GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009

PRODUCT INTERCHANGEABILITY AND BIOWAIVER REQUEST FOR CHEMICAL GENERIC DRUG

APPLICATIONS
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 12 - Page 1 of 4

APPENDIX 12 PRODUCT INTERCHANGEABILITY AND BIOWAIVER
REQUEST FOR CHEMICAL GENERIC DRUG
APPLICATIONS

Applicants are advised to be familiar with The ASEAN Guideline on the Conduct of
Bioavailability and Bioequivalence Studies
1
on the conduct of bioavailability (BA) and
bioequivalence (BE) studies for the purposes of drug registration. Applicants are also
advised to consult the relevant international guidelines from EMEA CHMP
2
, US FDA
3
or
WHO for the conduct and analysis of bioavailability and bioequivalence studies.

The report of a BA/BE study should include the complete documentation of its protocol,
conduct and evaluation in compliance with GCP and related ICH E3
4
guideline.
Deviations, additions, or omissions from existing guidelines must be explained, either by
introductory remarks or within each relevant module/part of the submission, whichever is
more appropriate.

With effect from 1
st
April 2004, in vivo bioequivalence (BE) data are required for
Prescription Only Medicines (POM) in oral solid dosage forms. Also, GDA-2 applications
will require bioequivalence data if the application is for a Prescription Only Medicine
(POM) in an oral solid dosage form, even if the first strength (GDA-1) application was
submitted to HSA before 1 April 2004. Applicants are advised to consult HSA for
guidance to determine whether the GDA-2 application requires in vivo bioequivalence
data. This requirement may be extended to other dosage forms in the future.

For generic products containing a different salt or ester form of the active substance
compared to the Singapore reference product, applicants are required to submit data to
demonstrate that the different salt/ester form does not affect the pharmacokinetic,
pharmacodynamic, efficacy or toxicity profile of the active substance in the reference
product.

Product Interchangeability

The generic or test product used in the BA/BE study should be the same as the
Singapore drug product submitted for registration. The generic product should also be
manufactured at the same drug substance and drug product manufacturing sites by the
same manufacturing processes as submitted in the Singapore application dossier.

It is recommended that the reference product used in the BE study be the same as the
Singapore reference product. i.e. the BE reference product should be of the same
strength as the generic product and manufactured from the Singapore registered drug
product manufacturing site. Details of the manufacturing source of the Singapore
reference product can be found by searching HSAs online database
5
.

If the BE reference product was manufactured by a non-Singapore registered
manufacturer, the following criteria must be fulfilled in order to accept the submitted BE
study:
a) The reference product is registered in and obtained from a country with a competent
regulatory system as defined by the WHO;


1
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html
2
http://www.emea.europa.eu/htms/human/humanguidelines/background.htm
3
http://www.fda.gov/cder/guidance/index.htm
4
http://www.ich.org/
5
http://eservice.hsa.gov.sg/prism/common/enquirepublic/SearchDRBProduct.do?action=load
GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009
PRODUCT INTERCHANGEABILITY AND BIOWAIVER REQUEST FOR CHEMICAL GENERIC DRUG
APPLICATIONS
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 12 - Page 2 of 4

b) It is documented that the reference product is marketed in the country of origin
i. by the same innovator company or corporate entity that markets the same drug
product (same dosage form and strength) in Singapore; or,
ii. through a licensing arrangement with the innovator company or corporate entity
that markets the same product in Singapore;
c) The reference product is a conventional, immediate-release oral dosage form (tablet,
capsule) or an enteric coated tablet or capsule formulation that releases the drug
substance promptly once the enteric coating has dissolved;
d) The ingredients in the BE reference product are qualitatively identical to those used in
the Singapore reference product, with exception of minor excipients that are unlikely
to affect the bioavailability of the product (e.g. colourants and inks);
e) The sponsor shall provide Certificates of Analysis for both the BE reference and
Singapore reference products, analysed under the proposed specifications for the
generic product;
f) The active ingredient has a well-described dose response curve and does not exhibit
the following:
i. a narrow therapeutic range or safety margin e.g. does not require careful
dosage titration or patient monitoring;
ii. a steep dose-response relationship;
iii. a risk of serious undesired effects; and/or,
iv. complicated or variable pharmacokinetics (PK) e.g. non-linear PK, variable or
incomplete absorption, site-specific absorption and substantial first-pass
metabolism (>40%); and,
g) The BE reference product
i. contains the same nominal quantity of active ingredient as the innovator product
marketed in Singapore;
ii. is the same as the Singapore reference product with respect to size, weight and
type of coating (e.g. uncoated, film-coated or enteric-coated); and,
iii. exhibits individual and mean dissolution profiles comparable to the Singapore
reference product.

Dissolution profiles should be determined in at least three dissolution media within the
physiological range (pH 1 to 7.5), including 0.1 N HCl, a pH 4.5 buffer and a pH 6.8
buffer. One of the dissolution media should be described in the BP or USP monograph, if
one exists. Thus, for comparative in-vitro dissolution studies, the following data should be
submitted:
a) individual dissolution data in each of the media;
b) mean, range and RSD values of 12 units conducted in the three different media; and,
c) statistical comparison using a procedure described in relevant international guidelines
e.g. F
2
calculations.

For more information on the conduct and reporting of comparative dissolution studies,
applicants are advised to refer to the ASEAN Guideline on the Conduct of Bioavailability
and Bioequivalence Studies
6
and other relevant international guidelines, as appropriate.

Only one bridging step is allowed for a BE study that deviates from the optimal BA/BE
study design (i.e., using the generic product submitted in the application and the
Singapore reference product of corresponding strength, pharmaceutical dosage form and
Singapore registered manufacturing site).
A quick reference on the acceptability of a BE study is given in Appendix 12A. If the
acceptability of a BE study is still in doubt, applicants are advised to email HSA at

6
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html
GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009
PRODUCT INTERCHANGEABILITY AND BIOWAIVER REQUEST FOR CHEMICAL GENERIC DRUG
APPLICATIONS
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 12 - Page 3 of 4

HSA_MedProd_Registration@hsa.gov.sg with the completed Appendix 12A. HSA will
respond to the applicants inquiry once a decision has been reached.

Biowaiver Request

Results from comparative bioavailability studies should be provided in support of the
safety and efficacy of each proposed product and proposed strength included in a GDA
submission. In the absence of such studies, a justification supporting a waiver of this
requirement should be provided for each product and strength.

In general, BE data or a justification for not providing such data are not required for the
following:
a) Simple or complex solutions that do not contain any ingredient which can be regarded
as a pharmacologically active substance;
b) Haemodialysis and peritoneal dialysis solutions;
c) Simple aqueous solutions intended for intravenous injection or infusion containing the
same active substance(s) in the same concentration as currently registered products.
Simple solutions do not include complex solutions such as micellar or liposomal
solutions;
d) Solutions for injection that contain the same active ingredients and excipients in the
same concentrations as currently registered products and which are administered by
the same route(s);
e) Products that are powder for reconstitution as a solution and the solution meets either
criterion (c) or (d) above;
f) Oral immediate release tablets, capsules and suspensions containing drug
substances with high solubility and high permeability and where the medicinal product
has a high dissolution rate, provided that the applicant submits an acceptable
justification for not providing BE data in terms of the CHMP/FDA guidelines;
g) Oral solutions containing the same active ingredient(s) in the same concentration as a
currently registered oral solution and not containing excipients that may significantly
affect gastric passage or absorption of the active ingredient(s);
h) Products for topical use provided the product is intended to act without systemic
absorption when applied locally;
i) Products containing therapeutic substances, which are not systemically or locally
absorbed (e.g., barium sulphate enemas, powders in which no ingredient is
absorbed). If there is doubt as to whether absorption occurs, a study or justification
may be required; and,
j) Otic or ophthalmic products prepared as aqueous solutions and containing the same
drug substance(s) in the same concentration.

For example, when a product is to be marketed in several strengths, if the formulation of
each strength contains the same medicinal and non-medicinal ingredients in the same
proportion, the results of a single comparative bioavailability study may be extrapolated to
all strengths in the series. In all cases, however, if comparative bioavailability data is not
provided for each formulation, the sponsor should provide a scientific justification for not
conducting studies on each strength. This justification may address issues such as the
nature of the kinetics of the drug (e.g., linear versus non-linear), and the proportionality of
the strengths for which a waiver is sought to the strength on which a comparative
bioavailability study was conducted. Similarly, if the submission involves a solution (e.g.,
oral solution, syrup, topical), which the sponsor believes should not require a comparative
bioavailability study, a scientific justification must be presented for the waiver of this
requirement.

GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009
PRODUCT INTERCHANGEABILITY AND BIOWAIVER REQUEST FOR CHEMICAL GENERIC DRUG
APPLICATIONS
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 12 - Page 4 of 4

In preparing a justification, the sponsor should address at least the following issues, as
applicable:
the nature of the dosage form;
the solubility of the drug substance(s)/active ingredient(s);
the comparative dissolution profiles across the physiological pH range (1-7.5) of
the products being considered;
the pharmacokinetic characteristics of the active ingredient(s), such as
permeability (or absolute bioavailability), linearity or otherwise, first pass effect (if
any) and its significance;
the clinical consequences of any potential differences in bioavailabilities of the
products under consideration (for example, increased dose leading to toxicity or
decreased dose leading to lack of efficacy);
the width of the margin between the minimum effective and minimum toxic plasma
concentration; and/or,
the similarities of, or differences between, the formulations being considered.

If the justification is not considered adequate, the sponsor will be required to provide
relevant biopharmaceutic data.

This document reflects the current thinking of HSA on the minimum data necessary for
assessment. HSA reserves the right to request additional information if deemed
appropriate.