training workshop on pharmaceutical quality, good manufacturing practice & bioequivalence, kiev...
TRANSCRIPT
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Training workshop on Pharmaceutical Quality, Good Manufacturing Practice & Bioequivalence, Kiev 3.-7.10.2005
Regulation documentation requirements
Saila Antila, PhDWHO consultant
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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
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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
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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)
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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
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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
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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)
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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
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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
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Modified release formulationsEMEA Prolonged release formulations Delayed release formulationsWHO, FDA Extended (controlled, prolonged,
sustained) release tablets, capsules, granules, pellets or
suspension Delayed release formulations
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Modified release formulations single dose, non-replicate cross-
over study in fasting conditions bioequivalence study under fed
conditions (to ensure absence of dose dumping)
multiple dose study
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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
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Modified release formsFood effect (EMEA)
Food affects absorption-> should perform a 2-way randomized single-dose study
after fasting with foodFood has no affect-> should perform
a 2-way randomized single-dose study
with food
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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
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Prolonged release formulations(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
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Prolonged release formulations (essentially similar to a marketed one) (continues)
food effect is comparable for both formulations after high fat meal
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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.
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Prolonged release formulation(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
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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
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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
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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
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Delayed release formulation
Gastro-resistant formulations (entero-coated formulations)
post-prandial bioequivalence studies are necessary
similar statistical procedures as for immediate release formulations
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Oral solution 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
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Fixed combination products 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
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Bioequivalence study is not neededThe 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
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Bioequivalence study is not needed 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)
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Immediate release formBioequivalence 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
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Transdermal drug delivery system 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
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Transdermal drug delivery system (continues)
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
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Non-linear pharmacokinetics 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
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Narrow therapeutic window 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)
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Highly variable drugs 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
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Highly variable drugs (continues) 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 variabilitycontinues
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Highly variable drugs (continues) no regulatory definition for these
drugs ICH has not accepted bioequivalence
as a topic several proposals in the literature
continues
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Highly variable drugs (continues)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
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Highly variable drugs (continues) 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 %
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Test product (oral) 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
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Test product (oral) 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)
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Test product (oral) 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
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Test product (oral) the content of the active drug
substances between the test and reference product should not differ more than ±5 %
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Reference product innovator product (full chemical,
biological, pharmaceutical, pharmacological, toxicological and clinical data)
EMEA (EU): the innovator product must be from a EU country
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Reference product
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
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Reference product
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
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Reference product 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