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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
bottle, the amount of warehouse space needed to quarantine them
is humongous!
The limitations of the batch Sterility Test led to the development of
parametric release of terminally sterilized LVPs. As the name suggests, parametric release is the release of batches of sterilized medicinal products based on key “parameters” of a validated sterilization
process, instead of the outcome of the batch Sterility Test. The key or
critical process parameters in parametric release include the temperature, pressure, sterilization time and bioburden (level of micro-organisms or microbial load) of the pre-sterilized solution of the injectable product. For a higher level of sterility and quality assurance, a
manufacturer should “design and build quality into the product”.
6.2. What is a High-Quality Medicinal Product?
We now know that the quality of a medicinal product is not determined by its appearance, smell, taste, touch and texture, or its overall visual presentation. Nor is the quality of a medicinal product
determined by the product passing some (QC) tests set by the manufacturer or the regulator. Having said this, there are still many
other products which are purchased o the shelves (for example,
toys, handphones, computers, laptops, or food items), whereby consumers often judge the quality of these products based on organoleptic properties alone, namely, appearance, smell, taste, touch and
texture of the product. They make use of their sense organs such as
the eyes, nose, ears, tongue and fingers to assess the quality of these
products. Although there may be some minimal safety tests which
these o-the-shelf products have to pass, the overall regulations
Manufacturing High-Quality Medicinal Products
governing their sale and supply are by no means as stringent as for
medicinal products. Thus, the purchaser of these products often
makes his decision on what he wishes to buy, based on his own perception of quality.
However, pharmaceutical quality is not so straightforward. The
quality of a medicinal product is not easy for the patient, consumer
and the general public to assess. Furthermore, the look and appearance of a medicinal product can be misleading. Reliance on labeled
claims, packaging and visual presentations, and organoleptic properties alone is not adequate. The quality of a medicinal product goes
beyond its appearance and the set of QC tests which the batch of
product has passed.
What then are the attributes of a high-quality medicinal product?
According to the definition from the International Organization for
Standardization based in Geneva, Switzerland, the quality for any
product is “fitness for purpose”. For a pharmaceutical or medicinal
product, quality has to be about fitness for a medicinal purpose.
Quality translates into fitness for use by consumers or patients who
are sick, unwell or of ill health. Patients expect safe and eective
medicinal product for each and every dose which they consume.
Therefore, in the case of medicinal products, critical quality attributes would include the identity and potency of the active ingredient(s) in the finished dosage form as well as the purity of the product,
or conversely, the freedom from impurities and other contaminants.
The quality of a medicinal product also includes critical 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 such as a tablet or capsule. In the case of liquid dosage
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
forms such as syrups, elixirs, suspensions and other mixtures, the
important quality attributes are pH, clarity, color index, microbial
limits and/or sedimentation rate. For semi-solids such as creams and
ointments, the viscosity, texture and microbial limits are crucial.
For sterile medicinal products such as injections and eye drops, their
sterility, particulate matter and endotoxin levels are critical quality attributes. Overall, for any medicinal product, the purity, stability
and homogeneity are also critical quality attributes.
Medicinal products in various dosage forms
6.3. Purity of a Medicinal Product: Elimination of Impurities and Contaminants
The identity and potency of the active ingredient(s) present in a
medicinal product can be determined or measured by various test
methods available in the QC laboratory of the manufacturing facility.
However, it is more challenging to measure the purity, or conversely,
the level of impurities in the product, especially when the impurities
Manufacturing High-Quality Medicinal Products
or contaminants are present in very small amounts, or worse still, if
their identities are unknown. Hence, there is a need to elaborate on
the concept of purity, which is the absence of impurities and other
contaminants from a medicinal product. In the quality assurance of a
medicinal product, contamination and cross-contamination control
during the production and packaging processes are of paramount
importance. All manufacturers of medicinal products must have an
eective contamination control program. A proper contamination
control strategy must be undertaken by all pharmaceutical manufacturers to keep out contaminants and extraneous matters as part of
their overall eort to assure high-quality medicinal products.
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Contamination control in manufacture of medicinal products
6.3.1. What is a Contaminated Medicinal Product?
According to the UK Rules and Guidance for Pharmaceutical Manufacturers and Distributors, a contaminated medicinal product is
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described as a product that contains undesirable foreign matters,
which may be of a chemical or microbiological nature, or they may
be non-specific in nature. These contaminants or undesirable foreign matters may be present in a starting material, intermediate,
bulk product or the finished product; or they may be inadvertently
introduced during manufacturing such as during sampling, production, packaging, re-packaging, storage or while being transported to the warehouse of the wholesalers, hospitals, pharmacies,
drug stores, doctors’ clinics and, ultimately, supply to the patients
and consumers.
Contaminants may be broadly classified as intrinsic or extrinsic
based on their origin. Intrinsic contaminants are present inherently in
the starting materials such as the APIs, excipients including water,
as well as the packaging materials for the product. Intrinsic contaminants are those unwanted materials which are not or cannot be
removed completely from the starting and packaging materials during manufacturing. Intrinsic contaminants are more commonly
referred to as impurities, and often they are specific in nature, and
may be identified and quantified by QC test methods. On the other
hand, extrinsic contaminants originate externally from sources such
as the manufacturing personnel, processing and packaging equipment as well as the overall manufacturing premises or environment. Extrinsic contaminants are often non-specific in nature.
6.3.2. Why is There a Need to Control Impurities?
The overall therapeutic eect of a medicinal product is dependent
not only on the pharmacological properties of the API(s) which
it contains, but also on the toxicity of impurities present in the
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API, container-closure system and, eventually, the final product.
These impurities may include process-related impurities, degradation products, polymorphs and stereoisomers. Hence, control of
impurities in both the starting and packaging materials, and ultimately the finished product, is an important part of drug development, manufacturing and GMP compliance, and overall regulatory assessment for marketing approval of the finished medicinal
product.
6.3.2.1. Types of Impurities from APIs
Process-related Impurities
Impurities in APIs or drug substances include process-related impurities such as, but not limited to, the following items:
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— un-reacted API starting material/intermediates;
— residual reagents and catalysts used during API synthesis;
— residual solvents from the API purification process;
— residual heavy metals and other metals from starting materials
used for making the API; and
— other by-products from synthesis and chemical reactions
involved in manufacture of the API.
Degradation products
Impurities in APIs may also include drug-related impurities such as
degradation products arising from the API after its synthesis.
Polymorphs
Impurities in APIs may also manifest themselves as polymorphs if
the API exhibits polymorphism. Common APIs which exhibit
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
polymorphism include ampicillin, carbamazepine, cimetidine,
mefenamic acid, prednisolone and other drug substances shown
below.
Common drug substances which exhibit polymorphism
Polymorphism refers to a phenomenon where a drug substance
exists in more than one crystalline form (polymorph). Drug substances which exist in a non-crystalline form are said to be amorphous. The type of polymorph formed is generally aected by
factors such as temperature, pressure and solvent(s) used. Dierent polymorphs of the same drug substance may exhibit dierent
physico-chemical properties such as melting point, solubility, and
dissolution rate, which may in turn aect drug stability, solubility
and bioavailability of the dosage form. Therefore, the appropriate
polymorph of the drug substance is needed for manufacture of the
finished product, especially solid dosage forms and liquid suspensions. In reality, it is not necessary to control the type of polymorph
for most drug substances used. However, some monographs stipulate the need to restrict the drug substance to a single polymorph,
e.g., carbamazepine, dextropropoxyphene and spironolactone.
The dierent polymorphs may be identified using techniques such
as Raman spectroscopy, infrared spectroscopy, X-ray diraction,
Manufacturing High-Quality Medicinal Products
electron microscopy, moisture absorption analysis, or a combination of these methodologies.
Infrared spectroscopy
X-ray diraction of paracetamol
powder
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Raman spectroscopy
Enantiomers and Stereoisomers
Stereoisomerism is exhibited by drug substances with one or more
chiral centers. A chiral center is an atom with four dierent groups
attached to it, in such a way that there are two identical, but nonsuperimposable, mirror images. This is illustrated by the molecule below,
where the chiral center is carbon with four dierent groups attached
to it. The two associated structures formed are non-superimposable
mirror images of each other, and they are known as enantiomers.
An example of a pair of enantiomers
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Hence, for drug substances which have chiral carbon centers, impurities may also include one of the enantiomers. The good thing is
that most drug substances are not known to have chiral centers.
Some examples of APIs which exist as stereoisomers include dexchlorpheniramine maleate, ibuprofen, propranolol hydrochloride,
warfarin sodium and other drug substances as shown below.
Some drug substances which exist as stereoisomers
Optical rotation is the property displayed by chiral substances in
rotating the plane of polarization of polarized light. Optical rotation is considered to be positive (+) for dextrorotatory (d) isomers,
i.e., those substances that rotate the plane of polarization in a clockwise direction, and negative (–) for levorotatory (l) isomers. Enantiomers have identical physico-chemical properties except for optical
rotation. However, when it comes to pharmacological properties,
enantiomers may have similar or very dierent properties. For
example, both the (d and l) enantiomers of ibuprofen and warfarin sodium have similar pharmacological properties. However, in
the case of propranolol hydrochloride, the l-isomer is the active beta
blocker while the d-isomer is inactive. Today, it is known that thalidomide, a notorious API, has two enantiomers. In the late 1950s and
early 1960s, many pregnant mothers were prescribed thalidomide
Manufacturing High-Quality Medicinal Products
to treat morning sickness. Many of these mothers eventually gave
birth to babies with “phocomelia”, which is a congenital medical
condition where the babies were born with severe birth defects,
including webbed limbs and other physical and mental deformities.
Subsequent investigations showed that the undesirable enantiomer
of thalidomide was the cause of phocomelia. Hence, the choice of
the correct stereoisomer in the formulation and manufacture of a
product is of critical importance. GMP compliance by the API manufacturer and process control can help assure isomeric purity. Conversely, the lack of GMP compliance and process control can lead to
the formation of the undesirable enantiomer (the impurity).
6.3.2.2. Types of Impurities from Container-Closure System
The container and closure used for packaging can be a source of
impurities too. These impurities include residual monomers and
polymers, namely polyethylene, polypropylene, vinyl chloride and
polyvinyl chloride, plasticizers, antioxidants, stabilizers, and resinous coating materials. They may be potentially present in primary containers especially the plastic ones. Some of these impurities may be toxic. Impurities such as adhesives and printing ink
on the labels may also seep into the product via the porous plastic
containers.
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6.3.3. Control of Intrinsic Contaminants
The strategies for controlling intrinsic and extrinsic contaminants
by the manufacturer and regulator are dierent as these contaminants originate from dierent sources. For intrinsic contaminants
(impurities) which originate from the starting materials such as the