SCHOOL OF PHARMACY

BACHELOR OF PHARMACY
PHARMACEUTICAL QUALITY ASSURANCE
(PPM 20502)
ASSIGNMENT 2

NAME: ID NO.
Nur Shazana Binti Nazeri 012013110197
Pavithira Paniker Ravandran 012013052148
Ravinderen Pichan 012013052149
Shakirah binti Suid 012013052143
Syafinaz binti Samsudin 012013052132

Lecturer : Mr. Sameer Dulli

 INTRODUCTION

Stability testing assesses how the quality of a drug substance or drug product (including its
packaging) varies with time under the influence of environmental factors, including
temperature, humidity and light. The process determines whether any physical, chemical or
microbiological changes affect the efficiency and integrity of the final product, thereby
ensuring that a pharmaceutical product is safe and effective, irrespective of where in the
world it will be supplied. Moreover, stability testing establishes the shelf life and
recommended storage conditions of a finished pharmaceutical product and the retest periods
for a drug substance. Comprised of two stages (stability storage and downstream analytical
testing), stability testing ensures compliance with international regulations that form part of
the registration process for a new drug substance or drug product. Throughout the duration of
the study, the stability of the drug is established through physical, chemical, biological and
microbiological tests. An example of these tests is stress testing, of which photo stability
testing is a specific case that assesses the effects of light exposure on the drug product or
substance. A shelf life and label storage instructions are then determined from the results of
the tests.
 FINISHED PHARMACEUTICAL PRODUCT (FPP) STABILITY TESTING
a) General

The design of the stability studies for the FPP should be based on knowledge of the behaviour
and properties of the API, information from stability studies on the API and on experience
gained from pre-formulation studies and investigational FPPs.

b) Selection of batches

Data from stability studies should be provided on at least three primary batches of the FPP.
The primary batches should be of the same formulation and packaged in the same container
closure system as proposed for marketing. The manufacturing process used for primary
batches should simulate that to be applied to production batches and should provide product
of the same quality and meeting the same specification as that intended for marketing. In the
case of conventional dosage forms with APIs that are known to be stable, data from at least
two primary batches should be provided. Two of the three batches should be at least pilot-
scale batches and the third one can be smaller, if justified. Where possible, batches of the FPP
should be manufactured using different batches of the API(s). Stability studies should be
performed on each individual strength, dosage form and container type and size of the FPP
unless bracketing or matrixing is applied.

c) Container closure system

Stability testing should be conducted on the dosage form packaged in the container closure
system proposed for marketing. Any available studies carried out on the FPP outside its
immediate container or in other packaging materials can form a useful part of the stress
testing of the dosage form or can be considered as supporting information, respectively

d) Specification

Stability studies should include testing of those attributes of the FPP that are susceptible to
change during storage and are likely to influence quality, safety, and/or efficacy. The testing
should cover, as appropriate, the physical, chemical, biological and microbiological
attributes, preservative content (e.g. antioxidant or antimicrobial preservative) and
functionality tests (e.g. for a dose delivery system). Examples of testing parameters in the
stability studies are listed in Appendix 2. Analytical procedures should be fully validated and
stability-indicating. Whether and to what extent replication should be performed will depend
on the results of validation studies. Shelf-life acceptance criteria should be derived from
consideration of all available stability information. It may be appropriate to have justifyable
differences between the shelf-life and release acceptance criteria based on the stability
evaluation and the changes observed on storage. Any differences between the release and
shelf-life acceptance criteria for antimicrobial preservative content should be supported by a
validated correlation of chemical content and preservative effectiveness demonstrated during
development of the pharmaceutical product with the product in its final formulation (except
for preservative concentration) intended for marketing. A single primary stability batch of the
FPP should be tested for effectiveness of the antimicrobial preservative (in addition to
preservative content) at the proposed shelf-life for verification purposes, regardless of
whether there is a difference between the release and shelf-life acceptance criteria for
preservative content.

e) Testing frequency

For long-term studies, frequency of testing should be sufficient to establish the stability
profile of the FPP. For products with a proposed shelf-life of at least 12 months, the
frequency of testing at the long-term storage condition should normally be every three
months over the first year, every six months over the second year and annually thereafter
throughout the proposed shelf-life. At the accelerated storage condition, a minimum of three
time points, including the initial and final time points (e.g. 0, 3 and 6 months), from a six-
month study is recommended. Where an expectation exists that results from accelerated
testing are likely to approach significant change criteria, testing should be increased either by
adding samples at the final time point or by including a fourth time point in the study design.
When testing at the intermediate storage condition is called for as a result of significant
change at the accelerated storage condition, a minimum of four time points, including the
initial and final time points (e.g. 0, 6, 9 and 12 months), from a 12-month study is
recommended. Reduced designs, i.e. matrixing or bracketing, where the testing frequency is
reduced or certain factor combinations are not tested at all, can be applied if justified.

f) Storage conditions

In general an FPP should be evaluated under storage conditions with specified tolerances that
test its thermal stability and, if applicable, its sensitivity to moisture or potential for solvent
loss. The storage conditions and the lengths of studies chosen should be sufficient to cover
storage, shipment and subsequent use with due regard to the climatic conditions in which the
product is intended to be marketed. Photo stability testing, which is an integral part of stress
testing, should be conducted on at least one primary batch of the FPP if appropriate. More
details can be found in other guidelines. The orientation of the product during storage, i.e.
upright versus inverted, may need to be included in a protocol where contact of the product
with the closure system may be expected to affect the stability of the products contained, or
where there has been a change in the container closure system. Storage condition tolerances
are usually defined as the acceptable variations in temperature and relative humidity of
storage facilities for stability studies. The equipment used should be capable of controlling
the storage conditions within the ranges defined in these guidelines. The storage conditions
should be monitored and recorded. Short-term environmental changes due to opening of the
doors of the storage facility are accepted as unavoidable. The effect of excursions due to
equipment failure should be assessed, addressed and reported if judged to affect stability
results. Excursions that exceed the defined tolerances for more than 24 hours should be
described in the study report and their effects assessed. The long-term testing should cover a
minimum of six or 12 months at the time of submission and should be continued for a period
of time sufficient to cover the proposed shelf-life.

In-use stability the purpose of in-use stability testing is to provide information for the
labelling on the preparation, storage conditions and utilization period of multidose products
after opening, reconstitution or dilution of a solution, e.g. an antibiotic injection supplied as a
powder for reconstitution. As far as possible the test should be designed to simulate the use of
the FPP in practice, taking into consideration the filling volume of the container and any
dilution or reconstitution before use. At intervals comparable to those which occur in practice
appropriate quantities should be removed by the withdrawal methods normally used and
described in the product literature. The physical, chemical and microbial properties of the
FPP susceptible to change during storage should be determined over the period of the
proposed in-use shelf-life. If possible, testing should be performed at intermediate time points
and at the end of the proposed in-use shelf-life on the final amount of the FPP remaining in
the container. Specific parameters, e.g. for liquids and semi-solids, preservatives, per content
and effectiveness, need to be studied. A minimum of two batches, at least pilot-scale batches,
should be subjected to the test. At least one of these batches should be chosen towards the end
of its shelf-life. If such results are not available, one batch should be tested at the final point
of the submitted stability studies. This testing should be performed on the reconstituted or
diluted FPP throughout the proposed in-use period on primary batches as part of the stability
studies at the initial and final time points and, if full shelf-life, long-term data are not
available before submission, at 12 months or the last time point at which data will be
available.

TABLET STABILITY TESTING

 a) Weight variation:

This test is based on the fact that, if the weight variation is not much then it can be said
that the amount of medicament will not vary considerably. Conversely, if the weight variation
is larger then it can be concluded that the active medicament will also vary considerably.
Weight variation is solely dependent on the poor flow property of granules and filling of die
cavity. Poor flow properties arise from improper lubrication, size of granules, adjustment of
lower punch.The U.S.P. weight variation test is run by weighing 20 tablets individually,
calculating the average weight, and comparing the individual tablet weights to the average.
The tablets meet the USP test if not more than 2 tablets are outside the percentage limit and if
no tablet differs by more than 2 times the percentage limit.

b) Content uniformity test:

Weight variation test is applicable when the amount of medicament in the tablet is high. in
potent drug the medicament is less in amount in comparison to the other excipients. The
weight variation may meet the pharmacopoeial limitation but this will not ensure the correct
variation of potency. hence, in this case the weight variation test is followed by content
uniformity test. In this test 30 tablets are randomly selected for sample, and at least 10 of
them are assayed individually according to the official assay method and 9 of the 10 tablets
must have potency within 15 % of the labeled drug content. Only one tablet may be
within 25%. If this conditions are not met then the tablets remaining from the 30 must be
assayed individually and none may fall outside 15% of the labeled content.

c) Tablet hardness:

The resistance of the tablet to chipping, abrasion or breakage under conditions of storage,
transportation and handling before usage depends on its hardness. The method of testing the
tablet hardness is a tablet is taken between the 2nd and 3rd finger and pressing it with the
thumb as fulcrum. If the tablet breaks with a sharp snap, yet, it does not break when it falls on
the floor is said to possess proper hardness. Instruments used for tablet hardness testing are,
Monsanto Hardness Tester, Strong Cobb Hardness Tester, Pfizer Hardness Tester and
Schleuniger Apparatus. If the tablets are too hard then it may not meet tablet disintegration
test. If the tablets are too soft then it may not with stand the handling, packaging and shipping
operations.

d) Friability:
Tablet hardness is not an absolute indicator of strength since some formulations, when
compressed into very hard tablets may produce chipping, capping and lamination problems.
Therefore another measure of tablet strength such as friability is often measured, i.e. the
friability. Objective of friability test is to evaluate the ability of the tablet to withstand
abrasion, in handling, packaging and shipping operation. The method is few tablets,
previously weighed are taken in the plastic chamber of the laboratory friability tester. In the
plastic chamber the tablets are subjected to abrasion and shock by rotating the plastic
chamber at 25 rpm for 4 mins (total 100 revolutions). Then, the tablets are dusted and
reweighed. Limit for conventional compressed tablet the weight loss should be within 0.5 to
1.0 %.

e) Disintegration test of tablets:

For most tablets, the first important step toward solution is breakdown of the tablet into
smaller particles or granules this process is known as disintegration. The time a tablet takes
to disintegrate is the disintegration time. To test the disintegration time one tablet is placed in
each tube, and the basket rack assembly is positioned in a 1-litre beaker of water, simulated
gastric fluid or simulated intestinal fluid, at 370C20C, such that the tablet remain 2.5 cm
from the bottom of the beaker.

A standard motor moves the basket up and down through a distance of 5 to 6 cm at a

frequency of 28 to 32 cpm (cycles per minute). Perforated plastic discs may also be placed on
top of the tablets to impart an abrasive action to the tablets. They are useful for tablets that
float.

USP disintegration test will be passed if all the tablets disintegrate and the particles
passed through the #10 mesh screen within the specified time. If any residue remains, it must
have a soft mass with no palpable firm core. Disintegration time is suggested for 5 minutes
for uncoated Aspirin tablets. Majority of the uncoated tablets have maximum disintegration
time (DT) of 30 minutes. Enteric coated tablets shows no evidence of disintegration after 1
hour in simulated gastric fluid. The same tablets are then tested in simulated intestinal fluid
and are to disintegrate in 2 hrs plus the time specified in the monograph.

f) Dissolution test:
Disintegration test simply identifies the time required for the tablet to break up under the
condition of the test but it does not ensure the drug release in the bulk of the fluid. Rate of
dissolution is directly related to the efficacy of the drug. Rate of dissolution is a good index
for comparing the bioavailability of two tablet products of the same drug.

In general, a single tablet is placed in a small wire mesh basket and immersed in the
dissolution medium (as specified in the monograph) contained in a 1000 ml flask at
370 0.50C. Generally it is rotated at 50 rpm unless otherwise specified.

CAPSULE STABILITY TESTING

 a) Weight variation

For hard capsules: Accurately weigh 10 capsules. By suitable means the contents of each
capsule should be removed. The weights of emptied shells should be recorded individually.
The difference of both the weights will yield the net weight of the contents. Then calculate
acceptance value.
For soft capsules: pre weigh 10 capsules. Cut the capsules by suitable means (either scissors
or any open blade) remove the contents by washing with a suitable solvent and let the
solvent evaporate by placing them at room temperature for about 30 mins. Weigh the
individual shells. Calculate the acceptance value.

b) Content uniformity:

Hard capsules containing 25 mg or more of the drug contents should meet content uniformity
requirements. Assay 10 capsules individually and calculate the acceptance value.

The requirement is met if the acceptance value of 10 capsules is less than or equal to 15%. If
acceptance value is greater than 15% or is about 25 % then, test the next 20 units and
calculate the acceptance value. The 30 capsules if less than or equal to 15% and no individual
unit is 1-25*0.01 nor more than 1+25*0.01.

c) Disintegration:

The disintegration of capsules is different from those of tablets because the determination of
end point is difficult owing to the adhesive nature of shell. The shell pieces after
disintegration may agglomerate forming large mass of gelatin taking more time to dissolve
and may adhere to the mesh thus, blocking the holes. According to USP, place one dosage
unit in each of the tubes of the basket with water or any other specified medium (depends on
individual monograph) maintained at 37 + 20C. Attach a removable wire cloth with a plain
square weave of 1.8-2.2 mm of mesh aperture and a wire diameter of 0.60-0.655 mm to the
surface of upper rack of the basket assembly. Observe the capsules for a time limit (specified
in individual monograph), at the end of prescribed time, all of the capsules must have been
disintegrated excluding the fragments from the capsule shell.

d) Dissolution:
Place each of the capsules in the apparatus 1, excluding air bubbles from the surface of the
capsule. Operate immediately at specified rate within specified dissolution medium at 37 +
0.50C. Aliquots should be withdrawn at specified time points mentioned in individual
monograph. The requirements are met if the quantity of active ingredients dissolved
conforms the following:
At stage 1- when 6 capsules are tested, amount of each of the dissolved content
should not be less than +/- 5% of the mentioned in monograph.
At stage 2- when 6 capsules are tested, the average of 12 (both from step 1 and
2) should be equal to or greater than 15% and no capsule should be than 15%.
At stage 3- when 12 capsules are tested, the average of 24 capsules (all 1,2 and
3 steps) should be equal to or greater than the amount mentioned in the
monograph, not more than two units are less than 15% and no unit s less than
25%.

e) Raw materials:

The gelatin of the capsule shells should be assayed for various physical properties like bloom
strength, viscosity and its loss (by atomic force microscopy). Chemical tests like purity,
microbial properties, and limits for heavy metals like arsenic, ash content should be
determined. The colorants should also be checked for purity, limits for heavy metals, color
properties, dye content, subsidiary dye content and color value.

f) Moisture content:

Moisture content can be monitored with the aid of data the drying kilns can be adjusted.

g) Loss on drying:

Determination of loss on drying via the oven method consumes more time. To prevent this
advanced methods like infrared balances, humidity meter etc.

h) Final inspection:

After the capsules are placed in final containers, samples are checked for various parameters
like dimensions, physical defects and color. These samples are also subjected to various
microbial tests also.

LIQUID ORAL DOSAGE FORM STABILITY TESTING

 a) Liquid Dosage Form:

Liquid formulation is frequently used in oral, parenteral, inhaled and topical routes. They
may face some common physical stability challenges such as inhomogeneity due to phase
segregation, drain ability issues due to viscosity changes, and coloration due to oxidation or
other degradation reaction. Storage of liquid formulations in a refrigerator or freezer, with the
objective to minimize potential chemical degradation and microbial contamination, can
decrease the solubility and potentially cause product haziness/cloudiness due to precipitation
of either active ingredients or excipients. Even for room temperature stable formulation, the
effect of short term temperature excursions outside the proposed label storage condition
should be evaluated.

b) Oral Solutions

Oral solution formulation is molecularly dispersed homogenous system such as syrup and
elixir. Solid-state characteristics of raw materials can have an effect on this dosage form in at
least 2 ways:

i) Particle size and physical characteristics of raw materials can affect dissolution rate in
the manufacturing process. Drug substance of a finer particle size usually dissolves
faster than those of larger particle size. The metastable form such as amorphous also
has higher dissolution rate and apparent solubility than the stable crystalline form.
 ii) It may influence the equilibrium between the liquid phase and potential solid phases
with respect to super saturation and precipitation. Heating or sonication may be
necessary to increase the dissolution rate of some drug substance or excipients.
However, the maximum upper concentration limit should be based on the
thermodynamic equilibrium solubility of the most stable crystalline form at its
intended storage temperature, with consideration of potential temperature fluctuation
and effect of excipients, to avoid super saturation.
If refrigerator storage is required due to chemical stability concern, potential
precipitation should be evaluated and easy re-dissolution of any precipitation upon
warming should be confirmed. The precipitation may be intentionally isolated to
examine the solid form. The precipitate may be intentionally isolated to examine the
solid form. When the precipitate cannot be easily re-dissolved, there is a great chance
that the original solution was supersaturated, a more stable crystalline form was
produced, or there was an interaction or incompatibility issue between the drug
substance and excipients.

The evaluation should include appearance (including formation of precipitate, clarity for
solutions), color, odor, assay, degradation products, pH, preservative content, and microbial
limits.

c) Suspensions

Suspension dosage forms contain uniform-sized fine particles with acceptable sedimentation
rates. Major stability factors include attributes such as particle size distribution, content
uniformity, viscosity, drain ability, re-suspend ability, dissolution rate, pH and zeta potential.
Small particles have a high degree of surface free energy and increased tendency to
aggregate, and eventually fuse together into a non-dispersible cake. Suspending agents are
often used to increase physical stability and to make easily re-dispersed suspensions.
Viscosity is important from both processing and dosing aspects. Proper viscosity is required
to minimize segregation, as well as to maintain proper drain ability. To avoid segregation,
many suspensions require continuous or periodic agitation during filling process. pH shifts of
suspension dosage forms during storage may affect the chemical stability ad solubility of the
active drug in solution.

Stokes Law provides useful information in determining the main parameters which control
the sedimentation rate in a suspension: The evaluation for suspension is the same as solution.
Additionally, for suspensions, re-dispersibility, rheological properties, and mean size and
distribution of particles should be considered. After storage, samples of suspensions should
be prepared for assay according to the recommended labeling (e.g., shake well before using).

d) Emulsions

An evaluation should include appearance (including phase separation), color, odor, assay,
degradation products, pH, viscosity, microbial limits, preservative content, and mean size and
distribution of dispersed phase globules.

TEST FOR ORAL LIQUID DOSAGE FORM:

a) Uniformity of content:

10 containers-85-115%-compiles
Fails-if > than 1 outside the 85-115% or if any 1 outside 75-125%
If any 1 outside 85-115% but within 75-125%-repeat with 20containers
30 containers-compiles-if not > than 3outside 85-115%&not > than 1outside 75-125%

b) Taste, Odor, Palatability and Appearance: The proper selection of taste, odor,
palatability, texture, color, and sweetness of a preparation may enhance patient
adherence to the agent. Much work has been done and is ongoing on enhancing the
palatability of oral drug. The compounder has the option of using commercially
available vehicles in which to incorporate the drug or to construct the entire
preparation; this would include the use of viscosity enhancers, sweeteners, flavoring
agents, preservatives, and colors. Coloring agents are used in pharmaceutical
preparations for purposes of esthetics. Certain agents-sulfur (yellow), riboflavin
(yellow), cupric sulfate (blue), ferrous sulfate (bluish green), and cyanocobalamin
 (red)-have inherent color and are not considered pharmaceutical colorants in the usual
sense of the term.
c) Chemical Instability: Drugs in extemporaneously prepared liquids may be susceptible
to chemical reactions leading to degradation. The most common reactions are
hydrolysis, oxidation and reduction. Usually the reaction rate or type is influenced by
pH. Other factors which may increase the rate of reaction include the presence of
trace metals. The rate of chemical degradation usually increases with temperature, a
factor which is the basis for accelerated stability trials of pharmaceutical formulations.
Drug in preparation may be totally or partially in solution or predominantly in the
solid state as a suspension. Drugs in solution are more susceptible to chemical
degradation than drugs in the solid state. However it cannot be assumed in all cases
that an extemporaneously prepared suspension is more stable than a solution. In a
suspension, equilibrium exists between drug in the solid state and drug in solution and
even though the amount of drug dissolved may be minimal the conditions could be
optimal for degradation.
d) Microbiological Instability: Microbial growth in an oral liquid may cause foul odor
and turbidity and adversely affect palatability and appearance. High titres of
microorganisms may be hazardous to health especially in very young or
immunocompromised patients. By-products of microbial metabolism may cause a
change in the pH of the preparation and reduce the chemical stability or solubility of
the drug. Microbial contamination during preparation must be minimized by using
clean equipment, sterile water and avoiding contaminated raw materials and
containers. Effective preservative systems are required. Many factors can reduce the
effectiveness of the preservative including use of contaminated materials, chemical
degradation, binding of preservative to suspending agents or tablet excipients,
incorrect storage or unhygienic use of the final product.
e) Physical Instability: Extemporaneously prepared oral suspensions may be susceptible
to sedimentation of insoluble drug causing caking. Difficulty in re-suspending the
drug or rapid sedimentation following shaking can lead to erratic dosage
measurement. Refrigeration, whilst usually desirable to maximize chemical stability
and reduce microbial growth, can also increase the viscosity of a suspension making
re-suspension more difficult or cause the precipitation of active drug or preservatives.
It is important to consider the effect on pH of all components of the formulation and
the possible impact on stability. Syrup, for example, is relatively acidic and if used in
 phenobarbitone sodium oral solution it will cause the precipitation of unionized
phenobarbitone.

TOPICAL AND TRANSDERMAL DOSAGE FORM STABILITY TESTING

Included in this broad category are ointments, creams, lotions, pastes, gels, solutions, and
non-metered aerosols for application to the skin. Topical preparations should be evaluated for
appearance, clarity, color, homogeneity, odor, pH, re-suspend ability (for lotions),
consistency, viscosity, particle size distribution (for suspensions, when feasible), assay,
degradation products, preservative and antioxidant content (if present), microbial
limits/sterility, and weight loss (when appropriate). Appropriate stability data should be
provided for products supplied in closed-end tubes to support the maximum anticipated use
period, during patient use, once the tube seal is punctured allowing product contact with the
cap/cap liner. Ointments, pastes, gels, and creams in large containers, including tubes, should
be assayed by sampling at the surface, top, middle, and bottom of the container. In addition,
tubes should be sampled near the crimp.

Stability studies for devices applied directly to the skin for the purpose of continuously
infusing a drug substance into the dermis through the epidermis should be examined for
appearance, assay, degradation products, leakage, microbial limit/sterility, peel and adhesive
forces, and the drug release rate.

a) Uniformity of dosage units: This test is applicable for TDS and for dosage forms
packaged in single-unit containers.
b) Water content: A test for water content should be included when appropriate. This test
is generally formulation dependent. Therefore, it is not included in the compendial
drug product monograph but is part of the manufacturers specification for the drug
product.
c) Microbial limits: Microbial examination of nonsterile drug products is performed
according to the methods given, unless the formulation itself is demonstrated to have
antimicrobial properties.
d) Antimicrobial preservative content: Acceptance criteria for antimicrobial preservative
content in multidose products should be established. They should be based on levels
of antimicrobial preservative necessary to maintain the products microbiological
quality at all stages throughout its proposed usage and shelf life.
e) Antioxidant content: If antioxidants are present in the drug product, tests of their
content should be established unless oxidative degradation can be detected by another
test method such as impurity testing. Acceptance criteria for antioxidant content
should be established. They should be based on the levels of antioxidant necessary to
 maintain the products stability at all stages throughout its proposed usage and shelf
life.
f) Sterility: Depending on the use of the dosage form the dosage form (e.g., ophthalmic
preparations, products that will be applied to open wounds or burned areas), sterility
of the product should be demonstrated as appropriate.
g) pH: When applicable, topically applied drug products should be tested at the time of
batch release and initially at designated stability test time points to set specifications
for batch-to-batch and shelf life monitoring. Because some topically applied drug
products contain very limited quantities of water or aqueous phase, pH measurements
may not always be warranted. This test is generally formulation dependent. Therefore,
it is not included in the compendial drug product monograph but is part of the
manufacturers specification for the drug product.

PARENTERAL DOSAGE FORM STABILITY TESTING

a) Small Volume Parenterals (SVPs)

SVPs include an extremely wide range of preparations and container-closure types products
such as Injection, Powder for Injection, Suspension for Injection, and Emulsion for Injection.
Parenterals (except ampoules) should be stored both upright and inverted/on-the-side
orientations in order to determine whether contact of the drug with closure system affects
product integrity.

Injection products should be evaluated for appearance, clarity, colour, assay,

preservative content (if present), degradation products, particulate matter, pH, sterility
and pyrogen/endotoxin.
Powder for Injection products should be evaluated for appearance, colour,
reconstitution time and water content. The stability of Powder for Injection products
should also be evaluated after reconstitution according to the recommended labelling.
Specific parameters to be examined at appropriate intervals throughout the maximum
intended use period of the reconstituted drug product, stored under condition(s)
recommended in labelling, should include appearance, clarity, odour, colour, pH,
assay (potency), preservative (if present), degradation products/aggregates, sterility,
pyrogen/endotoxin and particulate matter.
Suspension for Injection products should also be evaluated for particle size
distribution, redispersibility and rheological properties in addition to the parameters
cited above for Injection and Powder for Injection products.
Emulsion for Injection products should be evaluated for in addition to the parameters
cited above for Injection, phase separation, viscosity, and mean size and distribution
of dispersed phase globules.

b) Large Volume Parenterals (LVPs)

Stability tests for LVPs are similar to those appropriate for small-volume parenterals. All
container-closure sizes should be studied. LVPs should be evaluated for strength, appearance,
colour, assay, preservative content (if present), degradation products, particulate matter (USP
or equivalent), pH, sterility, pyrogen/endotoxin, clarity and volume.
Continued assurance of sterility for all sterile products may be assessed by a variety of
means, including examination of the counter-closure system, testing for preservatives (if
present), or sterility testing (at reasonable intervals).
For terminally sterilized drug products a specification for maximum process parameters
should be provided. Stability studies should evaluate and support the maximum release
specification for process lethality.
These products should be stored both upright and inverted/on-the-side orientations in order to
determine whether contact of the drug with closure system affects product integrity.

c) Drug Admixture

For any drug product or diluent that is intended for use as an additive to another drug product,
the potential for incompatibility exists. In such cases, the drug product labelled to be
administered by addition to another drug product (e.g. parenterals, inhalation solutions),
should be evaluated for stability and compatibility in admixture with the other drug products
or with diluents both in upright and in inverted/on-the side orientations, if warranted.

A stability protocol should provide for appropriate tests to be conducted at 0-, 6- to 8- and 24-
hour time points, or as appropriate over the intended use period at the recommended
storage/use temperature(s). Tests should include appearance, colour, clarity, assay,
degradation products, pH, particulate matter, interaction with the container/closure/device
and sterility. Appropriate supporting data may be provided in lieu of an evaluation of photo
degradation.

REFERENCES
1. http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/revisions/topical_and_trans
dermal.pdf
2. http://www.fda.gov/ohrms/dockets/98fr/980362gd.pdf
3. Revision of monograph on capsule: Final text addition to The International
Pharmacopoeia, WHO, March 2011. Retrieve from:
http://apps.who.int/medicines/publications/pharmacopoeia/Caps-GeneralMono-rev-
FINAL_31032011.pdf
4. Stability Testing on Active Pharmaeutical Ingredients and Finished Pharmaceutical
Products, WHO, 2009. Retrieve from:
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1
F/Stability_Guideline_WHO.pdf
5. http://www.pharmainfo.net/quality-control-capsules
6. Connors, K. A., Amidon, G. L., & Stella, V. J. (1986). Chemical stability of
pharmaceuticals: A handbook for pharmacists (2nd ed.). New York: Wiley-
Interscience.
7. Retrieved January 4, 2017, from
http://www.hsa.gov.sg/content/dam/HSA/HPRG/Western_Medicine/Overview_Frame
work_Policies/Guidelines_on_Drug_Registration/ASEAN%20STABILITY
%20GUIDELINE%20(version%206.0).pdf