Quality Workshop

Copenhagen – May 2014

Specifications
Hua YIN

1| Hua YIN | May 2014

 Outline

 Specification

 Example specification exercise

 Compendial Vs Non-compendial (In-house) standards

 Deficiencies

 Review tips

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 Information Source
 ICH Q6A Specifications: Test procedures and acceptance criteria for
new drug substances and new drug products: Chemical substances

 ICH Q3A - Q3D: Impurities

 Ph Int, USP, BP, EP, JP (recognized standards in PQP)

 PQP Generic Guideline – Quality Part

 Other regulatory guidelines

 Assessing specifications: Lynda Paleshnuik, PQP Quality Workshop,

Copenhagen – January 2012

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 Specifications

 A list of tests, reference to analytical procedures, and acceptance

criteria (numerical limits, ranges or other criteria), to which an API
or FPP should conform

 Confirm the quality, rather than fully characterize the API or the FPP

 Should focus on those characteristics found to be useful in ensuring

the safety and efficacy of the drug substance and drug product

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 Specifications
Universal tests/criteria

For both API and FPP

 Description /appearance
 Identification (IR, HPLC/UV diode array, etc.)
 Assay
 Impurities

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 Specifications
specific tests/criteria
API
BCS low solubility APIs (DSV > 250ml)

 Polymorphism should be investigated. If polymorphism is a factor, a

test is required in specs --ICH Q6 decision tree #4

 PSD limits (d10, d50, d90) are required in the API specs, based on the
results of the lot used in biostudies. --ICH Q6 decision tree #3

 Must be representative of the biolot characteristics.

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 Specifications
specific tests/criteria
API

 Physico-chemical properties: pH, melting point

 Water content (KF preferred)

 Inorganic impurities, Heavy metals

 Microbial limits

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 Specifications
specific tests/criteria
FPP
 Performance tests: e.g. dissolution, disintegration (where applicable)
 Uniformity of dosage units: mass or content uniformity, fill volume
 Physical tests: e.g. LOD/water content, pH, friability, hardness, particle
size
 Content of preservatives
 Microbial contamination
 Sterility, bacterial endotoxins, particulate matter (parenteral)

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 Specification Parameters - Description

Description: should be detailed (colour, shape,

coating, markings (score, ink, embossing))

A complete description is required to facilitate the visual identification

of spurious/falsely-labelled/falsified/counterfeit (SFFC) medicines.

It is also important to distinguishing

the look of different strengths

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 Specification Parameters - Description

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.

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 shelf-life specs).

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 Specification Parameters - Identification

 Identification should be specific to the API, i.e. should be able to

discriminate between compounds of closely related structure
(Q6A)—IR spectroscopy for API, not always applicable to FPP

 A single HPLC retention time is not regarded as being specific. Two

chromatographic procedures, where the separation is based on
different principles (HPLC + TLC) , or combination of tests into a
single procedure is generally acceptable, such as HPLC/UV diode
array, HPLC/MS, or GC/MS. (Q6A)

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 Specification Parameters - Assay

 Assay: should be stability indicating. May be non-specific, e.g.

titration, but need to achieve overall specificity, e.g. non-
specific assay plus suitable related substances test.

 The assay in the release specifications of FPP is ± 5% of the

label claim (i.e. 95.0-105.0%)..

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 Specification Parameters - Related substances
 Related compounds: need limits on
 specified (identified and unidentified *),
 unspecified (individual unknowns), and
 total related compounds.
*specified unidentified = structurally unidentified. It is identified
in the specs by means of e.g. RRT (relative retention time).
Limits must be suitably justified/qualified.

ICH Q3A, Q3B Thresholds for Reporting, Identification, and

qualification

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 Thresholds for impurities in API

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 Thresholds for degradation products in FPP

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 Thresholds for degradation products in FPP

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 Specification Parameters - Related substances

Any impurity

 > reporting threshold should be reported

 > Identification Thresholds (IT) should be Specified

 Unspecified (individual unknowns) ≤ Identification Thresholds (IT)

 > Qualification Thresholds (QT) should be qualified

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 Specification Parameters - Related substances
Qualification of limits: adopt limit  QT, or qualify:
 Level present in a product used in safety and/or clinical studies (ICH
Q3)
 If a limit refers to a significant metabolite, it is considered qualified
(confirm it is a metabolite, e.g. WHOPAR, EPAR, SmPC).
 Literature i.e. Pharmacopoeial (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

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 Case study 1
Zidovudine 300mg tablets, Maximum daily dose is 600mg.
Int.Ph: Imp A, B, C, D are identified. Imp C is a degradant
Monograph limits of zidovudine tablets:
 imp C ≤ 3.0%;
 any other imp ≤ 1.0%;
 total ≤ 4.0%

The applicant claims the same method and limits as Int.Ph. Is it

acceptable?

Note: RT= 0.1% ; IT= 0.2%; QT= 0.2%

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 Case study 1 cont'd

 imp C ≤ 3.0% √ qualified

 any other imp ≤ 1.0%; ×

 A, B, D ≤ 1.0%, but
 any other unknown individual should be ≤ 0.2%

 total ≤ 4.0% √ may be tightened as per the real results of primary

batches

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 Specification Parameters - Dissolution

 Dissolution is considered product-specific. The method and limits

should be appropriate for the proposed product.
 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/
 Surfactant use should be exceptional and appropriate.—not exceed
2% normally

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 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.
 For products containing water insoluble APIs, it is recommended to
have a two tire dissolution limit. For example Artemether dissolution:
NLT 40% in 1 hour and NLT 60% at the 3rd hour
 It should be ascertained that the dissolution limits are not overly wide,
compared to the actual results (even for an ORC limit).
ORC: officially recognized compendial

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 Specification Parameters - Dissolution
ICH Q6A decision trees #7 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: highly soluble and very
rapidly dissolving, plus 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.

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 Specification Parameters - Dissolution
Additional considerations are required when there is a BCS-based
biowaiver:

 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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 Case study 2

 Ethambutol hydrochloride 400mg tablets. The applicant claimed

USP standard for the product.

 Bioequivalent of the product is accepted as per BCS class 3 based

biowavier

 The applicant set the dissolution limits as below:

 NLT 80% (Q) in 45min at release
 NLT 75% (Q) in 45min at shelf life, which is in line with the
requirement of USP monograph.

 Is it acceptable? What limits should be applied?

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 Case study 2 cont'd

Answer: not acceptable

The dissolution limits at release and shelf life should be the same.

 A limit of NLT 80% (Q) in 15min should be set for both release
and shelf life as for the BCS class 3 biowaiver.

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 Specification Parameters
Uniformity of Dosage Units
PQP requirements are harmonized with the Ph Int:

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

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;

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 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. -– on a one-time
basis and does not need to be added to the specifications.

For example, 10mg tablets

split into 2 portions, each
portion contains 5mg --
mass uniformity
into 4 portions, each protion
contains 2.5mg – content uniformity

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 Fixed-dose combination FPPs

 distinguish each API in the presence of the other API(s) ,

 acceptance criteria for degradation products should be established
with reference to the API they are derived from.
 if an impurity results from a chemical reaction between two or more
APIs, its acceptance limits should be calculated with reference to
the worst case (the API with the smaller area under the curve).
 when one API is present at less than 5 mg or less than 5% of the
weight of the dosage unit, a test and limit for content uniformity is
required for this API in the FPP

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 Specification(s)
 Monographs of Ph. Int., USP, BP are acceptable + additional in-house
controls, e.g.
 Specific impurity related to the route of synthesis
 Individual unspecified impurity
 Residual solvents
 Particle size distribution, polymorphism form
 Those standard for the type of dosage form (e.g. friability, tablet hardness,
uniformity of dosage units, viscosity)
 Microbial limits
 ID and assay of preservatives
 If non-pharmacopoeial monograph, note for guidance ICHQ6A applicable
 For FPP : two set of specifications, i.e. Release and Shelf life are required

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 When compendial standard is claimed
 Generally, the monograph tests and limits should be adopted.
 The monograph is the minimum standard; the authority can impose
additional requirements (e.g. ICH IT for individual unspecified
related compounds)
 May use in-house methods
 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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 When in-house standard is claimed

 Generally, the tightest available monograph limits for assay and

purity should be adopted or justified.

 The available monographs can still be used as a general guideline for

requirements

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 When compendial methods are claimed…
(purity and assay methods)
 Ensure the same compendial method is adopted. 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 limits for EP and USP methods. If
these methods are adopted, the SST requirements should apply.

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 Validation, verification, equivalency
 Validation: full validation required for in-house methods, generally
specificity, linearity, accuracy, repeatability, intermediate precision,
plus for purity: LOD/LOQ--ICH Q2
 Verification: required for most compendial methods
 Equivalency: required for an in-house method, when compendial
standard is claimed

Refer to : Assessing specifications: Lynda Paleshnuik, PQP Quality

Workshop, Copenhagen – January 2012

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 Case Study 3
 pH of mobile phase: 3.3 Vs 2.2 (USP)= non USP method

 Ratio of the mobile phase 86:14 Vs 88:12 (USP) = USP method

<621>: NMT 0.2 pH units, NMT 10% absolute change in MP%

 Detector wavelength 254nm Vs 277nm (USP) = non USP method

 Dissolution test uses apparatus II Vs USP apparatus I = non USP

method

Non pharmacopoeial method → full validation required

Non pharmacopoeial method → equivalent to be demonstrated if

pharmacopeial standard is claimed

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 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, Zinc 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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 Periodic /Skip Testing

 Specified tests on pre-selected batches and /or at predetermined

intervals. e.g.
 Polymorphic form (e.g API)
 Genotoxic impurity (e.g. API)
 Residual solvents (e.g. solid dosage form)
 Microbiological testing (e.g. solid dosage form)
 Dissolution (high water soluble, ICH decision tree #7)-- carefully
justified
 Justified by supportive results for five production batches.

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 Periodic /Skip Testing

 If justified, skip test parameters should be in the specs: At minimum

every 10th batch, at least one batch annually, and at release and shelf-
life.
 Full testing must be reinstated as soon as any batch failure is
observed or conditions under which reduced/skip testing was
approved are no longer met.
 In all cases, the API or FPP should meet the full specifications if
tested
 This concept may be implemented post approval in accordance with
GMP, if sufficient data are available. E.g test results taken from the
API manufacturer's COA

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 Case study 4
The supplier's specification of Zidovudine includes the control of :
 Methyl methane sulfonate content (by GC-MS): NMT 2.5ppm
 Methyl-4-toluene sulfonate content (by HPLC) : NMT 2.5ppm
 Sum of Methyl methane sulfonate and Methyl-4-toluene sulfonate
content : NMT 2.5ppm
 to be performed every 10th individual batch and first individual batch of
every campaign:

The FPP manufacturer's specification of Zidovudine does not contain the

above test. Is it acceptable?

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 Case study 4 cont'd

 Answer: no

 The FPP manufacturer is requested to include that the same

control of above genotoxic impurities in the specification of
Zidovudine (include the same skip testing is acceptable).

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 Common Deficiencies

• The specification should include a reference number, version, date,

and appropriate standard

• The specification should be dated and signed by authorized

personnel

• Any differences between release and shelf-life tests and acceptance

criteria should be clearly indicated and justified.

• If an officially recognized compendial standard exists and an in-

house method is used, compliance to compendial requirements
should be demonstrated unless otherwise justified.

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 Common Deficiencies Cont’d

 The specification should include all standard drug product tests and
limits for that dosage form
E.g. solid orals: description, identity, uniformity of dosage units (CU
or MU), assay, related compounds, dissolution, microbial limits...

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 Review of API specification

CEP/ API- Impurity

PQ/ APIMF MDD

FPP RoS Specific User

manufacturer monograph tests specific
’s API tests
specification

Generic ICH Q6A

Guidance ICH Q3

QIS

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 Review of FPP specification

Review as per
FPP manufacturer’s • Compendial monograph
Signed and dated • generic guide
specification • ICH Q6A, Q3B

Review the
Compare the • Specific dosage form
summary in QIS • specific test as per the
comment manufacturing process

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 Summary and Key Advice
 Control of drug product and establishment of specifications key areas in
the marketing dossier
 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.
 Major concerns around impurities/degradation products and safety for
the patient
 Confirm the sameness to compendial methods if compendial standard is
claimed, when applicable
 Review QIS and confirm with the submitted dossier
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 Any questions?

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