Active Pharmaceutical Ingredient, API

• A substance or compound that is intended to

be used in the manufacture of a
pharmaceutical product as a therapeutically
active ingredient.
• Bioavailability means the rate and extent to
which the active drug substance or
therapeutic moiety is absorbed from a
pharmaceutical form and becomes available at
the site of action.
 Pharmaceutical equivalent

• It refers to drug products, which contain the

same active ingredient in the same strength
(concentration) and dosage form, and is
intended for the same route of administration.
• Pharmaceutical equivalent does not
necessarily imply therapeutic equivalence as
differences in the excipients and/or the
manufacturing process can lead to differences
in product performance.
 Pharmaceutical Alternatives

• Drug products are considered pharmaceutical

alternatives if they contain the same
therapeutic moiety, but are different salts,
esters, or complexes of that moiety, or are
different dosage forms or strengths.
• Pharmaceutical Product
• Any preparation for human or veterinary use
containing one or more APIs, with or without
pharmaceutical excipients or additives, that is
intended to modify or explore physiological
systems or pathological states for the benefit
of the recipient.
 reference product
• A reference product is a pharmaceutical
product with which the new product is
intended to be interchangeable in clinical
practice. The reference product will normally
be the innovator product for which efficacy,
safety and quality have been established
 Therapeutic equivalence

• Two pharmaceutical products are

therapeutically equivalent if they are
pharmaceutically equivalent and after
administration in the same molar dose their
effects, with respect to both efficacy and
safety, will be essentially the same as can be
derived from appropriate studies
 Bioequivalence

• Is defined as “the absence of a significant

difference in the rate and extent to which the
active ingredient or active moiety in
pharmaceutical equivalents or pharmaceutical
alternatives becomes available at the site of
drug action when administered at the same
molar dose under similar conditions in an
appropriately designed study”.
• A bioequivalence study is basically a
comparative bioavailability study designed to
establish whether or not there is
bioequivalence between test and reference
products.
 DESIGN
• If the number of formulations to be compared
is two, a balanced two-period, two sequence
crossover design is considered to be the
design of choice.

• Alternatively well-established designs such as

parallel designs for very long half-life
substances, could be considered.
• In general, single dose studies will suffice
• To avoid carry-over effects, treatments should
be separated by adequate wash-out periods.
• The sampling schedule should be planned to
provide an adequate estimation of Cmax and
to cover the plasma drug concentration time
curve long enough to provide a reliable
estimate of the extent of absorption.
• It is recommended that the number of
subjects should be justified on the basis of
providing at least 80 % power of meeting the
acceptance criteria. The minimum number of
subjects should not be less than 12. If 12
subjects do not provide 80 % power, more
subjects should be included.
• A minimum of 20 subjects is required for
modified release oral dosage forms.
• The subject population for bioequivalence
studies should be selected with the aim to
minimise variability and permit detection of
differences between pharmaceutical products.
Therefore, the studies should normally be
performed with healthy volunteers.
• Subjects may be selected from either sex.
• should be between 18 and 55 years of age.
• All subjects participating in the study should
be capable of giving
• informed consent should be taken.
• If the API under investigation is known to have
adverse effects and the pharmacological
effects or risks are considered unacceptable
for healthy volunteers, it may be necessary to
use patients instead, under suitable
precautions and supervision. In this case the
applicant should justify the use of patients
instead of healthy volunteers.
• The time of day for ingestion of doses should
be specified.
• As fluid intake may profoundly influence the
gastric transit of orally administered dosage
forms, the volume of fluid administered at the
time of dosing should be constant (e.g. 200
ml).
• Subjects should not take other medicines for a
suitable period prior to, and during, the study
and should abstain from food and drinks
which may interact with circulatory,
gastrointestinal, liver or renal function
• As the bioavailability of an active moiety from
a dosage form can be dependent upon
gastrointestinal transit times and regional
blood flows, posture and physical activity may
need to be standardised.
• For most drugs 12 to 18 samples including a
pre-dose sample should be collected per
subject per dose.
 When urine is collected:
• The volume of each sample should be
measured immediately after collection and
includedin the report.
• b) Urine should be collected over an extended
period and generally no less than seven times
the terminal elimination half-life,
• For a 24-hour study, sampling times of 0 to 2,
2 to 4, 4 to 8, 8 to 12, and 12 to 24 hours post-
dose are usually appropriate.
• The following bioavailability parameters are to be
estimated:
• a) AUCt, AUC infinity, Cmax, tmax for plasma
concentration versus time profiles.
• AUC t - Area under the curve (from time 0 to time of
Last Quantifiable Concentration).
• AUC infinity - Area under the curve (from time 0 to
infinity).
• Cmax = Maximum concentration.
• Tmax = Time to maximum concentration.
• AUCs are estimated by the conventional
trapezoidal rule
• Bioanalytical methods used to determine the
active moiety and/or its metabolic product(s)
in plasma, serum, blood or urine, or any other
suitable matrix, should be well characterised,
and fully validated and documented to yield
reliable results that can be satisfactorily
interpreted.
• immediate-release oral solid dosage forms
such as capsules, tablets and also suspension
dosage forms,
• Modified-release products include delayed-
release products and extended (controlled)-
release products. Delayed-release drug
products such as enteric-coated dosage forms.