Regulation
documentation
requirements
Saila Antila, PhD
WHO consultant
Training workshop on
Pharmaceutical Quality, Good
Manufacturing Practice &
Bioequivalence, Kiev 3.-7.10.2005
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)
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)



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

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
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
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



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 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
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
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
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)
Food affects absorption-> should
perform a 2-way randomized singledose 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


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)
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)

food effect is comparable for
both formulations after high fat
meal
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 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



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 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 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
Gastro-resistant formulations (enterocoated formulations)
 post-prandial bioequivalence studies are
necessary
 similar statistical procedures as for
immediate release formulations
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
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
Bioequivalence study is
not needed
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 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)
Immediate release form
Bioequivalence 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



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)



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



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





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



drugs and drug products exhibiting intrasubject 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)


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
(continues)



no regulatory definition for these drugs
ICH has not accepted bioequivalence as
a topic
several proposals in the literature
continues
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
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 %
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
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)
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
Test product (oral)

the content of the active drug
substances between the test and
reference product should not differ
more than ±5 %
Reference product


innovator product (full chemical,
biological, pharmaceutical,
pharmacological, toxicological and
clinical data)
EMEA (EU): the innovator product must
be from a EU country
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
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
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