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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
tablet compression speed. There is also continued verification of the
critical manufacturing processes beyond the three initial production batches. The new approach assures that the process remains
continually in a state of control and the medicinal products manufactured are consistently of good quality. Currently, both the conventional three-batch pharmaceutical process validation and the
newer approach of continuous process verification are acceptable by
most medicines regulatory authorities around the world. In a nutshell, both conventional process validation and continuous process
verification are essentially about pharmaceutical science, involving
extensive testing under worst-case scenarios, and with the application of statistical tools and techniques. The extensive testing conducted during pharmaceutical process validation is to justify the
less extensive testing regimen during routine QC.
6.6. Summary of High-Quality Medicinal Products
Patients expect eective, safe and high-quality medicinal products with every dose that they take. Thus, the manufacture of a
high-quality medicinal product is about assuring that each and
every dose of the medicinal product is eective, safe, free from contamination and quality defects, and fit for purpose. In short, the
quality of a medicinal product includes the identity and potency
of the active ingredient(s), and its purity or freedom from contaminants. Contaminants and impurities in small or trace amounts can
be highly toxic, rendering a product unsafe and harmful. Quality
also includes the pharmaceutical attributes of the finished dosage
form such as hardness, friability, particle size, disintegration time
and/or dissolution profile in the case of solid dosage forms; pH, clarity, color index, microbial limits, and/or sedimentation rate in the
Manufacturing High-Quality Medicinal Products
case of liquid dosage forms; viscosity for semi-solids; and sterility
and endotoxin levels in the case of sterile medicinal products. For
any medicinal product, stability and homogeneity are also critical
quality attributes. A stable product maintains its quality, safety and
ecacy throughout its shelf-life, whilst a homogeneous product
means that each and every unit of dosage form meets all its product
quality specification. Stability is demonstrated through a stability
study whilst homogeneity (consistency) is demonstrated through
process validation. A pharmaceutical product needs to be properly
formulated, stored, distributed and handled to assure its quality.
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Chapter 7
Stability and Shelf-Life Testing of
Medicinal Products
7.1 . Introduction to Stability and Quality
he quality of a medicinal product includes the identity
and potency of active pharmaceutical ingredients (APIs).
Quality also incorporates the critical quality attributes
T
friability, particle size, disintegration time and/or dissolution profile of solid dosage forms like tablets and capsules. For liquid dosage
forms such as syrups, elixirs and suspensions, CQAs include pH, clarity, color index, microbial limits and/or sedimentation rate whilst in
the case of semi-solids such as creams and ointments, CQAs include
viscosity, specific gravity and texture. For sterile medicinal products
such as injections and eye drops, the CQAs include sterility, endotoxin levels and particulate matter. For any pharmaceutical dosage
form, the overall quality of the medicinal product also encompasses
purity, homogeneity and stability. Purity is managed via a con-
(CQAs) of the finished dosage forms, such as the hardness,
Stability and Shelf-Life Testing of Medicinal Products
tamination control strategy to eliminate impurities and extrinsic
contaminants, whilst homogeneity is demonstrated through pharmaceutical process validation studies. The stability of a medicinal
product, which is the focus of this chapter, is demonstrated by the
manufacturer through stability testing or shelf-life studies, involving the APIs, excipients as well as the container-closure systems. The
International Council for Harmonization (ICH) quality requirements for market authorization (of a medicinal product stipulates
that the product quality dossier submitted to the medicines regulatory authority shall include, but not limited to, the following items:
• Product Development
• Control of Drug Substances (or APIs)
• Control of Excipients
• Control of Container-Closure System
• Control of Finished Product
• Control of Manufacturing Processes, including Impurities and
Contamination Control Measures, Process Validation Study and
Stability Testing.
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7.2 . Factors Influencing Stability of a Medicinal
Product
The factors influencing the overall stability of any medicinal product may be broadly categorized into product and environmental
factors. Product factors include the formulation, the physicochemical properties of the APIs and excipients, as well as the overall container-closure system and the types of primary packaging materials
used. On the other hand, environmental factors include the storage
temperature, moisture content or relative humidity (RH), light, oxygen, physical stress during transportation and in-use contamination
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
during consumption. The stability of a medicinal product and its
shelf-life (or expiry date) is determined through stability testing and
shelf-life studies conducted by the manufacturer, which are submitted to the medicines regulatory authority for review and approval.
Appended below are photographs of dierent types of medicinal
products showing how expiry dates are printed or incorporated on
the labels, containers and packaging materials of dierent types of
medicinal products.
The stability testing and shelf-life study program takes into consideration both product-related and environmental factors. The program
includes long-term study (in real time), beginning initially with six
months’ worth of data to support the market authorization application. This study is conducted under controlled storage conditions
in specially designed and constructed stability chambers. The storage conditions of the study depend on the intended market of the
medicinal product, e.g., 30°C +/– 2°C; RH 75% +/– 5% for hot and
very humid climatic conditions in markets like those of Singapore,
Malaysia and Southeast Asia in general. In addition to the long-term
real-time stability study, an accelerated study (under elevated conditions), e.g., 45°C +/– 2°C; RH 75% +/– 5%, is also carried out to allow
the manufacturer to forecast and propose a shelf-life of the product to the medicines regulatory authority for initial, in-principle
approval. The long-term (real-time) study continues to be conducted
as an ongoing stability program even after the granting of the market authorization. This is to confirm the proposed shelf-life of the
already approved marketed product. Stability testing and shelf-life
studies are conducted with a view to establish the shelf-life of the
medicinal product when stored, distributed and used under recommended temperature, RH and other environmental conditions. Stability testing is the responsibility of the quality assurance and quality control departments of the pharmaceutical manufacturer.
Stability and Shelf-Life Testing of Medicinal Products
Expiry date printed on outer carton
of tablet
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Expiry date printed on aluminium backing of blister-packed
tablets
Expiry date printed on bottle
label of syrup
Expiry date printed on vial of
reconstituted vaccine
7.3. Why is Proper Storage, Transportation and
Handling of a Medicinal Product Important?
7.3.1 . Why is Proper Storage Important?
Elevated temperature during storage of a medicinal product can
lead to:
(a) degradation of product or more precisely the API, resulting in
loss of potency, and hence a loss in ecacy, with the life of the
patient at stake. This is especially so if the products are of low
therapeutic index, e.g., glyceryl trinitrate tablets for treating
angina and warfarin tablets for blood thinning.
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
(b) evaporation of solvent, resulting in loss of vehicle from liquid
preparations, and hence an increase in concentration of the
API(s) to a level which is much greater than 100% of the labelled
amount, resulting in a toxic or harmful product.
(c) loss of moisture content, resulting in hardening of tablets, and
hence changes in dissolution profile of the product, alterations
in bio-availability, changes in rate and extent of systemic absorption, and ultimately a loss in ecacy and therapeutic failure of
the products.
Elevated RH during storage of the medicinal product can result in:
(a) formation of toxic degradation products through hydrolysis;
these include:
• acetic acid from the degradation of aspirin or acetyl salicylic
acid, resulting in a sub-potent and smelly product;
• epi-anhydrotetracycline from tetracycline, which can cause
renal damage; and
• penicillanic acid from beta-lactam antibiotics, which can
cause anaphylaxis or anaphylactic shock.
(b) plastic screw caps of bottles losing torque, thus aecting pack-
age integrity and contents in the bottle;
(c) loss in clarity of the label — this can be critical if essential label
information is obliterated; and
(d) loss of adhesion of transdermal patch, which can result in the
patch dropping o, causing no medication to be administered.
7.3.2 . Why is Proper Transportation of a Medicinal Product Important?
During transportation, there may be increased agitation and
vibration of bottles or units of medicinal products. The increased
Stability and Shelf-Life Testing of Medicinal Products
agitation and vibration may lead to ingress of micro-organisms into
the content of the product, arising from poor container-closure
integrity or hairline cracks, with a resultant drop in microbiological
quality of the product. A product with poor microbiological quality
ultimately becomes an unsafe product, especially if it is intended to
be sterile such as in the case of injections and eye drops.
7.3.3. Why is Proper Handling of a Medicinal Product during Use Important?
Poor handling of a medicinal product during use can bring about
contamination of the products, leading to a drop in its microbiological quality and ultimately an unsafe product. This is the main
reason multi-dose eye drops should not be used beyond one month
after first opening. It is also why some eye drops are formulated for
use as a single dose.
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7.4. International Quality Guidelines on Stability
Testing
The ICH Quality Guidelines were published in 1993 soon after the
ICH was established by the regulators and industries of the US, EU
and Japan. The subject of stability and shelf-life must have been so
crucial that the newly formed ICH accorded it top priority then.
There are currently seven ICH Quality Guidelines that concern stability testing, namely ICH Q1 A, B, C, D, E and F, as well as ICH Q5C
on Stability Testing of Biological Products. The ICH and other international guidelines on stability testing contain a lot of fine details.
The authors will share only the key principles of stability testing
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
which are the same regardless of whether the guidelines are published by ICH, WHO, ASEAN or the pharmacopoeias.
7.4.1 . Number and Size of Batches
For long-term stability study (conducted in real time):
• There should be a minimum of three normal production batches
(which must be homogeneous).
• Initial six months data of long-term study must be submitted to
the medicines regulatory authority to support the application
for market authorization.
• Continual long-term stability study is required to be conducted
by the pharmaceutical manufacturer to support the provisional
(or proposed) shelf life.
For accelerated stability study (at elevated temperature or under
stress conditions):
• One production batch is adequate; this single batch can be
smaller than the normal production batch size.
• The accelerated study complements the long-term real-time
study.
• Accelerated testing shall not be performed at too high temperatures for very short duration, with extrapolation of results.
• This is because actual mechanism of degradation at very high
temperatures may be dierent from that at room temperature
or lower.
Stability and Shelf-Life Testing of Medicinal Products
7.4.2 . Testing Frequency
Long-term testing (in real time) should cover a minimum of six or
12 months at the point of submission to the medicines regulatory
authority.
• Testing should continue for a sucient period to cover the provisional or proposed shelf-life:
— During the 1st year: samples are tested every 3 months.
— During the 2nd year: samples are tested every 6 months.
— From the 3rd year onwards: samples are tested every
12 months, i.e., annually.
— In summary, a test schedule of: 0, 3, 6, 9, 12, 18, 24 months
and annually until the proposed shelf-life.
• In contrast, accelerated testing should cover a minimum of three
time points, i.e., at 0, 3, and 6 months under elevated (storage)
temperature or stress conditions.
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7.4.3. Storage Conditions
• For products stored under controlled room temperature, the
actual (room) temperatures and RHs should be recorded.
• Merely stating that the product is stored at room temperature
without specifying the actual temperature is vague and insucient for determining stability.
• Room temperature must be defined and controlled, for example: Store at 15
o
C to 25oC or Store at 15oC to 30oC.