Medicines Control Authority of

Zimbabwe
Regional Centre of Regulatory Excellence
(RCORE)
In
Medicine Evaluation & Registration
Bioequivalence Workshop

MCAZ Evaluations & Registration Division

15 – 19 October 2018

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Medicines Control Authority of
Zimbabwe
Bioequivalence Workshop

2. Principles of
Interchangeability &
Bioequivalence
MCAZ Evaluations & Registration Division
15 – 19 October 2018

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 At the end of the session…
You should be able to:
1. Articulate what interchangeability is and how it
can be demonstrated
2. Explain the basis and requirements for
bioequivalence requirement for generic
products
3. Describe the approaches to demonstrate BE (in
vitro and in vivo)
4. Demonstrate the ability to interpret regulatory
requirements
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 Introduction
• Bioavailability/ bioequivalence requirements for
generics is well-established over last 5-decades
• Limited experience & practice with
bioequivalence & WHO requirements for African
manufacturers and regulators
• Few NMRAs adapted / adopted WHO BA/BE
Guidelines
- First WHO BA/BE Guideline published in 1996 – WHO
Technical Report Series # 863, Annex 9

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 Brief introduction to bioequivalence
• Multi-source (generic) drug products need to conform
to the same standards of quality, efficacy and safety
required of the originator's (innovator/brand)
products.
• A reasonable assurance must be provided that they
are, as intended, clinically interchangeable with
innovator product or acceptable comparator products
• Pharmaceutically equivalent multi-source
pharmaceutical products must be shown to be
therapeutically equivalent to one another in order to
be considered interchangeable

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 Types of equivalence studies

Sensitivity to detect differences

• Pharmacokinetic studies
• Pharmacodynamic studies and
• Comparative clinical trials
• In vitro studies
- In vitro studies are rarely validated as surrogate of BE
- But if validated, they are the most sensitive
- BCS Biowaiver, IVIVC,

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 Bioavailability / Bioequivalence
• Bioavailability of a drug is:
- Rate and extent to which the API is absorbed
from a pharmaceutical form and reaches the
systematic circulation intact
• Two pharmaceutical products are bioequivalent if they are:
- Pharmaceutically equivalent or pharmaceutical alternatives, and
their bioavailabilities, in terms of peak (Cmax and Tmax) and total
exposure (area under the curve (AUC)) after administration of the
same molar dose under the same conditions, are similar to such a
degree that their effects can be expected to be essentially the
same.

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 A Bit of History
Hatch-Waxman
Act of 1984
1980s
GL Amidon,
1995
WHO TRS
863, 1996 1990s
FDA BCS
Guideline, 2000
WHO TRS 2000s
937, 2006

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 A Bit of History cont’d,
EU BA/BE
Guideline
2010
FDA (draft)
Updated
Guidelines

WHO TRS
2015
992, 2015

Convergence of regulatory
requirements: BCS biowaivers
Class I & III

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• All pharmaceutical products,
including multisource
products, should be used in
a country only after
approval by the national or
regional authority.
Regulatory authorities
should require the
documentation of a
multisource pharmaceutical
product to meet the
following:
• –– GMP;
• –– QC specifications;
• –– pharmaceutical product
interchangeability

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 Generic product - drug application

Quality Quality

Pre-clinical Pre-clinical

Innovator Generic
-Efficacy/Safety product
product Clinical
Clinical application
application Pharmacokinetics
BE studies
Pharmacovig
Pharmacov
ilance igilance

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 Requirements for Generic medicines

Lembit Rago and Budiono Santoso, Chapter 6: Drug Regulation: History, Present and Future: In Drug Benefits and Risks: International Textbook of
Clinical Pharmacology, revised 2nd edition, Edited by C.J. van Boxtel, B. Santoso and I.R. Edwards. IOS Press and Uppsala Monitoring Centre, 2008.

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 Principles of interchangeability
• Bioequivalence is direct proof that the generic
product can be used for new patients with the
same benefit and risk:
- “Prescribability” (new prescriptions, without any adjustment in dose
or other additional therapeutic monitoring)
• A patient already under treatment with the
innovator product can generally be switched to
the generic product: “Switchability” (additional
prescriptions)
• Bioequivalence is also generally considered as
indirect proof of “switchability” between generics
/ multisource products
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 Therapeutic equivalence vs.
Bioequivalence
• Therapeutic equivalence can be assured when the
generic product is both pharmaceutically
equivalent/alternative and bioequivalent.
• Bioequivalence based on blood level determination
of Cmax and AUC has become the most commonly
used and successful biomarker for safety and
efficacy of the drug product.

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 Therapeutic equivalence
• Direct practical demonstration of therapeutic
equivalence in a clinical study usually requires
large numbers of patients.
• Such studies in humans can be financially
daunting, are often unnecessary and may be
unethical

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Scope of the Bioequivalence Guideline
• This guidance is generally applicable to orally
administered multisource products, as well as
to non-orally administered pharmaceutical
products for which systemic exposure
measures are suitable for documenting
bioequivalence (e.g. transdermal delivery
systems and certain parenteral, rectal and
nasal pharmaceutical products).

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Scope of the Bioequivalence Guideline
• Systemic action
– Oral Immediate Release or Modified Release Products
– Transdermal products with systemic action
– Certain parental products (e.g. prolonged release),
– Rectal, nasal, etc. with systemic effect
• Local action
– Inhalation products
• For systemic safety (FDA, Canada, EU)
• Lung deposition (total and pattern of deposition in EU) as surrogate of efficacy
– Nasal products
• For systemic safety (nasal suspensions in FDA draft guidance)
– Gastrointestinal tract (certain drug specific guidance in FDA webpage)
• For systemic safety + in vitro dissolution

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 Biowaiver
• Proportional formulations
- Bioequivalence has been shown with one strength (most sensitive
strength)
- Same manufacturing process
- Similar dissolution profile
• Certain dosage forms (e.g. oral solutions)
- For some classes of product, including – most evidently – parenteral
formulations of highly water-soluble compounds, interchangeability is
adequately assured by implementation of GMP and evidence of
conformity with relevant pharmacopoeial specifications.
• BCS Biowaivers
- In selected cases, in vitro comparison of dissolution profile of the
multisource product with that of the comparator product, or dissolution
studies, may be sufficient to provide indication of equivalence

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 Biowaiver for certain dosage forms
Pharmaceutical equivalence may be enough in
case of:
– Oral aqueous solutions (excluding active excipients)
– Aqueous Intravenous solutions (similar excipients)
– Aqueous Intramuscular / Subcutaneous solutions (similar excipients and
viscosity)
– Oily Intramuscular / Subcutaneous solutions (same oil)
– Aqueous Optic / Ophthalmic solutions
– Cutaneous solutions (if same Qualitative and Quantitative composition)
– Nasal Solutions (if same quali and quanti + in vitro testing for device
performance)
– Powders / Granules for reconstitution as solution
– Gases

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 When equivalence studies are not necessary (a)

• The following types of multisource pharmaceutical product are

considered to be equivalent without the need for further documentation:
• (a) when the pharmaceutical product is to be administered parenterally
(e.g. intravenously, subcutaneously or intramuscularly) as an aqueous
solution containing the same API in the same molar concentration as the
comparator product and the same or similar excipients in comparable
concentrations as in the comparator product.
• Certain excipients (e.g. buffer, preservative and antioxidant) may be
different provided it can be shown that the change(s) in these excipients
would not affect the safety and/or efficacy of the pharmaceutical product

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 Scenario b
• (b) when pharmaceutically equivalent products
are solutions for oral use (e.g. syrups, elixirs and
tinctures), contain the API in the same molar
concentration as the comparator product, and
contain essentially the same excipients in
comparable concentrations.
• Excipient(s) known to affect gastrointestinal (GI)
transit, GI permeability and hence absorption or
stability of the API in the GI tract should be
critically reviewed;

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 Scenario c - d
• (c) when pharmaceutically equivalent
products are in the form of powders for
reconstitution as a solution and the resultant
solution meets either criterion (a) or criterion
(b) above;
• (d) when pharmaceutically equivalent
products are gases;

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 Scenario e
• (e) when pharmaceutically equivalent products
are optic or ophthalmic products prepared as
aqueous solutions and contain the same API(s) in
the same molar concentration and essentially the
same excipients in comparable concentrations.
• Certain excipients (e.g. preservative, buffer,
substance to adjust tonicity or thickening agent)
may be different provided their use is not
expected to affect safety and/or efficacy of the
product

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 Scenario f
• (f) when pharmaceutically equivalent
products are topical products prepared as
aqueous solutions and contain the same
API(s) in the same molar concentration and
essentially the same excipients in comparable
concentrations;

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 Scenario g
• (g) when pharmaceutically equivalent products
are aqueous solutions for nebulizer inhalation
products or nasal sprays, intended to be
administered with essentially the same device,
and contain the same API(s) in the same
concentration and essentially the same excipients
in comparable concentrations.
• The pharmaceutical product may include
different excipients provided their use is not
expected to affect safety and/or efficacy of the
product.
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 Scenarios (cont)
• For situations (b), (c), (e), (f) and (g) above, it is
incumbent upon the applicant to demonstrate that the
excipients in the pharmaceutically equivalent product
are essentially the same and in concentrations
comparable to those in the comparator product or,
where applicable (i.e. (e) and (g)), that their use is not
expected to affect the safety and/or efficacy of the
product.
• In the event that this information cannot be provided
by the applicant and the drug regulatory authority
does not have access to the relevant data, it is
incumbent upon the applicant to perform appropriate
studies to demonstrate that differences in excipients or
devices do not affect product performance.

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Bioequivalence cannot be assumed
• Pharmaceutical Equivalent Products
Pharmaceutical equivalence does not necessarily imply
therapeutic equivalence Test
Reference
• Differences in:
– Raw materials Possible Differences
• Drug (e.g. particle size, polymorphism, etc.)
• Excipients (e.g. grade) Drug particle size, ...
– Formulation / composition Excipients
• Q1 and Q2 (effect on in vivo dissolution and
absorption) Manufacturing process
– Manufacturing process (e.g. dry vs. wet granulation)
Equipment
– Equipment
– Site of Manufacturing Site of manufacture
– Batch size
Batch size ….
• May affect the bioavailability of pharmaceutical
equivalents or pharmaceutical alternatives.
• Then, bioequivalence has to be demonstrated Documented Bioequivalence
= Therapeutic Equivalence

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 Bioequivalence / Comparative
Bioavailability is required
 In vivo documentation of equivalence is needed
when there is a risk that possible differences in
bioavailability may result in therapeutic
inequivalence.
 When the innovator develops a new formulation
– During the drug-development process (before approval)
– As a variation of the marketed product after approval
 When the innovator develops a new dosage form
– Line extension
 When a multisource (generic) product is applied
for marketing authorisation

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 Interchangeability
 The concept of interchangeability includes the
equivalence of the dosage form as well as of the
indications and instructions for use.
– If BE is shown, it is equivalent in all indications if used
according to the instructions of use.
– Some indications may be protected by patent
– Interchangeability
• If both products in the same dosage form in some countries (e.g. USA)
• Between capsules and tablets (e.g. Canada)
• All oral immediate release dosage forms (e.g. EU)

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 Summary
• Bioequivalence ensures a similar
biopharmaceutical quality or in vivo
performance.
– This may require more than one study
• Fasted state
• Fed state

 Then, it is assumed that the multisource product can be used

instead of the reference in all type of patients
– Elderly, Children
– Renal / Hepatic impairment.

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