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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
Changi Airport to Schiphol International Airport. When we landed
at Schiphol, I remember that it was early in the morning of the same
day that the Committee of Ocials Meeting was supposed to take
place. We could take a train from Schiphol Airport to Utrecht — a
city in central Netherlands, where there was another train connection to Zeist. But the train rides would take far too long a time for
us to reach our meeting destination. As time was not on our side,
we thought that taking a cab (taxi) directly from Schiphol Airport
to the meeting venue in Zeist was the quickest and most seamless
way to reach our destination, and be on time for our meeting, hopefully. So, o we went in a cab from Schiphol Airport to Zeist. But
it was a case of Murphy’s Law. The cab driver was not familiar with
the route to Zeist and there were no Global Positioning System then.
The driver had to rely on road signs to guide him, and Lady Luck was
not on our side. The cab driver lost his way, making several side and
U-turns along the journey, and by the time we reached our destination, we were late for our meeting. In addition to being late, the cab
fare cost us a bomb. When we eventually stepped into the meeting
room, I remember seeing a sea of Caucasian men and women seated
in a huge hall in a roundtable format. Then it dawned upon us that
Singapore was the first Asian country trying to join an exclusively
European club. In 1998, PIC/S comprised only European Union (EU)
countries and the only non-European member was Australia. The
atmosphere within the meeting room appeared quite intimidating
to us. However, the Rapporteur for Singapore — Mr. Robert Tribe,
a nice, tall and friendly gentleman greeted and introduced us very
quickly to all the ocials (in formal attire) in the meeting room.
And soon after the introduction, a stocky man by the name of
Mr. Bernhard Schertz, who was then the Chairman of the PIC/S
Committee of Ocials, started to quiz us on Singapore’s application
Evolution of Pharmaceutical Inspection in Singapore and Benchmarking to PIC/S
to join PIC/S. It did not help that he had a deep booming voice when
he asked his questions; I learnt later that he was a former Colonel in
the Swiss army. From one question to another, we got the message
that the pharmaceutical inspection system of Singapore did not
measure up and was not up to scratch yet. My Director and I left
Zeist feeling quite demoralized and dejected, but more determined
than ever before, to be the first Asian medicines regulator to break
into this highly exclusive and prestigious European Club named
PIC/S. Following this highly disappointing episode, we worked very
hard to close the gaps and weaknesses in our pharmaceutical GMP
inspection system, to make it equivalent to the PIC/S framework.”
1.5.1. Levelling Up the Pharmaceutical Inspection System of Singapore
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As part of Singapore’s journey of accession to PIC/S, an intensive
program to build up expertise in the field of GMP inspection and
to level up the local pharmaceutical manufacturing industry was
initiated by the GMP Audit Unit. These included activities such as,
but not limited to, the following items:
• Organizing GMP Training Seminars and Workshops
Between 1998 and 2000, the GMP Audit Unit had organized or
co-organized a series of workshops and seminars mainly in collaboration with the GEA-NUS Pharmaceutical Processing Research Laboratory (GEANUS PPRL) at the National University of Singapore.
The co-author, Dr. Chan Lai Wah, was a Co-Founder of GEANUS
PPRL. During these three years alone, more than a dozen GMP
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
training seminars and workshops were organized. They covered topics such as Pharmaceutical Process Validation, Analytical Method
Validation, Pharmaceutical Utilities, Good Documentation Practice and Computerized Systems Validation for the Pharmaceutical
Industry. The topics for seminars and workshops had been identified based on feedback provided by the local pharmaceutical manufacturing industry that skills and knowledge were lacking in these
areas. These workshops were very well attended by manufacturing
and QC personnel from the generic and MNC pharmaceutical manufacturing industry, as well as GMP inspectors from the regulatory
authority. The speakers for these seminars and workshops included
experts from the industry, the contract testing laboratories, academia, as well as the GMP Audit Unit. The major seminars and
workshops co-organized by the GMP Audit Unit, in collaboration
with GEANUS PPRL, included the following:
1. Pharmaceutical Process Validation (February 1998)
2. Analytical Method Validation (May 1998)
3. How To Develop a Pharmaceutical Process Validation Program
(August 1998)
4. Microbiological Aspects of GMP (November 1998)
5. GMP Inspection: The Auditor’s and Auditee’s Perspective (February 1999)
6. Good Documentation Practices I (May 1999)
7. Good Documentation Practices II (December 1999)
8. Environmental Monitoring (December 1999)
9. Pharmaceutical Utilities (June 2000)
10. Computerized Systems Validation (August 2000)
11. Quality Control and Analytical Method Validation (November 2000)
12. GMP for CPM Manufacturers (December 2000)
13. Manufacture of Oral Medicinal Products (September 2007)
Evolution of Pharmaceutical Inspection in Singapore and Benchmarking to PIC/S
Shown here is a photograph of one of the GMP seminars co-organized
by the GMP Audit Unit in collaboration with GEANUS PPRL.
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GMP seminar co-organized by GMP Audit Unit and GEANUS PPRL
• Certification to ISO 9000 Quality Management System (QMS)
Standard
Having a quality management system (QMS) was one of the prerequisites for membership in PIC/S. Thus, by the end of 1998, a QMS
was developed by the GMP Audit Unit. In September 1999, the quality system of the GMP Audit Unit was assessed by the Singapore
Productivity and Standards Board and found to be in conformance
with ISO 9002:1994 QMS standard. The ISO 9000 Certificate of
achievement is appended on the next page.
Then, the GMP Audit Unit was one of the very few inspection agencies in the world, after the Medicines Control Agency (MCA) of the
UK and the Therapeutic Goods Administration (TGA) of Australia,
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
to have a certified QMS. The QMS developed and implemented by
the GMP Audit Unit had provided for consistency of GMP inspection
and overall quality assurance of its GMP inspection system. It had
also provided the GMP Audit Unit with procedures for recruitment,
training and incorporation of technical experts into the inspection
team, where necessary.
• Developing Technical Guidance Notes
In order to assist the local pharmaceutical manufacturing industry
in Singapore, a series of guidance notes was developed to provide
Evolution of Pharmaceutical Inspection in Singapore and Benchmarking to PIC/S
technical help, as well as to enable our inspectors to maintain
consistency of GMP inspections. Between 1999 and 2000, more
than a dozen sets of technical guidance notes were developed by
the GMP Audit Unit with professional inputs from the Quality
Control Advisory Committee of the Ministry of Health as well
as adaptations of existing guidance notes published by the PIC/S,
US Food and Drug Administration (FDA), Australia TGA and UK
MCA. The list of technical guidance notes developed by the GMP
Unit are as follows:
— Preparation of a Site Master File
— Inspection and Licensing of Pharmaceutical Manufacturers
— Microbiological Monitoring Program for Manufacturers of
Non-sterile Products
— Sterility Testing
— Preparation of Validation Master Plan
— Installation Qualification and Operational Qualification
— Non-Sterile Process Validation
— Cleaning Validation
— Validation of Aseptic Processes
— Water Systems for Manufacturers of Non-sterile Products
— Validation of Analytical Methods
— Validation of Moist Heat Sterilization
— Cleanrooms for Pharmaceutical Manufacturing
— Heating, Ventilating and Air-Conditioning System
— Good Distribution Practice
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• Assessment by two PIC/S Delegations
Two separate PIC/S delegations visited Singapore in April 1999 and
November 1999 to assess the GMP Audit Unit on its system of pharmaceutical inspection and licensing of manufacturers of medicinal
products. The 1st assessment by a PIC/S delegation comprising five
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
assessors from Australia, Belgium, Switzerland and UK took place
from 14 to 18 April 1999. Displayed below are some photographs
taken during the 1st assessment by the PIC/S delegation.
1st assessment by PIC/S delegation from 14 to 18 April 1999
After a week-long assessment, the PIC/S delegation observed the following major deficiencies in the system for inspection and licensing
of pharmaceutical manufacturers in Singapore:
• The Site Master File (SMF) was not made a pre-requisite before
conducting an inspection;
• The inspection reports written by the inspectors were not in the
prescribed PIC/S format;
• GMP deficiencies were not communicated to the manufacturer
during the Exit Meeting;
Evolution of Pharmaceutical Inspection in Singapore and Benchmarking to PIC/S
• There was a lack of a defined period for manufacturers to
respond to GMP deficiencies;
• The frequency of inspection was not based on a risk assessment
approach;
• Contract testing laboratories were not subject to prior clearance
by the inspectors; and
• The QMS of the inspectorate was not in full compliance with
the PIC/S Quality System Requirements for Pharmaceutical
Inspectorates.
Having a good understanding of the local pharmaceutical regulatory framework and its inspection gaps, allaying the concerns of the
local pharmaceutical manufacturing industry, as well as obtaining
“buy-in” of the stakeholders, were crucial to address the deficiencies
identified by the PIC/S assessors. Singapore submitted a corrective
action and preventive action (CAPA) report to the PIC/S delegation soon after the 1st assessment in April 1999. All the deficiencies
observed by the PIC/S delegation were quickly rectified, as follows:
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— The SMF was made a pre-requisite requirement before con-
ducting an inspection;
— The inspection report format was aligned to the PIC/S
requirement;
— A defined period was specified for manufacturers to respond
to GMP deficiencies;
— A risk-based approach was developed to determine the fre-
quency of inspections; and
— The pharmaceutical laws of Singapore were amended to sub-
ject contract testing laboratories to prior clearance by the
inspectors, and the PIC/S GMP standard was adopted as the
legal standard for Singapore.
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
A 2nd assessment was carried out from 29 November to 1 December
1999 by another PIC/S delegation to verify the CAPA report. It was
the first time in the history of PIC/S that an applicant for membership had to be assessed twice. It was learnt subsequently through
the Rapporteur (Mr. Robert Tribe of Australia TGA) that it was a
decision from the PIC/S Committee of Ocials which wanted to
make doubly sure that Singapore had indeed made the cut. After all,
the hitherto European-based club was admitting its first ever Asian
member into PIC/S. By the end of 1999, the PIC/S delegations and
assessors concluded that the Singapore system of GMP inspection
and licensing was “equivalent to that of PIC/S member authorities,
and Singapore had set a new benchmark for other ASEAN and Asian
pharmaceutical inspectorates to match.” With eect from 1 January
2000, Singapore became the first Asian country to accede to PIC/S.
Co-author (Sia Chong Hock) with Chief Pharmacist and PIC/S assessors (Robert
Tribe and Gordon Munro) — 2nd, 3rd, 4th and 5th from left — 1 December 1999.
Evolution of Pharmaceutical Inspection in Singapore and Benchmarking to PIC/S
Singapore’s membership in PIC/S was extremely significant; it was
a milestone achievement. Dr Clarence Tan, the CEO-designate of
the soon-to-be-established HSA informed the co-author (Sia Chong
Hock) personally with great pride: “Singapore’s accession to PIC/S
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