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Regulation documentation requirements. Saila Antila, PhD WHO consultant. Guidelines. WHO: Marketing Authorization of Pharmaceutical Products with Special Reference to Multisource (Generic) Products / Regulatory Support Series, No 5 (WHO/DMP/RGS/98.5) continues. Guidelines ( continues).

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Regulation documentation requirements

Regulation documentation requirements

Saila Antila, PhD

WHO consultant

Training workshop on Pharmaceutical Quality, Good Manufacturing Practice & Bioequivalence, Kiev 3.-7.10.2005


Guidelines
Guidelines

WHO:

  • Marketing Authorization of Pharmaceutical Products with Special Reference to Multisource (Generic) Products / Regulatory Support Series, No 5 (WHO/DMP/RGS/98.5)

    continues


Guidelines continues
Guidelines(continues)

EMEA (EU)

  • Note for Guidance on the Investigation of Bioavailability and Bioequivalence CPMP/EWP/QWP/1401/98

  • Note for Guidance on Modified Release Oral and Transdermal Dosage Forms: Section II (Pharmacokinetic and Clinical Evaluation) CPMP/EWP/280/96

    continues


Guideline continues
Guideline (continues)

  • Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations (FDA, March 2003)

  • Guidance for Industry: Bioequivalence Guidance (FDA, October 9, 2002)

  • Guidance for Industry: Conduct and Analysis of Bioavailability and Bioequivalence Studies – Part A: Oral Dosage Formulations Used for Systemic Effects (Canada, 1992)


Immediate release product
Immediate release product

  • Preparations showing a release of the active substance(s) which is not deliberately modified by a special formulation design and/or manufacturing method

    • tablets

    • capsules


Immediate release product1
Immediate release product

  • usually a single dose study in fasting state is adequate

  • if the application contains several strengths of the active substance, bioequivalence study only with one strength may be acceptable dissolution profiles with each strength

  • if food enhances or interferes with drug absorption, a bioequivalence study in fed state should be performed


Immediate release product2
Immediate release product

  • if label indicates ’should be administered in fed or fasting state’ then bioequivalence study should be performed accordingly

  • a single dose study at a higher than approved dose may be appropiate for certain drugs ( difficulties in bioanalytics)


The amount of bioequivalence studies with preparations containing several strengths
The amount of bioequivalence studies with preparations containing several strengths

  • if the application contains several strengths of a immediate release oral dosage form bioequivalence study only with one strength may be acceptable. The following conditions should be fulfilled:

  • the products are manufactured by the same manufacturer and process

  • qualitative composition of the different strength is the same

    continues


The amount of bioequivalence studies with preparations containing several strengths1
The amount of bioequivalence studies with preparations containing several strengths

  • ratio between amounts of active substance and excipients is the same (or in case of preparations containing low concentration of the active substance; <5 %; the ratio between amount of excipients is similar)

  • the dissolution profiles of the test products are similar

  • the drug input should be linear over the therapeutic dose range


Modified release formulations
Modified release formulations containing several strengths

EMEA

  • Prolonged release formulations

  • Delayed release formulations

    WHO, FDA

  • Extended (controlled, prolonged, sustained) release

    • tablets, capsules, granules, pellets or suspension

  • Delayed release formulations


Modified release formulations1
Modified release formulations containing several strengths

  • single dose, non-replicate cross-over study in fasting conditions

  • bioequivalence study under fed conditions (to ensure absence of dose dumping)

  • multiple dose study


Modified release forms prolonged and delayed release formulations food effect
Modified release forms (Prolonged and delayed release formulations) Food effect

  • As different modified release preparations may differ with respect to food, the influence of food should be investigated (the effects on efficacy and safety)

  • Predefined high fat meal immediately before dosing


Modified release forms food effect emea
Modified release forms formulations) Food effectFood effect (EMEA)

Food affects absorption-> should perform a 2-way randomized single-dose study

  • after fasting

  • with food

    Food has no affect-> should perform a 2-way randomized single-dose study

  • with food


Modified release formulations essentially similar to a marketed one
Modified release formulations essentially similar to a marketed one

  • if two products differ in their release controlling excipients or mechanism but show similar in vitro dissolution profiles these products can be considered belonging to same category of pharmaceutical form and are considered essentially similar after showing bioequivalence

  • if the products differ in their release controlling excipients or mechanism and show different dissolution profiles then clinical trials should be considered


Prolonged release formulations essentially similar to a marketed one
Prolonged release formulations marketed one(essentially similar to a marketed one)

Single and multiple dose studies

  • the test formulation exhibits the claimed prolonged release characteristics of the reference

  • the active drug substance is not released unexpectantly from the test formulation (dose dumping)

  • performance of the test and reference product is equivalent after single dose and at steady state

    continues


Prolonged release formulations essentially similar to a marketed one continues
Prolonged release formulations (essentially similar to a marketed one) (continues)

  • food effect is comparable for both formulations after high fat meal


Prolonged release formulation essentially similar to a marketed one
Prolonged release formulation: (essentially similar to a marketed one)

Many strengths

  • Single unit:

  • single dose study in fasting conditions with each strength

  • multiple dose study with the highest strength if the pharmacokinetics is linear, the quality of the products is the same etc.


Prolonged release formulation essentially similar to a marketed one1
Prolonged release formulation marketed one)(essentially similar to a marketed one)

Many strengths

  • Multiple unit:

  • linear pharmacokinetics and the composition of the lower strengths are proportional to that of the highest strength, the formulation contains identical beads or pellets and dissolution profiles are acceptable

    single dose study under fasting conditions with the highest strength


Modified release formulation vs immediate release formulation
Modified release formulation vs. immediate release formulation

  • new indications  clinical studies

  • bioavailability should be investigated (rate and extend of absorption, fluctuations, variability, dose proportionality, risk of unexpected release characteristics)

  • rate and extend of absorption from a modified release formulation should be evaluated with an immediate release formulation (reference product) following single and repeated dosing


Modified release formulation vs immediate release formulation1
Modified release formulation vs. immediate release formulation

  • AUC, Cmax, Cmin, fluctuation

  • inter-individual variability of modified release formulation should not exceed variability of immediate release formulation


Modified release formulation vs immediate release formulation2
Modified release formulation vs. immediate release formulation

  • dose proportionally

    • linear pharmacokinetics: modified release formulation and immediate release formulation at one dose level following multiple dose administration

    • non-linear pharmacokinetics: modified release formulation and immediate release formulation at the highest and lowest dose level following multiple administration


Delayed release formulation
Delayed release formulation formulation

Gastro-resistant formulations (entero-coated formulations)

  • post-prandial bioequivalence studies are necessary

  • similar statistical procedures as for immediate release formulations


Oral solution
Oral solution formulation

  • bioequivalence study is not required if the product is in aqueous solution and contains active substance in the same concentration as an oral solution currently approved and the excipients in the product do not affect gastrointestinal transit, absorption and in vivo stability of the active substance

  • if the solution has to be tested against immediate release formulation, a comparative bioavailability study is required


Fixed combination products
Fixed combination products formulation

  • bioequivalence should be assessed of individual active substance separately (new combination) or as existing combinations

  • design a way that drug-drug interactions should be detected


Bioequivalence study is not needed
Bioequivalence study is not needed formulation

The product is

  • a parenteral solution

    • aqueous intravenous solution containing same active substance in the same concentration

    • aqueous or oily intramuscular or subcutaneous solution containing same active substance and same comparable excipients

  • gas for inhalation


  • Bioequivalence study is not needed1
    Bioequivalence study is not needed formulation

    • locally applied product (oral, nasal, inhalation, ocular, dermal, rectal vaginal etc) without systemic absorption  pharmacodynamic or clinical studies are required (note: if the product has systemic effects a BE study is required)


    Immediate release form bioequivalence study is needed in vitro dissolution is not enough
    Immediate release form formulationBioequivalence study is needed, in vitro dissolution is not enough:

    Properties of the active substance:

    • narrow therapeutic index

    • absorption is not complete and/or small bioavailability

    • poor water solubility of the drug

    • risk of bioinequivalence

    • risk of therapeutic failure or adverse drug reaction


    Transdermal drug delivery system
    Transdermal drug delivery system formulation

    • bioequivalence should be assessed after single dose and after multiple dose administration

    • the site of application should be the same body area for both test and reference product

    • multiple strengths-> bioequivalence study with the highest strength

      • proportionality in the formulation

      • there is an acceptable in vitro test

        continues


    Transdermal drug delivery system continues
    Transdermal drug delivery system (continues) formulation

    • intraindividual variability should be assessed (replicate design)

    • if products with different release mechanism are compared, a replicate design is required (formulation interaction)

    • the products should have the same or less degree of local irritation, adhesiveness to skin, phototoxicity, sensitization and similar systemic adverse event profile compared to the reference drug


    Non linear pharmacokinetics
    Non-linear pharmacokinetics formulation

    • if pharmacokinetics is non-linear, extrapolating the results from one bioequivalence study to other strengths is not possible

    • drugs that exhibit nonlinear pharmacokinetics at steady state (saturable metabolism, active secretion) -->multiple dose study

    • if the pharmacokinetic system is non-linear, plasma concentrations of the parent drug and the metabolite should be measured and analysed separately


    Narrow therapeutic window
    Narrow therapeutic window formulation

    • examples of narrow therapeutic drugs: digoxin, litium, warfarin, theophylline

    • drug concentrations or pharmacodynamics are monitored

    • Cmax and AUC confidence intervals 80-125 % unless otherwise justified

    • the applicant should consider additional tests and controls to ensure interchangeability of the products

    • (Ctox/Cther < 5)


    Highly variable drugs
    Highly variable drugs formulation

    • drugs and drug products exhibiting intra-subject variability greater than 30 % CV for AUC and Cmax (CV=coefficient of variation)

    • number of subjects required for a study with highly variable drugs is higher than normally

    • ethical concerns of exposing large number of healthy volunteers to the studies

      continues


    Highly variable drugs continues
    Highly variable drugs (continues) formulation

    • replicate designs often used to reduce the sample size

      • sample size may reduce up to 50 %

      • takes longer time to finalize the study

      • drop-outs may increase

    • group sequence design

      • useful when uncertainty about the estimates of variability

        continues


    Highly variable drugs continues1
    Highly variable drugs (continues) formulation

    • no regulatory definition for these drugs

    • ICH has not accepted bioequivalence as a topic

    • several proposals in the literature

      continues


    Highly variable drugs continues2
    Highly variable drugs (continues) formulation

    Regulatory approaches in different regions:

    • EMEA: Cmax in certain cases e.g. 75-133 % provided that there is no safety concerns

    • South Africa: CI 75-133 % for Cmax except for narrow therapeutic drugs

    • Canada: a limit is placed only on the means (point estimate) for Cmax. The sponsor may add more subjects, if random variation or a larger than expected relative difference

      continues


    Highly variable drugs continues3
    Highly variable drugs (continues) formulation

    • Japan: wider limits allowed for less potent drugs

      • dissolution rates should be equivalent,

      • log AUC and Cmax log(0.9)-log(1.11),

      • total number of subjects 20 or pooled sample size 30

    • USA: CI 80-125 %


    Test product oral
    Test product (oral) formulation

    • test product used in bioequivalence studies should be indentical to the projected commercial pharmaceutical product

      • composition and quality characteristics (including stability) should be the same

      • manufacturing methods should be the same

    • test product should preferably be from the industial scale


    Test product oral1
    Test product (oral) formulation

    • pilot or production batches may be used provided that they are not smaller than 1/10 of the expected full production batch

    • EMEA (EU): batch size at least 100000 units or 1/10 of the production batch whichever is higher (unless otherwise justified)


    Test product oral2
    Test product (oral) formulation

    • certificate of analysis of the test product should be included in the documentation

    • batch numbers and expiry dates should be provided in the bioequivalence study documentation


    Test product oral3
    Test product (oral) formulation

    • the content of the active drug substances between the test and reference product should not differ more than ±5 %


    Reference product
    Reference product formulation

    • innovator product (full chemical, biological, pharmaceutical, pharmacological, toxicological and clinical data)

    • EMEA (EU): the innovator product must be from a EU country


    Reference product1
    Reference product formulation

    WHO:

    • the innovator product should be obtained from a well regulated market (such as Australia, Canada, European Union member states, Japan, USA, Switzerland)

    • a generic product should not be used as an innovator


    Reference product2
    Reference product formulation

    WHO:

    • when the innovator product is not available, the market leader may be used as reference product provided its efficacy, safety and and quality has been established


    Reference product3
    Reference product formulation

    • galenic development: innovator products are not exactly the same as those with full quality, safety and efficacy -> should still used as reference product

    • fixed dose combinations should not be used as comparators unless full clinical trials establishing the safety and efficacy of the product


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