Quality Workshop
Copenhagen – January 2012
Assessing
specifications:
FPP
(solid orals)
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Lynda Paleshnuik | January 2012
Outline
Compendial versus in-house standards:
● When compendial standard is claimed
● When in-house standard is claimed
● When compendial methods are used
● When in-house methods are used but compendial
standard is claimed
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Lynda Paleshnuik | January 2012
Outline
● Specific parameters in brief
● Unnecessary tests in specifications
● Example specifications exercise
● Review tips
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Lynda Paleshnuik | January 2012
Specifications 
 The set of criteria to which a FPP should conform
to be considered acceptable for its intended use.
 A list of tests, reference to analytical procedures,
and acceptance criteria (numerical limits, ranges
or other criteria) [ICH Q6A]
 Confirm the quality, rather than fully
characterize, the FPP
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Lynda Paleshnuik | January 2012
Specifications
 Specifications should include, at minimum, tests for
appearance, identification, assay, purity, performance tests (e.g.
dissolution), physical tests (e.g. loss on drying, hardness,
friability, particle size), uniformity of dosage units, and as
applicable, identification and assay of antimicrobial or chemical
preservatives (e.g. antioxidants) and microbial limit tests.
 Several guidelines outline tests in addition to those in Q6A, e.g.
for other dosage forms:
 New WHO PQP quality guideline P.5.1
Other regulatory guidelines (e.g. HC, EMA)
Pharmacopoeia
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Lynda Paleshnuik | January 2012
Officially recognized pharmacopoeia
 PhInt, USP, BP, EP, JP are recognized standards in PQP
PhInt S2 available as CD-ROM or on-line
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Lynda Paleshnuik | January 2012
Validation, verification, equivalency, SST
(assay and purity methods) 
 Validation: full validation required for in-house methods,
generally specificity, linearity, accuracy, repeatability,
intermediate precision, plus for purity: LOD/LOQ.
 Verification: required for most compendial methods
 Equivalency: required for an in-house method, when
compendial standard is claimed
 SST: part of methodology, parameters determined via
robustness; tested every time the method is run to ensure
adequate performance
NB: CU and dissolution are assay methods, residual solvents
(organic granulating solvents) is a purity method
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Lynda Paleshnuik | January 2012
When compendial standard is claimed 
1. Generally, the monograph tests and limits should be adopted.
2. The monograph is the minimum standard; the authority can
impose additional requirements (e.g. ICH IT for individual
unspecified related compounds)
3. All monograph tests/limits need not be included in
specifications (may use in-house methods, provide justification
for not including certain parameters).
But The product must comply with the monograph, if tested (see
equivalency testing).
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Lynda Paleshnuik | January 2012
When compendial standard is claimed 
 BP “Official Standards” and EP “General Statements”:
An article is not of pharmacopoeial quality unless it
meets all monograph requirements. However,
performance of all tests is not necessarily required to
assess compliance before release. Assurance of
pharmacopoeial quality may instead be obtained from
validation studies of the manufacturing process and
from IPCs.
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Lynda Paleshnuik | January 2012
When in-house standard is claimed 
1. Generally, the tightest available monograph limits for
assay and purity should be adopted (assay) or justified
(specified related compounds). Justification is more
difficult for the FPP because related compounds
are mainly degradants in the monographs (but not
always).
2. The available monographs can still be used as a
general guideline for requirements
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Lynda Paleshnuik | January 2012
When compendial methods are claimed… 
(purity and assay methods)
 Ensure they have really adopted the method as is. If not:
 Check the deviations against published accepted deviations:
 USP <621> Chromatography
 EP 2.2.46 Chromatographic separation techniques
 Note that there are specific SST RSD limits for EP and USP
methods. If these methods are adopted, so should be the SST
requirements.
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Lynda Paleshnuik | January 2012
When compendial methods are adopted
Verification data is required:
The compendial methods as published are typically validated
based on an API or an FPP originating from a specific
manufacturer. Different sources of the same API or FPP can
contain impurities and/or degradation products that were not
considered during the development of the monograph. Therefore
the monograph and compendial method should be demonstrated
suitable to control the impurity profile of the API from the
intended source(s).
The FPP may also contain excipients not present in the FPP(s)
for which the the compendial method was developed.
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Lynda Paleshnuik | January 2012
When compendial methods are adopted
Verification data:
Assay method: specificity, accuracy and repeatability (method
precision).
Related substances method: full validation for any additional (to
the monograph) specified related substances and absence of
interference from placebo; If there is no monograph limit on
individual unknowns (or it is higher than the IT/acceptable
limit), repeatability of the API at the limit for unknowns
(usually 0.2%) should be established.
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Lynda Paleshnuik | January 2012
Compendial standard claimed,
but in-house method used 
 Full validation is required for an in-house purity/assay method.
 In addition, if compendial standard is claimed, equivalency
must be demonstrated compared to the compendial method
(assay: assaying aliquots of the same samples using the two
methods; related compounds: as above, spiking samples with
specified related compounds at the limits)
 If they can not demonstrate this, they may claim in-house
standard but not compendial standard
 Note that a compendial method becomes an in-house method
when adjustments are made outside the allowable adjustments
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Lynda Paleshnuik | January 2012
Equivalency - note
Equivalency is essentially two things:
 Ensure the in-house method is not inferior (in which
case they should adopt the compendial method)
 Ensure the compendial test can be met, if applied.
Two samples are sufficient.
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Lynda Paleshnuik | January 2012
Question
Q: Compendial standard is claimed.
The compendial monograph uses a TLC method. The inhouse method is HPLC, which is an improvement over
TLC. Is the applicant required to provide equivalency
testing?
A: Demonstrating “equivalency” per se is not so
important, but the product must still pass the compendial
tests if tested, or they must change to an in-house
standard.
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Lynda Paleshnuik | January 2012
Example
 USP standard claimed for FPP, in-house assay/degradation
methods used, plus the USP degradation test is included in
specs.
 First assessor asks for equivalency data; 2nd says no with the
following justification: a) “The in-house assay method is very
similar to that of the USP method. The only differences are pH
of the buffer soln (2.2 vs 3.3), ratio of the mobile phase to
buffer (66:11 vs 88:12), and with respect to diluents used.”
 b) “The applicant’s method is same as the draft PhInt (except
w.r.t diluent) and has been sufficiently validated including
specificity through forced degradation studies.”
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Lynda Paleshnuik | January 2012
Example
Adjustment of method outside <621> (NMT 0.2 pH units, NMT
10% absolute change in MP%)
Similarity to PhInt method is immaterial (plus a draft monograph
is referenced)… USP standard is claimed.
In this case equivalency is required for the assay method, but not
for the degradation method. Why?
In the specs the USP degradation method is applied as well as the
in-house method. Equivalency is to demonstrate the monograph
standards are met if tested. USP testing for degradants will be met.
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Lynda Paleshnuik | January 2012
Specification Parameters
Description
Description: should be detailed (colour, shape,
coating, markings (score, ink, embossing))
A complete description is also required to facilitate the visual
identification of spurious/falsely-labelled/falsified/counterfeit
(SFFC) medicines.
FPPs for which taste is critical (especially paediatrics):
dispersible, sublingual/buccal, soluble, effervescent, and chewable
tablets, and powders and granules for dispersion/solution or to be
used as sprinkles.
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Lynda Paleshnuik | January 2012
Specification Parameters
Description
Palatability (including taste) should be demonstrated as part of
pharmaceutical development. Taste may exceptionally be part of
specs if an artificial taster is available. (Ideally would be in shelflife specs).
Descriptions in compendial monographs:
“Statements given under this heading are not to be interpreted in a
strict sense and are not to be regarded as analytical requirements.”
[PhInt, BP, EP etc]
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Lynda Paleshnuik | January 2012
Specification Parameters
Identification
 Identification - establish the identity of the API(s) in the FPP
and discriminate between compounds of closely related
structure which are likely to be present. Identity tests should be
specific for the API, e.g., IR spectroscopy. [stated for FPP as
well as API in Q6A, although rarely seen in FPP specs]
 Identification solely by a single chromatographic retention time,
for example, is not regarded as being specific. However, the use
of two chromatographic procedures, where the separation is
based on different principles, or combination of tests into a
single procedure, such as HPLC/UV diode array, HPLC/MS,
or GC/MS, is generally acceptable. (Q6A)
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Lynda Paleshnuik | January 2012
Specification Parameters
Identification
 Note that for PQP, we have recently removed the
requirement to include a test for the identification of
colourant(s) in specifications.
 [This is no longer in the Q guideline.]
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Lynda Paleshnuik | January 2012
Specification Parameters
Identification
 Q: When might identification of the salt in the FPP be a
critical parameter?
 A: When there is a risk of in-situ conversion during
FPP manufacture. [Beware of bicarbonates and
hydroxides (K, Na) in the formulation, except in minor
amounts to adjust pH.]
 Pharmaceutical equivalence definitions are about the
API form “contained” in a product, not what it is
“formulated with”.
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Lynda Paleshnuik | January 2012
Specification Parameters
Assay and Related Compounds
 Assay: may be non-specific, e.g. titration, but need to achieve
overall specificity, e.g. non-specific assay plus suitable related
substances test.
 Limits should be 95.0-105.0% at release, may be 90.0-110.0%
in shelf-life specs if justified by stability results.
 Related compounds: need limits on specified (identified and
unidentified), unspecified (individual unknowns) and total
related compounds. Limits must be suitably qualified.
 Limits may be in S specs only, but only if there is no significant
degradation observed in stability studies. Otherwise, need R
limits which are tighter than S limits.
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Related compounds
Qualification of limits: adopt limit  QT, or qualify:
 If a limit refers to a significant metabolite, it is considered
qualified (confirm it is a metabolite, e.g. WHOPAR, EPAR,
SmPC).
 Level used in safety studies and/or clinical studies (ICH Q3B)
 Literature i.e. ORC limits for specified related compounds are
considered qualified; an unspecified/unknown limit in a
monograph is not qualified.
 Limit is similar to levels found in unstressed innovator product.
 An enantiomer is excluded from ICH ITs and QTs (Q6A)
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Lynda Paleshnuik | January 2012
Related compounds
Note that unlike the API impurities, the FPP specified related
compounds are degradants. Therefore if the means of
qualification are inadequate, there is an additional consideration:
reducing the degradant to below the QT.
A more protective container
closure system may be investigated.
Watch for organic solvents used as granulating fluids (e.g. ethanol,
isopropyl alcohol). Such solvents require a limit in the
specifications (no skip testing, no justification for removal of test).
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Lynda Paleshnuik | January 2012
Specification Parameters
Microbial limits (solid orals)
Microbial limits test: a general test is required for
solid orals unless justified by the submission of acceptable results
for 5 production batches. If justified, skip test parameters should
be in the specs: At minimum every 10th batch, at least one batch
annually [R], and at release and shelf-life [S].
 PhEur limits are generally acceptable: 5.1.4
 Generally: include limit on total count of aerobic
microorganisms, total count of yeast and molds, and absence of
objectionable bacteria (e.g. E. coli). (Q6A)
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Lynda Paleshnuik | January 2012
Specification Parameters
Uniformity of Dosage Units
PQP requirements are newly harmonized with the PhInt:
Mass uniformity: for the API(s) present at  5 mg and  5% of the
weight of the dosage unit, a test and limit for weight variation may
be established in lieu of content uniformity testing;
Content uniformity: a test and limit for content uniformity is
required for each API present in the FPP at < 5 mg or < 5% of the
weight of the dosage unit
Criteria for application as above, otherwise, the ICH PDG
harmonized text is used, i.e. limits e.g. AV NMT 15%.
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Lynda Paleshnuik | January 2012
Specification Parameters
Uniformity of dosage units – scored tablets
 Uniformity of split portions: content uniformity requirement
applies to tablets containing < 5mg or 5% of API per portion.
What this effectively means: e.g. for a single breakline,
tablets must be 10 mg or more for weight uniformity
testing.
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Lynda Paleshnuik | January 2012
Specification Parameters
Dissolution
Dissolution is considered product-specific. The method and limits
should be appropriate for the proposed product. Surfactant use
should be exceptional and appropriate.
Dissolution specs at release and shelf-life should be identical. It is
useful to have the parameters (medium, apparatus, speed) in specs.
Some accepted specifications can be checked e.g. FDA site
“Dissolution Methods for Drug Products”
www.accessdata.fda.gov/scripts/cder/dissolution/
Careful consideration is required for dissolution specifications
when a biowaiver was accepted (see “BE considerations for
quality” talk).
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Lynda Paleshnuik | January 2012
Specification Parameters
Dissolution
 The limits should be expressed as “Q”, which also implies three
stage testing as per harmonized texts. Ideally the stages are
expressed in the specs (i.e. S1 all individual values  Q+5%)
 There should be a discussion if the time is > 45 minutes.
 It should be ascertained that the dissolution limits are not overly
wide, compared to the actual results (even for an ORC limit).
 Especially for a modified release tablet, the method should be
demonstrated to be discriminatory (sensitive to changes e.g.
qualitative and/or quantitative difference in excipients, API
particle size, process parameters or have different in-process
test specifications for hardness, coating thickness etc.
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Lynda Paleshnuik | January 2012
Specification Parameters
Dissolution
ICH Q6A decision trees 7(1) to 7 (3) can be used to assess the
proposed dissolution criteria, however:
For considering accepting DT in place of dissolution: all the
considerations should be carefully assessed (not just highly soluble
and rapidly dissolving: accepted rarely and only with significant
supporting development data – including when DT is more
discriminating or has a demonstrated relationship to dissolution,
robustness of the formulation/manufacturing process have been
demonstrated wrt DT, etc.)
Some terms are not in agreement with established definitions,
e.g. rapidly dissolving (80% in 15 min vs 85% in 30 min)
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Lynda Paleshnuik | January 2012
Specification Parameters
Dissolution
 Additional considerations are required when there is a BCSbased biowaiver (see BE considerations for Q assessment talk):
BCS Class 1 (e.g. emtricitabine, stavudine, zidovudine,
levofloxacin, ofloxacin): The test and comparator products must
be at least rapidly dissolving. (NLT 85% in 30 minutes)
BCS Class 3 (e.g. abacavir sulfate, lamivudine, ethambutol,
isoniazid, pyrazinamide):The test and comparator products must
be very rapidly dissolving (NLT 85% in 15 minutes).
 Dissolution limits must meet the biowaiver requirements.
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Lynda Paleshnuik | January 2012
Specification Parameters
Water
 Water content should be included in specs when appropriate.
Specs may be justified by data on the effects of hydration or
absorption on the FPP. Q6A
 LOD may be considered adequate, but a water test (i.e. specific
detection procedure such as Karl Fischer titration) is preferred.
 If a product is to be stored in semi-permeable blisters (i.e. not
Al/Al), then water should be included in stability specs.
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Lynda Paleshnuik | January 2012
Dosage form – specific tests
for specific solid oral dosage forms
Chewable tablets: hardness and friability
are critical (Q6A)
Effervescent tablets: it is critical to
control moisture throughout manufacture
and storage
Dispersible tablets: DT (NMT 3 min),
fineness of dispersion (a type of palatability
test)
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Lynda Paleshnuik | January 2012
Dosage form – specific tests
Scored tablets:
Q: When might you require breakability in the release specs?
A: When a score has been added but no scored batch has been
manufactured. The test may be removed once uniformity of split
portions has been ascertained.
Q: When might you require breakability in the stability specs?
A: When there is known to be significant change in tablet hardness
during storage. [See EMA Quality of Medicines Q&A document]
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Lynda Paleshnuik | January 2012
Unnecessary tests in specifications
 In-process tests: used for the purpose of adjusting process
parameters within an operating range; e.g. hardness, friability
(see exception for chewable tabs), individual tablet weight
 Impurities from the API synthesis which are not degradants; not
normally controlled in FPP testing, and not included in the total
impurities limit. Note that the enantiomer should be controlled.
(Q6A)
 Shelf-life specifications do not need to include tests that are not
stability-indicating, such as identity and content uniformity.
 Redundant tests: e.g. MU when CU is required and included
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Lynda Paleshnuik | January 2012
Example specifications
 See separate handout. Full result slides will be provided after
the workshop.
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Lynda Paleshnuik | January 2012
Review tips
 Specifications should have been developed based on the results
of the primary batches, primarily the biolot.
 A comparison of the specs to the biolot results should result in
questions or further considerations when the specs are much
wider than, or are not representative of, the results.
 Updated specs should always be compared to the previous
version submitted, or at minimum the change history should be
reviewed. The result of the comparison must be in the
report, with a discussion of solicited and unsolicited
changes.
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Lynda Paleshnuik | January 2012
Review tips
Scanning specs into reports:
and
 Always include page tops (including e.g. “page 1 of 5”
specifications codes/versions)
 Always include page bottoms (so it is clear the full specs
were included)
 Always include the final page, even if “only” footnotes.
The footnotes and related compound names are a critical part of
specs! (Names should be conducive to knowing structure, ie EP
impurity A or 6 -ethinyl estradiol)
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Lynda Paleshnuik | January 2012
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Lynda Paleshnuik | January 2012