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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
APIs, excipients and container-closure system, the control strategies
as illustrated in the diagram below include:
• QC testing of APIs and other starting materials, as well as fin-
ished products by the manufacturer for impurities that are specific in nature, and which are known to the manufacturer;
• GMP compliance by the manufacturer;
• Assessments of impurity profile by product reviewers of the
medicines regulatory authority (e.g., Singapore HSA, Australia
TGA, US FDA, UK MHRA), and the rejection of starting materials and finished products with unacceptable levels of impurities
before pre-market approval; and
• Periodic GMP audits by inspectors from the medicines regula-
tory authority.
Control of intrinsic contaminants (impurities)
6.3.4. Control of Extrinsic Contaminants
On the other hand, extrinsic contaminants are non-specific in nature
and may come from the manufacturing personnel, production
Manufacturing High-Quality Medicinal Products
equipment, packaging equipment and premises. From the personnel, the extrinsic contaminants include bacteria, fungi, particles,
fibers, hair, dirt, saliva, perspiration and body fluids. From the equipment, extrinsic contaminants may include rust, corroded materials,
product residues, grease, lubricants and leached chemicals. From the
manufacturing premises, extrinsic contaminants may potentially
include flies, rats, cockroaches, other pests and rodents, and their
body parts, feces and droppings, as well as cross-contaminants from
adjacent or adjoining production premises, in addition to pollutants
from the external environment, outside of the manufacturing company. As extrinsic contaminants are non-specific in nature and often
unknown, they cannot be picked up via QC testing. Hence, extrinsic
contaminants have to be controlled and regulated through GMP
compliance and various cross-contamination measures undertaken
by the pharmaceutical manufacturer, as illustrated in the diagram
below.
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Control of extrinsic contaminants (non-specific)
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Some of these measures include sampling of starting materials for
QC testing within a designated sampling room or under controlled
environment with eective partitioning to prevent cross-contamination. The sampling room in the warehouse has to be a closed system with positive air pressurization. Sampling of starting materials
should also be performed by trained personnel who are properly
gowned with observation of good personal hygiene. Clean stainless
steel sampling tools are also needed to collect the samples. In addition to the sampling of starting materials for QC testing or evaluation, 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, cross-contaminants and extraneous matters at all stages of manufacturing.
6.3.5. General Assessment of Cross-Contamination Risks
As a general assessment of the overall contamination risk of a manufacturing facility, a simple rule of thumb may be used by the GMP
inspector. According to this rule, operations or activities within a
given manufacturing facility is likely to increase risks for contamination. For example, if only a single medicinal product or API is manufactured, the cross-contamination risk from another drug product
or API is virtually absent, and risk is at its lowest. Current GMP regulations require manufacturers of APIs which are highly sensitizing,
such as penicillin and cephalosporin, to be manufactured in dedicated
and self-contained facilities or buildings. Although the manufacture
of hormones, steroids and other materials that are highly potent
is allowed to be carried out in dedicated and self-contained areas
or rooms within the same facility, it can still pose an intermediate
Manufacturing High-Quality Medicinal Products
level of cross-contamination risk. On the other extreme, there are
generic drug manufacturers which produce multiple products in
non-dedicated facilities, using multi-purpose production equipment,
and often lacking a robust cross-contamination program. This group
poses the greatest risk for cross-contamination.
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General assessment of contamination risk
Thus, it is prudent for GMP inspectors to pay most attention to
generic drug manufacturing facilities producing large numbers of
medicinal products using multi-purpose equipment. Such “overcrowded” pharmaceutical manufacturing facilities pose the greatest cross-contamination risks in the same way that over-crowded
workers’ dormitories have resulted in very high transmission of the
coronavirus during the COVID-19 pandemic in some countries.
Today, human resource managers, public health regulators, building construction companies and government authorities have realized the need for proper dormitory design, eective segregation
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Overcrowded workers’ dormitory
and ventilation to avoid or reduce the transmission and cross-transmission of viruses and other pathogenic microorganisms. The
subject of purity and contamination control in the manufacture
of medicinal products is further elaborated under Chapters 15
and 16 on Active Pharmaceutical Ingredients and Pharmaceutical
Excipients respectively, Chapter 21 on Looks are Deceiving, and
Chapter 22 on Nitrosamine Saga and Control of Impurities.
6.4. Stability and Shelf-Life Testing of a Medicinal Product
The stability of a medicinal product is determined through a stability testing program. The factors influencing the stability of a
Manufacturing High-Quality Medicinal Products
medicinal product may be categorized into product-related factors and environmental factors. Product-related factors include
the formulation of the product, the physico-chemical properties of
drug substance(s) as well as the primary containers and packaging
materials used. On the other hand, environmental factors include
temperature, moisture, relative humidity, light, oxygen, physical
stress during transportation as well as potential in-use contamination during consumption. Therefore, the stability testing program
takes into consideration both product-related and environmental
factors. The program includes real-time studies under appropriate
controlled storage conditions, which are dependent on the intended
market(s), as well as accelerated studies under stressed conditions,
to estimate the shelf-life of the product. Stability testing studies are
conducted with a view to establish the shelf-life of product when
stored, distributed and used under recommended temperature, relative humidity and other environmental conditions.
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6.4.1. Why is Proper Storage, Distribution and Handling of a Medicinal Product Important?
Elevated temperature during storage of a medicinal product can
result in loss of potency (through degradation) and hence loss in
ecacy, putting the life of the patient at stake. This is especially
critical if the product has an API with a low therapeutic index, that
is, the dierence between the eective concentration and toxic concentration of the API is small. Such an API has a narrow safety margin or band. Elevated temperature during storage can also result in
loss of vehicle or solvent through evaporation, leading to increase in
concentration of the API with potential for overdosage. Moreover,
elevated temperature during storage can cause hardening of tablets
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
through loss of moisture content, leading to change in dissolution
profile, alteration in bioavailability and associated change in rate
and extent of systemic absorption, and ultimately a loss in ecacy
and therapeutic failure of the product.
Elevated relative humidity or moisture content during storage
can result in the formation of toxic degradation products through
hydrolysis. For example, acetic acid can arise from the degradation
of aspirin containing acetyl salicylic acid; epi-anhydrotetracycline
from tetracycline, with potential to cause kidney damage; and
penicillanic acid from beta-lactam antibiotics, with potential to
cause anaphylaxis or anaphylactic shock. Elevated relative humidity
or moisture content can also bring about a loss of package integrity and label clarity with resultant obliteration of essential label
information. In the case of a transdermal patch, elevated relative
humidity or moisture content can also result in a loss of adhesion
of the patch to the skin and thus in non-delivery of the transdermal
medication.
During transportation of a consignment of a medicinal product to
its final destination, there may be increased agitation and vibration
during the journey by air, sea or road. Increased agitation and vibration may lead to ingress of micro-organisms into the product. The
ingress may arise from poor container-closure integrity or hairline
cracks, resulting in a drop in microbiological quality of the product
and thus an unsafe, harmful product if it is intended to be sterile.
Moreover, poor handling of a product such as eye drops or eye ointment during in-use can bring about inadvertent contamination of
product with potential to cause eye infections and even blindness.
Manufacturing High-Quality Medicinal Products
The stability of a medicinal product and its impact on shelf-life and
expiry date is further elaborated under Chapter 7 on Stability and
Shelf-Life Testing of Medicinal Products.
6.5. Homogeneity of a Medicinal Product and
Process Validation Study
The homogeneity or consistency of a medicinal product is the extent
of how uniform the active ingredients are dispersed throughout
each individual dosage form or unit of the product. Homogeneity
may be demonstrated through a process validation study.
Whether it is US FDA, UK MHRA, Australia TGA, PIC/S or WHO,
process validation is defined as the means of ensuring and providing
documentary evidence that the manufacturing processes are capable of consistently producing a finished product of required quality.
There are several major steps involved in a process validation study.
Using the tablet dosage form as an example, the first step in a process validation study is to identify the critical quality attributes. For
a tablet, the critical quality attributes include the blend homogeneity, hardness, thickness, friability, particle size of the drug substance and dissolution profile. Then, the critical process parameters,
namely blending, milling and tablet compression, are identified,
and this is followed by the design of the sampling plan. For blending, 10 samples are taken from the top, middle and bottom of the
blender. For milling, one representative sample (about 100 g) may
be drawn from the mill; and for tablet compression, six samples of
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
20 tablets each may be collected at four equal time intervals from
the tablet compression machines, covering three compression
speeds (low, target and high speeds). You can see that pharmaceutical process validation is about extensive testing under worst-case
scenarios. After the design of the sampling plan, the testing plan is
developed. For blend uniformity, the content of blended samples is
assayed, and for the compressed tablets, tests for hardness, friability,
thickness, potency and dissolution profile are carried out. Then the
acceptance criteria are set; typically, they are set at within 90% to
110% of the labeled amounts of the API content. Finally, statistical
analysis (both intra-batch and inter-batch) are performed on three
consecutive full-scale batches of the product. For intra-batch analysis, process capability studies are carried out and the process capability indices are measured. For inter-batch analysis (of the three
consecutive production batches), an analysis of variance is carried
out. The objective of intra-batch analysis is to demonstrate the consistency of all the three validation batches. Intra-batch analysis is
performed on blend content uniformity test results. The objective
of inter-batch analysis is to demonstrate the equivalency amongst
the three validation batches and the pilot batch (used for clinical
trial and stability studies). Inter-batch analysis is performed on the
dissolution test results.
In process validation study, there is a Rule of Three to explain why a
conventional process validation study is often performed on three
consecutive batches. The explanation or rationale is as follows:
• One Successful Run – It’s a Fluke
• Two Successful Runs – It’s a Coincidence
• Three Successful Runs – It’s Scientific!
Manufacturing High-Quality Medicinal Products
Another perspective for the Rule of Three is:
• One Successful Batch – It’s an Accident
• Two Successful Batches – It’s Luck
• Three Successful Batches – There Is Linearity and Correlation!
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There is now a newer approach to process validation. As described
earlier, the conventional or traditional approach to process validation applies the Rule of Three, that is, it must be demonstrated that
three full-scale and consecutive production batches must have been
validated during the study. Re-validation is conducted only when
there are significant changes to critical quality attributes and critical process parameters. With the new approach, also referred to
as continuous process verification, there is extensive process design
and process qualification, monitoring of critical process parameters such as mixing time, duration of drying, temperature, and