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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
• Participate in joint inspections with other PIC/S Inspectors to
“calibrate” one another’s inspection skills; and
• Allow appeal by aggrieved manufacturer through legal channels under national laws on inspection and licensing of pharmaceutical manufacturers.
In general, manufacturers also frown upon unannounced or surprise inspections. They prefer or expect the inspector to perform
scheduled inspections and to announce the dates of inspection and
names of inspectors who are visiting their facilities. In Singapore,
routine (announced) inspections are the norm, whilst surprise or
unannounced inspections are the exception. Singapore HSA conducts surprise inspections only during investigational or “for cause”
inspections, when there is feedback from the public or a whistleblower about irregularities or illegal operations at certain manufacturing sites, or when there are serious quality problems and
product recalls. HSA, like most other medicines regulatory authorities, would like to work in collaboration with the manufacturers.
However, from time to time, the inspectors do come across black
sheep among the manufacturing fraternity; in such a situation,
unannounced inspections are warranted.
Manufacturers also wish that the drug regulatory authority keep
the GMP standard constant. They do not like to see too frequent
changes to the GMP standard which the inspector uses as the yardstick for inspection. However, science, pharmaceutical technology,
biotechnology, computer technology, and process and analytical
technologies are dynamic, and they change with time. Hence, GMP
standards and pharmaceutical regulations will have to change in
tandem. The regulator and the industry have to adapt accordingly.
What the authority can help is to give ample grace period for the
industry to adjust to these changes.
Compliance of Pharmaceutical Manufacturers to Good Manufacturing Practice Standards
5.6. Who Inspects the Inspectors?
All PIC/S members must implement a Quality Management System
(QMS) that meets the PIC/S Quality System Requirements for Pharmaceutical Inspectorates. In addition, some drug regulatory authorities such as the Singapore HSA, Malaysia National Pharmaceutical Regulatory Agency (NPRA) and UK Medicines and Healthcare
products Regulatory Agency are also certified to the ISO 9001 QMS
standard. So, the pharmaceutical inspectorates and their inspectors
are inspected by their professional counterparts from PIC/S as well
as third-party assessors from conformity assessment bodies (CABs).
Over the years, the GMP inspectorate of HSA has been subject to
regular audits by assessors from other PIC/S member countries
as well as third-party CABs. The quality journey of the Singapore
inspectorate started way back in 1997 when the GMP Audit Unit or
inspectorate was first established, and its subsequent membership
of PIC/S as its first Asian member on January 2000 (see Chapter 1).
During its journey, the GMP Audit Unit had been subject to regular
assessments by CABs as well as PIC/S delegations.
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In 2017, the Singapore GMP Audit Unit was subject to a reassessment by a delegation of PIC/S assessors, and was declared to have
met all its 78 indicators (criteria) which included the availability
of a legal framework for inspection and licensing of pharmaceutical manufacturers, provisions to revoke manufacturing authorizations, implementation of an eective QMS, implementation of the
PIC/S GMP standard, and competency of inspectors based on actual
observed inspections of three manufacturing sites. Singapore HSA
continues to be a PIC/S Participating Authority.
In summary, it must be emphasized that Singapore’s membership
of PIC/S has created many opportunities for both the regulatory
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
authority (HSA) and the pharmaceutical manufacturing industry
in Singapore. A successful GMP inspection is one where the manufacturers work in close partnership with the inspectors, and where
mutual expectations are met or clarified. For the manufacturer,
a successful inspection sells the commitment of the company to
quality, and enhances its strength, branding and reputation. For
the inspector, a good track record of GMP compliance by a manufacturer leads to less need to scrutinize the manufacturer and
therefore less frequent inspection of the facility. After all, both the
manufacturer and regulator do share a common mission of protecting the health and well-being of the patient and consumer.
Reassessment of HSA for PIC/S membership: 18–22 September 2017
Chapter 6
Manufacturing High-Quality
Medicinal Products
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6.1. Historical Development of Pharmaceutical Quality
he concept and understanding of pharmaceutical quality have evolved over the years. Historically, the development of pharmaceutical quality may be divided into three
T
inal products were made personally by an apothecary or a pharmacist, whose compounding skills determined the quality of the product. A skillful compounding pharmacist could produce rounder pills,
clearer and tastier elixirs, or smoother and whiter creams. Round
pills, clear elixirs and smooth white creams were considered to be
well-made or well-compounded, and therefore a proxy indicator of
good-quality medicinal products. It was an era when you judge the
phases. The first phase is the era prior to 1880 when medic-
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
quality of a medicinal product by its appearance, just as some people would today still judge a book by its cover. Look at the range of
magazines highlighted below; they have very colorful and attractive
covers. In contrast, look at the other two publications on the next
page — the covers are plain and unattractive, but these publications
are the United States Pharmacopoeia and the British Pharmacopoeia respectively. These are books of standard, containing scientific,
authoritative and invaluable contents, and as a corollary, should be
deemed as high-quality publications. But when these publications are
displayed side by side in a bookstore, more people will be attracted by
the magazines rather than the pharmacopoeias. This is because people are generally and superficially attracted by colorful and cheery
visual presentations, and good and attractive looks, whether it is a
book, a medicinal product or any object.
Colorful, cheery and attractive magazines
Manufacturing High-Quality Medicinal Products
The second phase in the historical development of pharmaceutical
quality is between 1880 and 1960, a period lasting about 80 years,
when the results of end-product testing was the measure of product
quality. This phase started when the first assay method to quantify
liquid extracts of ergot was developed in 1880. (Just for additional
information, ergot is a fungus, and its extract contains ergotamine
for treating migraine, and ergometrine for treating post-partum
hemorrhage, which is serious vaginal bleeding in the mother following delivery of the baby.) Since then, numerous test methods had
been developed over the years. This period may be described as the
era of testing quality into the product, or simply quality by testing.
Testing quality into the product means that when a product is made,
it is tested largely at the end of the batch manufacturing process,
and if it passes the test(s) or comply with the product specifications,
it is deemed to be of good quality. However, many of us are now
aware that product or quality control (QC) testing has its limitations.
Firstly, conventional QC tests are “destructive”, i.e., they destroy the
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
product in the course of testing. Therefore, QC tests are performed
only on a small, statistically “representative” sample size with the
assumption that the batch is homogeneous. You do not (or cannot)
perform QC testing on 100% of the product because if you do so,
there will be nothing left of the batch of product for consumption.
So, the analyst conducts QC tests on a sample of the product, and
if the sample passes the test, he extrapolates the result to the entire
batch and then releases the batch for sale and supply. This is the first
limitation of quality by testing, that is, product testing and its sampling process is limited by statistics and probability. Secondly, you
can test only when you know the specific analyte. (An analyte is the
substance in a product that you want to analyze or quantify.) Only
when you know what is the analyte, or suspect its presence in the
product, then only can you set out to quantify it with the help of the
test method and reference standard. And thirdly, the test method
has to be suciently specific, accurate and reliable. Otherwise, you
cannot quantify the analyte accurately or pick up low concentrations
of an analyte or impurity. In short, test methods have to be validated
for key analytical attributes such as specificity, accuracy, precision,
robustness, linearity, limits of detection and limits of quantitation.
On 12 September 2008, The Straits Times newspaper reported that
some babies were found to have kidney stones arising from the
consumption of milk contaminated with melamine. This case
illustrates clearly why test methods must be specific, accurate and
reliable. Unscrupulous manufacturers know that milk powders are
tested for nitrogen content as a proxy or indicator of (milk) protein content. So, these manufacturers added melamine, which contains high amounts of nitrogen, to the milk powder to boost the
nitrogen content. But, the fact is that melamine is basically a type
of plastic which can cause kidney stones and acute kidney failure
Manufacturing High-Quality Medicinal Products
when consumed. The World Health Organization prohibits the use
of melamine in food products, including milk powder.
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This brings us to the third phase in the development of the concept
of pharmaceutical quality, i.e., the post-1960 or modern era, where
compliance to Good Manufacturing Practice (GMP) by the manufacturer and quality assurance of the product became the yardstick of
quality. This yardstick has moved upstream, and it includes monitoring and controlling quality during product design and formulation
of the pharmaceutical dosage form, control of starting materials used
in production and packaging processes, pharmaceutical process validation, as well as GMP compliance by the producers of the starting
materials as well as manufacturers of the finished products. The third
phase is the era of “designing and building quality into the product”,
or simply, Quality by Design, with increasing use of process analytical technology and other innovative Industry 4.0 technologies.
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
One of the earliest applications of quality by design is “parametric
release”, which is the release of a batch of medicinal products based
on critical process parameters. In the case of an injectable product
which has been terminally sterilized by a validated moist heat
sterilization process, parametric release is the release of that batch of
Moist heat sterilization (autoclaving)
injectable product without the need to conduct batch sterility testing
on the finished injectable product. Moist heat sterilization (also
known as autoclaving) is a form of heat treatment using saturated
steam at high temperature and high pressure to kill micro-organisms
in pharmaceutical products intended to be injected into the human
body. The development of parametric release evolved when it was
realized that the Sterility Test conducted on the batch of finished
injectable product has several limitations. Firstly, it has been shown
that if a sample of 20 vials or ampoules of a batch of 1,000 units of an
injection is subject to the compendial batch Sterility Test, there is
Manufacturing High-Quality Medicinal Products
only a 2% probability of rejection, or conversely, almost a 98% chance
of passing the Sterility Test even though there is a 0.1% contamination, i.e., 1 in 1,000 units is contaminated (non-sterile). For 1% contamination rate or 1 in 100 bottles contaminated (non-sterile), the
chance of passing the Sterility Test is still very high, at 82%. The table
on limitations of batch sterility test is shown below.
Limitations of batch sterility test
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So, it is quite clear that for a sterile medicinal product such as injections, infusion fluids, dialysates or eye drops, the batch Sterility Test,
which is performed on the end-product at the end of the sterilization
process, is not a highly dependable test, and therefore not a reliable
indicator of sterility assurance level. There is a high statistical probability of passing the batch Sterility Test even when contamination
rates are relatively high. Additionally, the cost of a Sterility Test is
by no means cheap and at least two weeks of incubation period are
needed for the Sterility Test. During this incubation period, the sterilized product cannot be released in real time for distribution to the
market; they have to be quarantined in the warehouse. This results
in large amounts of the sterilized medicinal products being stuck in
the warehouse, and incurring expensive storage space during quarantine. For bulky injectable products such as large-volume parenteral products (LVPs), such as those with a volume above 100 mL per