API Assessment:
Common Deficiencies
Isabel Ortega and Antony Fake
WHO Prequalification of Medicines Programme
Assessors training, Copenhagen
January 2012
1
Overview
1. API information.
2. What are we looking for.
3. A summary of deficiencies found in APIMFs
assessed within PQP.
4. Common deficiencies.
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API Common Deficiencies
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API Information
There are different options that can be used by applicants to
submit API information.
• Use of a prequalified API
• Use of an EDQM CEP
• Use of an APIMF
• Provision of full API information in the product dossier.
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API Information
• Regardless of the option chosen the same information is
required.
• The API information assessed within PQP is compiled in
the Common Technical Document format (CTD).
• This is regardless of whether the API is pharmacopoeial or
not.
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API Information
3.2.S.1. General information
3.2.S.1.1.
Nomenclature
3.2.S.1.2.
Chemical structure
3.2.S.1.3.
General properties
3.2.S.2. Manufacture
3.2.S.2.1.
Manufacturer(s)
3.2.S.2.2.
Description of Manufacturing Process and Process Controls
3.2.S.2.3.
Control of Materials
3.2.S.2.4.
Controls of Critical Steps and Intermediates
3.2.S.2.5.
Process Validation and/or Evaluation
3.2.S.2.6.
Manufacturing Process Development
3.2.S.3. Characterization
3.2.S.3.1.
Elucidation of Structure and other Characteristics
3.2.S.3.2.
Impurities
3.2.S.4. Control of the API
3.2.S.4.1.
Specification
3.2.S.4.2.
Analytical Procedures
3.2.S.4.3.
Validation of Analytical Procedures
3.2.S.4.4.
Batch Analyses
3.2.S.4.5.
Justification of Specification
3.2.S.5. Reference standards or Materials
3.2.S.6. Container closure system
3.2.S.7. Stability testing
3.2.S.7.1.
Stability Summary and Conclusions
3.2.S.7.2.
Post-approval Stability Protocol and Stability Commitment
3.2.S.7.3.
Stability Data
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API Common Deficiencies
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Overview
1. API information.
2. What are we looking for.
3. A summary of deficiencies found in APIMFs
assessed within PQP.
4. Common deficiencies.
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Is the starting point of the
manufacturing process acceptable?
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Traditional manufacturing
Raw
materials
Final API
Traditionally, the API manufacturer manufactured the API
from simple raw materials at their own facility.
This meant it was safe to assume that the molecule used in
the first step at the API manufacturer's factory was an
appropriate API-SM.
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Contemporary manufacturing
Intermediate
API-SM
API-SM
Raw Material
Final API
Increasingly, intermediates late in the synthesis are being
purchased.
This means the API-SM can not be assumed to be the
molecule used in the first step at the API manufacturer's
factory.
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API Starting material
Choice of API-SM
ASSESSORS
Simpler
molecules
Final API
INDUSTRY
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API Starting material
API manufacturers prefer to have the API-starting material (APISM) defined as late in the synthesis as possible because:
• It reflects the manufacturing steps undertaken at their
factory under their control.
• The API-SM is the point at which GMP applies to
manufacture.
• This can be financially advantageous when API
manufacturers buy reaction intermediates from secondary
manufacturers that do not operate under API GMP.
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API Starting material
The problem for assessors is:
• Information on the preparation of a complex API from one
or two steps makes determination of impurities in the API
very difficult.
• If the SM is complex it is hard to judge the acceptability of
the API-SM specifications.
• The guarantee of quality API is the result of good
manufacture and control throughout all the steps (GMP).
Comprehensive testing of the final API does not replace
this.
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Are the manufacturing process and
process controls adequately
described?
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Manufacturing Process
A detailed and complete
flow diagram is required
A detailed narrative
description is required.
API starting material
API intermediate(s)
Final API intermediate
Crude API
Final API
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2012
What are the potential impurities?
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Potential impurities
API SM impurities
API starting
material
Reagents
Solvents
Catalysts
Reaction by-products
API intermediate
Reagents
Solvents
Catalysts
Reaction by-products
Crude API
Crystallisation solvent
Degradation products
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Final API
API Common Deficiencies
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Potential impurities
• Residue of the SM
• Residue of the intermediate
• Impurities in the SM
• Reagents
• Solvents
• Catalysts
• Reaction by-products
• Degradation products
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Can the potential impurities be
carried over into the final API?
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2012
Are the potential impurities
detectable by the analytical
procedure?
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2012
Final API
Specifications
Control
Analytical procedures
Reference standards
Stability
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Container/closure system
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Are the API specifications
acceptable?
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Can a retest period and
recommended storage
conditions be established?
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Overview
1. API information.
2. What are we looking for.
3. A summary of deficiencies found in APIMFs
assessed within PQP.
4. Common deficiencies.
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Summary of deficiencies
• I have started to investigate commonly observed
deficiencies with APIMFs assessed by the PQ programme.
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Investigation overview
• The initial assessment reports for 90 APIMFs were
investigated (assessed between 2007-2011).
• This includes 45 HIV, 24 MA, 19 TB and 2 IN APIMFs.
• For more than 70% of the products, an official
compendial monograph was available at that time.
A total of 2828 deficiencies classified by CTD section
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Deficiencies by CTD section
Number
of
deficiencies
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% of deficiencies by CTD section
Common deficiencies
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Overview
1. API information.
2. What are we looking for.
3. A summary of deficiencies found in APIMFs
assessed within PQP.
4. Common deficiencies.
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Top 9 deficiencies (by CTD section)
1- Manufacturing process (3.2.S.2.2)
2- Starting material quality (3.2.S.2.3)
3- Quality of all other materials (3.2.S.2.3)
4- Control of intermediates (3.2.S.2.4)
5- Polymorphism (3.2.S.3.1)
6- Impurities (3.2.S.3.2)
7- Specifications (3.2.S.4.1 and 3.2.S.4.5)
8- Validation of analytical procedures
9- Stability deficiencies (3.2.S.7.1, 3.2.S.7.2 and 3.2.S.7.3)
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1- Manufacturing process (3.2.S.2.2)
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Information on the API preparation is not
sufficiently detailed
A detailed flow diagram of synthesis indicating chemical
structures, molecular weights, solvents, reagents should be
presented. When an APIMF is used this information should be
provided in both the open and closed sections.
A detailed narrative of each synthetic step should be presented,
including: the types and quantities of reagents and solvents;
reaction conditions; critical steps, in-process controls; and yields.
• The description of the API manufacturing process represents the
applicant’s commitment for the manufacture of the API.
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January 2012
The proposed API SM is too complex
• It is often observed that the proposed API SM is merely
the molecule that is used in the first manufacturing step at
the API manufacture site.
• This is not a sufficient justification.
• The API SM should be a relatively simple molecule. In
general it should be one or more synthetic steps from the
final intermediate.
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January 2012
The proposed API SM is too complex
There are exceptions to this rule. For instance
• Artemisinin is accepted as a API SM despite it’s
complexity because it is derived from a plant.
• Aminobutanol is accepted as the API SM for ethambutol,
despite being a one step synthesis, because both the API
SM and AP are simple molecules.
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January 2012
The proposed API SM is too complex
The point at which the API SM is introduced is the starting point
of the application of GMP requirements.
The API SM itself needs to be proposed and justified by the
manufacturer and accepted as such by assessors.
• In these cases, the applicant is requested to redefine the API-SM as
a synthetic precursor one or more synthetic steps prior to the final
key intermediate.
• The manufacturer of the key intermediate should be included as an
API intermediate manufacturing site and should be GMP compliant.
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January 2012
The information on reprocessing is not
sufficiently detailed
Steps where reprocessing may occur should be identified and
justified.
• Reprocessing is the repetition of a step of manufacture for a
batch of API or intermediate that is considered substandard.
• The frequency of reprocessing should be stated because
excessive reprocessing indicates the manufacturing process is
not under control. This is not in line with GMP.
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January 2012
The maximum batch size is not clearly stated
The description of the process should indicate the scale of
manufacture and the range for which the considered process
may be used. It may be helpful to indicate the yield or yield
range produced at each stage.
• Often the intended scale (or range) of manufacture is not
categorically stated.
• The applicant should be able to provide evidence of
manufacture at this scale (at a minimum batch data).
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January 2012
The maximum batch size is not clearly stated
• We need to know what is the maximum batch size for
which the applicant has experience with the defined
method.
• Also, if blending occurs it has to be confirmed that each
batch incorporated into the blend is individually tested and
found to meet specifications set for the final API prior to
blending.
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API Common Deficiencies
January 2012
Solvents used are not clearly identified in the
process
All solvents used in the manufacture (including purification
and/or crystallization step(s)) should be clearly identified.
Quantities of solvents reflecting the representative batch scale
for commercial manufacture should be stated.
Solvents used in the final steps should be of high purity.
• Specifications should be provided for all solvents.
• The carry-over of all solvents into the final API needs to be
assessed.
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API Common Deficiencies
January 2012
The information on recovery of solvents is
not sufficiently detailed
The recovery of materials, if any, should be described including
the step they are taken and re-introduced into the process.
Use of recovered solvents in the final steps of purification and/or
crystallization is not recommended.
• Often no comment is made as to whether the recovery of
materials occurs or not.
• The recovery of solvents is very common.
• The use of multiple solvents and reagents for different
purposes within a process leads to the formation of solvent
mixtures.
• The potential for cross contamination needs to be assessed
(the impurity profile of the API should remain unaffected).
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2- Starting material quality (3.2.S.2.3)
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January 2012
The information on API SM preparation is not
sufficiently detailed or is missing.
• Information on the API SM preparation is needed to determine
the appropriateness of the specifications.
• Detailed information is usually not required, because the SM
should be relatively simple.
• This information is often supplied in form of a flow-chart
(synthetic transformation, reagents, and solvents).
• If there are two or more suppliers of the API SM, information
on the preparation of the SM from each supplier should be
provided.
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January 2012
Information on the API SM manufacturer is
missing
For each SM, the name and manufacturing site address of
the manufacturer should be indicated.
If there are several manufacturers, it should be clarified
whether the SM obtained from different sources is prepared
by the same route of synthesis or if different routes are used.
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January 2012
The API SM specification is not satisfactory
The SM specifications should include among others an identity
test and tests and limits for assay and for specified,
unspecified and total impurities.
• The API SM impurity limits should be justified by the
demonstrated ability to manufacture API from batches of SM
with similar impurity levels.
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January 2012
The API SM specification is not satisfactory
• Each API SM supplier does not have to have the same
specifications but a single SM specifications should be
defined by the API manufacturer and applied to all sources
of SM.
• The carry-over of impurities into the final API should be
considered and discussed. The same applies for solvents,
reagents, and catalysts used in the SM preparation, as
needed.
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3- Quality of all other materials
(3.2.S.2.3)
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January 2012
The specifications for raw materials, solvents,
reagents, catalysts are unsatisfactory.
Information of the quality and control of these materials should
be provided.
Information demonstrating that materials meet standards
appropriate for their intended use should be provided.
• The specifications for all materials used should be provided.
• They should include at least an identification test and assay
limit.
• Limits for benzene in toluene, methanol, ethanol and acetone
are commonly requested as this can be an impurity.
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January 2012
The specifications for recovered solvents are not
satisfactory.
Recovery operations should be adequately controlled such that
impurity levels do not increase over time.
Use of recovered solvents in the final steps of purification and/or
crystallization is not recommended.
• Their specifications should include appropriate limits for assay,
impurities and non-volatile matter (0.1%).
• Any lessening of quality of the recovered solvent limits needs to be
justified.
• It should be demonstrated that recovered solvents with impurity
levels approaching the limits proposed affords API of an acceptable
quality.
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4- Control of intermediates
(3.2.S.2.4)
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January 2012
The specifications for isolated intermediates
are not satisfactory.
Information on the quality and control of intermediates
isolated during the process should be provided.
The specifications should include tests and acceptance
criteria for identity, purity (individual and total impurity
limits) and assay, where applicable.
• The limits chosen should be justified and demonstrated to
be acceptable (in terms of carry-over into the final API).
• Often the proposed limit for total impurities is too high.
• Control of certain impurities in the intermediate may
eliminate the need to control this impurity in the final API.
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5- Polymorphism (3.2.S.3.1)
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January 2012
The information on API polymorphism is not
sufficiently detailed
Information on the potential for forming polymorphs should be
included.
API manufacturers are expected to have adequate knowledge
about the polymorphism of the APIs produced.
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January 2012
The information on API polymorphism is not
sufficiently detailed
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Polymorphism known
Polymorphism not known
Highly
soluble API
The polymorphic form
produced should be
assigned.
The crystalline form produced
should be determined.
Non-highly
soluble API
The polymorphic form
produced should be
assigned. Stability of the
form should be determined
The crystalline form produced
should be assigned. Crystallinity
under different crystallisation
condition should be
investigated.
Stability of the form should be
determined
API Common Deficiencies
January 2012
The information on API polymorphism is not
sufficiently detailed
• Polymorphic forms may possess different chemical and
physical properties, that can have a direct impact FPP
properties, such as stability, dissolution and bioavailability.
• Unexpected appearance or disappearance of a
polymorphic form may lead to serious pharmaceutical
consequences.
• We need to know what polymorph is consistently
produced and if it is stable.
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6- Impurities (3.2.S.3.2)
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January 2012
Insufficient discussion on potential impurities
Regardless of whether a pharmacopoeial standard is
claimed, a discussion should be provided of the potential
and actual impurities arising from the synthesis,
manufacture or degradation of the API.
The discussion of pharmacopoeial APIs should not be
limited to the impurities specified in the API monograph
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API Common Deficiencies
January 2012
Insufficient discussion on potential impurities
• Monographs are developed based upon how the API
was prepared historically. A particular manufacturer's
manufacturing method may lead to unexpected
impurities, due to a different route of synthesis, different
reagents, etc.
• When the absence of a certain impurity, reagent,
solvent or catalyst has not been adequately
demonstrated, a test and limit should be included in the
API specification.
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API Common Deficiencies
January 2012
The API has not been investigated for the
presence of potential impurities cited in the
monograph (or draft)
If there are identified impurities specified in an official
compendial monograph that are not controlled by the
proposed routine in-house analytical procedure, a
justification for their exclusion from routine analyses should
be provided.
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API Common Deficiencies
January 2012
The API has not been investigated for the
presence of potential impurities cited in the
monograph (or draft)
• Some of the Ph. listed impurities can be excluded by the
applicant with a justification that they are not potential
impurities from the proposed route of synthesis.
• If justifications are not acceptable and the routine in-house
method is not capable of detecting the pharmacopoeial
listed impurities, their absence can only be shown by testing
several recent batches with the pharmacopoeial method.
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API Common Deficiencies
January 2012
A specific discussion on potential genotoxic
impurities is missing
The absence of known established highly toxic impurities
(genotoxic) used in the process or formed as by-product
should be discussed and suitable limits should be
proposed.
59
•
Certain chemical structures "alert structures" are
considered to be genotoxic, except if also present in the
API.
•
The most common situation that arises is the use of the
sulphonic acid reagents that in the presence of alcohols
like methanol or ethanol. They can form sulphonate esters
(genotoxic).
API Common Deficiencies
January 2012
7- Specifications
(3.2.S.4.1 and 3.2.S.4.5)
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API Common Deficiencies
January 2012
The format of the API specifications is
unsatisfactory
Copies of the API specifications, dated and signed by
authorized personnel (e.g. the person in charge of the quality
control or quality assurance department) should be provided.
• It is important that the manufacturer provides a signed, dated
and version-numbered specification. This is to ensure
traceability of testing requirements in case of GMP audits and
future variations.
• The API specifications should also include reference to
analytical procedures and whether they are compendial or not
(i.e. pharmacopoeial reference or in-house reference).
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API Common Deficiencies
January 2012
Absence of certain tests and limits in the API
specification
• It should include a limit and test for heavy metals. Heavy
metals can also come from the process (e.g., leaching from
pipes and other equipment) or occur naturally (e.g., from
naturally derived plant or mineral sources).
• The specification for a chiral API should include
enantioselective tests for identity and purity (optical rotation
and enantiomeric purity).
• When the absence of certain residual solvent, reagent or
catalyst has not been shown, a limit and test needs to be
included in the API specification.
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January 2012
The proposed limits for impurities are
unsatisfactory
Specified impurities (=known impurities qualified or ≤ ICH
qualification threshold; can be identified or unidentified i.e
RRT but no structure)
Any unspecified impurities (=unknown imp. ≤ ICH
identification threshold)
Total impurities (=sum of impurities > the ICH reporting
threshold)
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API Common Deficiencies
January 2012
The proposed limits for impurities are
unsatisfactory
• When there is an official compendial monograph, the limits
for specified impurities should comply the ones of the
monograph and regardless of the related substances
requirements a test for any unknown impurity and total
impurities should be included.
• ICH limits for unknown impurities are generally required
(with exceptions), rather than the general limits of the
monograph.
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January 2012
8- Validation of analytical procedures
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API Common Deficiencies
January 2012
The validation of analytical procedures is
insufficient or missing
The objective of the analytical validation information is to
demonstrate that the analytical procedures are suitable for their
intended purpose
• All non-pharmacopoeial methods must be fully validated,
particularly assay, related substances and residual solvents
methods, as outlined in ICH Q2.
• These methods should be able to separate/detect the potential
impurities/solvents of the manufacturing process.
• The pharmacopoeial methods should also be shown suitable for
determination of impurities related to the manufacturer's specific
route of synthesis and not covered by the monograph.
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January 2012
Cross-validation data are not submitted when
in-house methods are used for controlling
pharmacopoeial APIs
If an officially recognized compendial standard is claimed
and an in-house method is used in lieu of the compendial
method (e.g. for assay or for specified impurities),
equivalency of the in-house and compendial methods
should be demonstrated.
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API Common Deficiencies
January 2012
Cross-validation data are not submitted when
in-house methods are used for controlling
pharmacopoeial APIs
By performing duplicate analyses of one sample by both
methods or by spiking the API with impurities at
concentrations equivalent to their specification limits.
• This is the way to check that the Ph. listed impurities can
be detected with the in-house methods and that the inhouse is superior or at least equivalent.
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January 2012
9- Stability deficiencies
(3.2.S.7.1, 3.2.S.7.2 and 3.2.S.7.3)
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API Common Deficiencies
January 2012
Methods for assay or impurities methods are
not shown stability-indicating
Stress testing of the API can help identify the likely
degradation products, which can in turn establish the
degradation pathways and the intrinsic stability of the
molecule and validate the stability indicating power of the
analytical procedures used.
• In-house analytical procedures for assay and impurities
should be fully validated and should be shown stabilityindicating.
• They should be able to detect significant changes in the
quality of the product (i.e. increase of degradation products).
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API Common Deficiencies
January 2012
The primary stability data have not been
conducted at 30ºC
The required long-term storage conditions for APIs in the PQP is
either 30ºC/65%RH or 30ºC/75%RH.
Studies covering the proposed re-test period at these conditions will
provide better assurance of the stability of APIs at the conditions of
the supply chain corresponding to the WHO and PQP environments .
• This is required unless it has been demonstrated that the API is
inherently unstable at 30ºC/65%RH or 30ºC/75%RH.
• If there is no data available at 30ºC then the API manufacturer is
requested to commit to initiating long-term stability trials at 30ºC
and to change the recommended storage conditions to stored
below 30ºC.
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API Common Deficiencies
January 2012
The stability data provided do not support the
proposed retest period
A retest period should be derived from the stability information
and should be displayed on the container label.
Limited extrapolation of the real-time data from the long-term
storage condition can be undertaken to extend the retest period.
• There are minimum data required at the time of submission (6
months in accelerated and long-term conditions).
• Most of the times the stability data included in the first
submission do not support the proposed retest period and
updated stability data are needed.
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API Common Deficiencies
January 2012
A storage condition is not proposed
A storage statement should be established for display on the
label based on the stability evaluation of the API.
The WHO stability guideline includes a number of
recommended storage statements to be used, when
supported by stability studies.
• The prequalification programme recognises the following
conditions: store below 30ºC, store below 25ºC, and store
between 2 - 8ºC.
• In addition, the ancillary statements protect from humidity or
protect from light should also be considered.
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Questions?
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January 2012