monitoring program;
— Complaints and product recalls, their investigations and closed-
out reports; and
— Qualification status of key equipment and utilities, e.g., steam,
water, and heating, ventilating and air-conditioning (HVAC)
system.
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The inspector will verify whether product quality review results
have been trended, investigated with CAPAs taken based on root
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
cause analysis, and whether statistical tools such as control charts
have been used for trending the quality parameters.
5.3.8.2. Assessing Program for Managing Complaints and
Product Recalls
The complaints and product recalls program of the manufacturer
is audited by the inspector in accordance with the PIC/S Guide
to GMP for Medicinal Products Chapter 8. For handling of complaints, the inspector checks for compliance to the following
requirements:
• A designated person is responsible for handling complaints and
deciding on actions to be taken;
• A written procedure (SOP) on handling complaints is in
place;
• All complaints are recorded, investigated and closed out with
decisions taken documented;
• All complaint records are reviewed regularly for any recurring
trend; and
• The Competent Authority (National Medicines Regulatory
Authority) is notified if manufacturer is considering product
recall following serious quality defects, faulty manufacture and
evidence of counterfeit products.
For handling of product recalls, the inspector checks for compliance
with the following requirements:
• A designated person, independent of sales and marketing, is
responsible for coordinating and executing recalls;
Compliance of Pharmaceutical Manufacturers to Good Manufacturing Practice Standards
• An approved written procedure (SOP) is in place for product
recall;
• Distribution records are readily available to the designated
person;
• The Competent Authority (National Medicines Regulatory
Authority), where the product is distributed, is notified if manufacturer is considering product recall;
• Recalled products are stored securely while awaiting decision on
their fate;
• Progress of recall process is recorded and a final report issued,
including a reconciliation between delivered and recovered
products; and
• Eectiveness of recall procedure is evaluated regularly.
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5.3.8.3. Assessing Self-Inspection Program
The self-inspection program of the manufacturer is audited by the
inspector in accordance with the PIC/S Guide to GMP for Medicinal
Products Chapter 9. The following requirements are checked by the
inspector:
• Self-inspections are carried out periodically in accordance with
pre-arranged program;
• The areas covered during self-inspection include production,
QC, premises, equipment, personnel and documentation, i.e.,
all nine chapters and relevant annexes of PIC/S GMP standard;
• Self-inspection is conducted in an independent and detailed way
by designated competent persons from the company;
• Independent audits by external experts are conducted, when
they are deemed useful;
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• All self-inspections are recorded, including observations made
and the proposed CAPAs; and
• Statement(s) of eventual action(s) taken are recorded.
5.3.8.4. Fish Bone Diagram: Link between GMP Compliance and
Product Quality
GMP compliance is an integral and critical component of quality
assurance. The Fish Bone Diagram is used to illustrate the relationship between GMP compliance and product quality. Product quality, which is represented by the fish head, is aected by the four Ms,
namely, Manpower, Machine, Method, Material, and one P, namely,
Premises. The backbone of the fish represents the overall pharmaceutical quality system of the manufacturer, which includes product quality review, quality risk management and the programs for
Compliance of Pharmaceutical Manufacturers to Good Manufacturing Practice Standards
handling complaints and recalls and self-inspection. It is very clear
from the Fish Bone Diagram that GMP compliance by the pharmaceutical manufacturer is integral and directly linked to product
quality.
5.4. The 20 Annexes of PIC/S GMP Standard
Annex 1 – Manufacture of Sterile Products
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Manufacture of sterile products
Annex 1 describes the GMP requirements for the manufacture of
sterile products such as injections, eye drops and eye ointments, and
the need for Clean Rooms to be designed with special airlocks and
air-handling systems to keep out particles and micro-organisms.
Annex 1 also stipulates the types of PPE such as hair covers, masks,