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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5577_Библиотеки_им_академика_М_И_Перельмана.pdf
212
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
The following are some examples of storage conditions (based on
WHO Good Storage and Distribution Practice):
• Do Not Store Over 30°C (means Store at 2°C to 30°C)
• Do Not Store Over 25°C (means Store at 2°C to 25°C)
• Do Not Store Over 15°C (means Store at 2°C to 15°C)
• Do Not Store Over 8°C (means Store at 2°C to 8°C)
• Do Not Store Below 8°C (means Store at 8°C to 25°C)
WHO has divided the world into four climatic zones. They are:
• Zone I: Temperate Climate, e.g., UK, US, Russia, North
Europe
• Zone II: Sub-Tropical and Mediterranean Climate, e.g., South
Europe, Japan, South Korea
• Zone III: Hot and Dry Climate, e.g., India, Iraq
• Zone IVa: Hot and Humid Climate, e.g., Egypt, Iran
• Zone IVb: Hot and Very Humid Climate, e.g., Brazil, Singapore
and ASEAN
For medicinal products intended for storage in a refrigerator, the
long-term study shall be carried out at 5
o
C +/– 3°C, whilst for medicinal products intended for storage in a freezer, the long-term study
shall be carried out at –20
o
C +/– 5°C.
7.4.4. Test Methods
• Test methods for stability testing shall be validated for accuracy,
sensitivity, specificity and reproducibility.
Stability and Shelf-Life Testing of Medicinal Products
• They shall be stability-indicating, i.e., the test methods must
be able to distinguish active ingredient from any degradation
products and be able to make a reliable quantitation of any degradation product(s). Examples are the HPLC test methods. Volumetric and titration test methods are unsuitable for stability
testing.
• For manufacturers who rely on contract-testing laboratories for
stability testing, specific quality agreements shall be established.
• Likewise, re-packers who rely on stability studies performed by
the manufacturer must have in place copies of relevant stability
study reports necessary to support shelf-life of the product(s).
7.4.5. Container-Closure Systems
213
• Testing must be performed in the same container-closure system where the product is sold.
• All container sizes should be subjected to stability testing.
• However, if a product is marketed in the same container type of
several sizes, e.g., bottles containing 100, 500 and 1,000 tablets,
stability testing can be performed on the smallest container size
(i.e., bottle of 100), based on the principle of bracketing, which
takes into account the worst-case scenario.
• The US FDA, ICH, WHO and ASEAN Guidelines on Stability
Testing provide guidance on bracketing and matrixing.
By applying the principles of bracketing and matrixing, the testing
frequency may be reduced, or certain combination of factors need not
be tested at all time points of a stability study schedule, if justified.
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
In bracketing:
• The principle of “worst-case scenario” is relied upon. The stability schedule is designed in such a way that only samples at
extremes are tested at all time points.
• When bracketing is applied to dierent volumes of the same
container system, the lowest volume is tested due to its highest
surface area-to-volume ratio, and therefore greatest potential
for contact with product.
• Other examples of bracketing include dierent weights or sizes
of tablets with the same formulation, or dierent shell sizes of
capsules with the same composition.
In matrixing:
• The stability schedule is designed such that a selected subset of
product combination factors (e.g., batches, strengths, pack sizes)
is tested at a specific time point.
• At another time point, another subset of combination factors is
tested.
• Matrixing assumes that the stability of each subset represents
the stability of all samples at a given time point. Over the period
of the test schedule, all combinations of factors would have been
adequately tested.
Repacking of products into dierent types of containers is a common primary assembly activity. The following considerations are
appliable to the repacking of medicinal products:
• The US FDA allows repacking into container-closure systems
with comparable temperature and RH protection without the
need to perform new stability studies.
Stability and Shelf-Life Testing of Medicinal Products
• Comparisons may be based on literature references, e.g., studies
on moisture or gas permeation properties of dierent container
materials.
• Re-packing of solid dosage forms from plastic into glass containers is allowed as glass is known to be a more superior moisture
and gas barrier.
• However, this rationale is not applicable to liquid dosage forms
due to pH problems which may arise from the alkaline nature
of glass.
• In addition to literature references, comparisons may also be
based on results of stress testing at high temperature and RH.
7.4.6. Stress Testing as a Component of Stability and Shelf-Life
Study Program
215
• Stress testing serves the following purposes:
— Identification of likely degradation products of drug sub-
stances (or APIs).
— Establishment of degradation pathways and intrinsic stabil-
ity of APIs.
— Validating the stability-indicating performance of test meth-
ods used.
— Providing supporting data for the handling of temperature
excursions.
• Stress testing is carried out on a single batch of drug substances.
• It includes the eects of temperature in 10°C increments (e.g.,
50°C, 60°C, 70°C) above that for accelerated testing (e.g., 40°C),
and RH (e.g., 75% RH or greater). Hence, stress testing supplements accelerated testing.
• For solutions or suspensions, stress testing should also include
hydrolysis of drug substances across a wide range of pH values.
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
• Where appropriate, photostability testing and eects of oxidation should be an integral part of stress testing.
7.5. Stability Study Schedule and Report
A Stability Study Schedule needs to be drawn up before proceeding with a stability testing program. A typical Stability Study Schedule for a Tablet Dosage Form, namely, Paracetamol Tablet 500 mg, is
shown below. The storage period of up to 60 months and the storage
conditions for long-term as well as for accelerated testing for the
three batches under study are indicated.
Typical stability study schedule (for paracetamol tablet 500 mg)
Stability and Shelf-Life Testing of Medicinal Products
Last but not least, a Stability Testing Report containing the follow-
ing details is put up:
217
Stability testing report format
7.6. Temperature Excursions and Product Stability
Temperature can fluctuate during storage and transportation. Fluctuations include seasonal variations, e.g., lower temperatures during
winter and higher temperatures during summer seasons. Hence,
stability testing under defined conditions has to consider the climatic zone of the countries of export, including excursions during
storage and transportation. Storage conditions should be monitored
and recorded. Equipment used should be capable of controlling the
storage conditions within defined limits. Short-term environmental
changes due to transient opening of doors of refrigerators or storage
facilities are accepted as part and parcel of the study and are unavoidable. However, eects of excursions due to equipment failure should
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
be assessed, addressed and reported if they aect stability results.
Excursions that exceed the defined tolerances for more than 24 hours
should be described in the study report and their eects assessed.
7.7. Cold Chain Products and Management of
Temperature Excursions
Cold chain products are particularly sensitive to changes in storage
and environmental conditions. Cold chain products include vaccines
and biopharmaceuticals as well as other medicinal products which
are stored in refrigerators and freezers. Some examples of cold chain
products and their storage temperature are shown below:
• Products Stored in a Refrigerator (2°C to 8°C). Examples of such
products include insulin injections, MMR vaccine and many
types of eye drops such as Lantanoprost Eye Drops used in the
treatment of glaucoma.
• Products Stored in a Freezer (−25°C to −10°C). Examples of such
products include Varicellar vaccine and Herpes Zorster vaccine.
• Products Stored in Ultra-Cold Freezer (−70°C and below). Wellknown examples include the Pfizer-BioNTech mRNA vaccine
and Ebola vaccine.
There is yet another category of products which needs to be stored
in a cool place (i.e., 8°C to 15°C). They are sometimes referred to
as “Cool Chain Products”. There are also many medicinal products which are required to be stored at controlled room temperature (20°C to 25°C/30°C). It is important to specify actual room
temperature as the room or ambient temperature varies from one
Stability and Shelf-Life Testing of Medicinal Products
geographical location to another. For example, in Europe, room
temperature has to be specified clearly as not exceeding 25
o
C, while
in Singapore, room temperature has to be specified, for example,
as not exceeding 30
o
C. It must be emphasized that during shipping
and transportation of medicinal products across dierent climatic
zones, temperature excursions can and do go wrong, especially for
cold chain products.
7.8 . Cold Chain Products and Temperature Excursions
The contributing factors for temperature excursions during transportation include:
— multiple product transfers during transportation journey;
— extreme temperatures while the container with the product is
on the tarmac;
— mishandling of product due to lack of instructions or human
error; and
— delays arising from long custom clearance, transportation
changes and weather conditions.
219
Temperature excursions should be properly managed like any other
manufacturing deviation. It is necessary to communicate temperature excursions to all parties involved, including the shipper,
transportation provider and manufacturer as well. Performance
of root cause analysis must include the entire supply chain from
pack-out (at manufacturing site) to delivery and receipt. It is to be
noted that the implementation of corrective action and preventive
action plan may aect or impact the procedures for supply chain
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
and transportation selection and the choice of transport providers
and their contracts. There is a need to monitor the eectiveness of
actions taken to prevent recurrence of temperature excursions.
When a temperature excursion occurs, it is important to know what
needs to be done to minimize product loss and the business impact.
Quite obviously, there is a need to understand the responsibilities of
the various stakeholders, namely the shipper, transport provider(s),
receiver and, of course, the manufacturer. The temperature excursion needs to be communicated to all relevant parties for resolution
as quickly as possible. Data from long-term and accelerated stability
studies, as well as temperature excursion studies are required to be
evaluated. Moreover, the impact of the temperature excursion on
product quality during transportation has to be carefully assessed.
All these will help to minimize or prevent product loss and any
potential adverse business impact.
For cold chain products stored between 2
o
C and 8oC, the following
are some key pointers in managing temperature excursions:
• Temperature excursions are allowed from down to 0
o
to 15
C during storage, shipping and distribution.
o
C and up
• However, in such cases, the mean kinetic temperature (MKT)
must not exceed 8
• Transient spikes of up to 25
o
C.
o
C are also permitted for no more
than 24 hours, unless there are additional supporting data from
the manufacturer.
Stability and Shelf-Life Testing of Medicinal Products
• The Arrhenius equation and temperature data collections are
used for calculation of MKT and decision-making.
7.9. Use of Mean Kinetic Temperature (MKT) in a
GMP/GDP Environment
The following are some points to note when using MKT in a GMP/
GDP environment:
• MKT is a tool for evaluating impact of temperature on product
stability, and hence product quality.
• It is a known fact that changes in storage temperatures can
aect the rate at which products degrade. At the same time, it is
challenging to store a product consistently under a fixed temperature. Temperatures are bound to fluctuate.
• MKT was first proposed (by J.D. Haynes in 1971) to guide stability studies, but is now used as a tool to evaluate temperature
excursions.
• MKT is really a “virtual temperature” which takes into account
the expected temperature variability in a given region.
• Haynes used the Arrhenius equation which is commonly employed
to show how a chemical reaction rate is aected by temperature.
According to this equation, chemical reaction rate at ambient
temperatures doubles with every 10oC increase in temperature.
• The use of MKT is increasingly being advocated in GMP/GDP
environments.
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