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Quality Workshop Copenhagen


Quality Workshop Copenhagen May 2014 Specifications Hua YIN Validation, verification, equivalency Validation: full validation required for in-house methods ... – PowerPoint PPT presentation

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Title: Quality Workshop Copenhagen

Quality Workshop Copenhagen May 2014
  • Specifications
  • Hua YIN

  • Specification
  • Example specification exercise
  • Compendial Vs Non-compendial (In-house) standards
  • Deficiencies
  • Review tips

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 Generic Guideline Quality Part
  • Other regulatory guidelines
  • Assessing specifications Lynda Paleshnuik, PQP
    Quality Workshop, Copenhagen January 2012

  • 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

Specifications Universal tests/criteria
  • For both API and FPP
  • Description /appearance
  • Identification (IR, HPLC/UV diode array, etc.)
  • Assay
  • Impurities

Specifications specific tests/criteria
  • API
  • BCS low solubility APIs (DSV gt 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

Specifications specific tests/criteria
  • API
  • Physico-chemical properties pH, melting point
  • Water content (KF preferred)
  • Inorganic impurities, Heavy metals
  • Microbial limits

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)

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-labe
    lled/falsified/counterfeit (SFFC) medicines.
  • It is also important to distinguishing
  • the look of different strengths

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).

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
  • 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.

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)..

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

Thresholds for impurities in API
Thresholds for degradation products in FPP
Thresholds for degradation products in FPP
Specification Parameters - Related substances
  • Any impurity
  • gt reporting threshold should be
  • gt Identification Thresholds (IT) should
    be Specified
  • Unspecified (individual unknowns)
    Identification Thresholds (IT)
  • gt Qualification Thresholds (QT) should
    be qualified

Specification Parameters - Related substances
  • Qualification of limits adopt limit ? QT, or
  • 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

Case study 1
  • Zidovudine 300mg tablets, Maximum daily dose is
  • 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

Case study 1 cont'd
  • imp C 3.0 v qualified
  • any other imp 1.0
  • A, B, D 1.0, but
  • any other unknown individual should be 0.2
  • total 4.0 v may be tightened as per the real
    results of primary batches

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
  • Surfactant use should be exceptional and
    appropriate.not exceed 2 normally

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 ? Q5)
  • There should be a discussion if the time is gt 45
  • 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

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/manufac
    turing process have been demonstrated wrt DT, etc.

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

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
  • 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?

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.

Specification Parameters Uniformity of Dosage
  • 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 lt 5 mg or lt 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

Specification Parameters Uniformity of dosage
units scored tablets
  • Uniformity of split portions content uniformity
    requirement applies to tablets containing lt 5mg
    or 5 of API per portion. - on a one-time basis
    and does not need to be added to the
  • For example, 10mg tablets
  • split into 2 portions, each
  • portion contains 5mg --
  • mass uniformity
  • into 4 portions, each protion
  • contains 2.5mg content uniformity

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
  • 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

  • Monographs of Ph. Int., USP, BP are acceptable
    additional in-house controls, e.g.
  • Specific impurity related to the route of
  • 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

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
  • 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
  • But the product must comply with the monograph,
    if tested (see equivalency testing).

When in-house standard is claimed
  • Generally, the tightest available monograph
    limits for assay and purity should be adopted or
  • The available monographs can still be used as a
    general guideline for requirements

When compendial methods are claimed (purity and
assay methods)
  • Ensure the same compendial method is adopted. If
  • Check the deviations against published accepted
  • USP lt621gt 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.

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
  • Equivalency required for an in-house method,
    when compendial standard is claimed
  • Refer to Assessing specifications Lynda
    Paleshnuik, PQP Quality Workshop, Copenhagen
    January 2012

Case Study 3
  • pH of mobile phase 3.3 Vs 2.2 (USP) non USP
  • Ratio of the mobile phase 8614 Vs 8812 (USP)
    USP method
  • lt621gt 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
  • Non pharmacopoeial method ? equivalent to be
    demonstrated if pharmacopeial standard is claimed

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
  • 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

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.

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
  • 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

Case study 4
  • The supplier's specification of Zidovudine
    includes the control of
  • Methyl methane sulfonate content (by GC-MS) NMT
  • 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

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).

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.

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

Review of API specification
Impurity MDD
FPP manufacturers API specification
User specific tests
RoS Specific tests
Generic Guidance
Review of FPP specification
FPP manufacturers Signed and dated specification
  • Review as per
  • Compendial monograph
  • generic guide
  • ICH Q6A, Q3B

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

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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