Jitendra et al.

International Journal of Drug Regulatory Affairs; 2013, 1(2), 1-6 ISSN: 2321 - 6794

DRUG PRODUCT REGISTRATION IN SEMI-REGULATED MARKET

Available online at www.ijdra.com

REVIEW ARTICLE
1
Badjatya Jitendra Kumar*, 2Bodla Ramesh
1
(Department of Pharmacy, J.J.T University, Chudela, Jhunjhunu, Raj. India)
2
(Department of Pharmaceutical Chemistry, DIPSAR New Delhi, India)
*Corresponding Author’s E-mail: [email protected]

ABSTRACT:
There found a diversity of regulatory requirement in Semi regulated market. This region consists of mainly the
countries from Asia pacific, Latin America, Eastern Europe, Africa and Gulf countries. Countries from Asia pacific
and Gulf have somewhat harmonized their regulatory environment through The Association of Southeast Asian
Nations (ASEAN) and Gulf Co-operation Council (GCC) organizations, ROW countries yet to be harmonized
regulations in their respective regions.
The urgent requirement to rationalize & harmonize regulation was required by instance of rising cost of health care,
research & development and to meet the public requirement for safe and efficacious treatments to patient in need.
ICH committee has given priority to harmonize the format of reporting data for quality, safety and Efficacy in the
application dossier.
The commercial significance of ROW markets is increasing globally. It is crucial that pharmaceutical companies keep
up-to-date with the latest regulatory developments to ensure their place on the ROW market.
This paper favors the regulatory processes for gaining marketing authorization in ROW countries in terms of
technical data requirement for the dossier.
Key words: DRA, ASEAN, GCC, BMR, ROW, CIS, DMF, TSE/BSE, ICH, FP.

during technical data submission which

will help in export registration.
Introduction
 Enormous diversity of regulatory
 Drug Regulatory Affairs is constantly
requirements are there, however,
evolving and growing and is the one which
harmonisation occurs as clusters in some
is least impacted during the Acquisition
Semi regulated countries e.g. ASEAN,
and Merger, and also during recession.
Gulf
Global harmonization in standards has led
to consistent approach in regulatory
submissions and hence its review. Pharma Market is divided into:
 Systematic formulation development acts 1. Regulated Market: US, EU (UK,
as a back bone for any dossier preparation Germany, France, Ireland, Sweden etc.),
in export registration Japan, Canada, Australia, New Zealand,
 There are different requirements in South Africa
different countries for registration It is 2. Semi regulated Market: (ROW
difficult for any company to develop Countries):
product for each region Therefore; we (a) Asia (Sri Lanka, India, Bangladesh,;
need to consider majority of requirements ASEAN: 10 Countries group - Philippines,

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 Jitendra et al. International Journal of Drug Regulatory Affairs; 2013, 1(2), 1-6 ISSN: 2321 - 6794

Vietnam Singapore, Malaysia, Thailand, Administrative Documents:-

Indonesia, Laos, Cambodia, Brunei  Certificate of Pharmaceutical Product
Darussalam, Myanmar
(b) African countries (Algeria, Zambia,  Product Permission
Ethiopia, Ghana, Kenya, Malawi,  Manufacturing License
Mozambique, Namibia, Nigeria, Sierra
Leone, Tanzania, Zimbabwe etc)  WHO-GMP Certificate
(c) Middle East countries (Gulf Co-  Free Sale Certificate/Export Certificate
operation Council countries i.e. Bahrain,
Kuwait, Oman, Qatar, Saudi Arabia, UAE)  Artwork (Carton, Label & Package Leaflet)
(d) Latin America (Mexico, Brazil, Panama, Chemistry, Manufacturing & control
Peru, Guatemala, Argentina, Chile, documents
Dominican Republic)
API DMF Open part – Following data
(e) CIS (common wealth of independent
should be available in Open Part
states): Russia, Ukraine, OFSUs (Armenia,
Azerbaijan, Belarus, Georgia, Kazakhstan,  Nomenclature
Kirghizstan, Moldova, Tajikistan,  General Properties
Turkmenistan, Uzbekistan etc.)
 Name of the Manufacturer and Site of
manufacture
Difference from Regulated Market  Route of Synthesis, flow diagram in brief
Degrees of implementation are different.  Structural Elucidation
Intensity of audits/ inspections is different and  Impurities
similarly penalties for GMP violations are
different. Regulated market guidelines are  Specifications and Method of Analysis
very clear and are to be adhered to 100%  Container Closure System
Recent Queries raised by various ROW  Stability testing – Retest period & Storage
markets
API Specification and Method of Analysis &
 Computation of batch size. COA of API by the Applicant
 Chromatograms during method validation Justification for Impurity Limits
for assay and impurities.
The following factors to be considered while
 Complete supporting data for process fixing the specification limits
validation
• API impurity limits data (COA)
 Cleaning validation report
• Check ICH requirements.
 Reconstitution Stability (For oral
suspensions): • Check pharmacopoeial limits, if any.

 Preservative content and microbial limits • API stability data.

 Redispersibility and rheological properties • Finished product stability data etc.

 Particle size distribution Manufacturing Formula & Process

Registration Requirements for Rest of the  Manufacturing Formula

World  Description of manufacturing/packaging

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Jitendra et al. International Journal of Drug Regulatory Affairs; 2013, 1(2), 1-6 ISSN: 2321 - 6794

 Scale, Equipment by type, capacity,  Excipients not in compendia are generally

process parameters for steps (e.g. time, not recommended. Some standard
temp, pH), Environmental conditions, e.g. mixtures comprising excipients in
Relative Humidity for Hygroscopic Pharmacopoeia are allowed (e.g. Opadry
materials Colors). In such cases table with
composition of such mixtures and
 Description of In process controls/test
specifications with test form the supplier
 Flow Diagram- Indicate critical steps , In- should be provided
process controls
 For Excipients described in compendia,
 Master formula copy of Monograph along with copies of
 Batch manufacturing Record – Copy of the methods referred to in monograph but
the Master BMR or Completed BMR not appearing in monograph should be
provided.
 Process Validation Protocols and /or
reports-3 batches process validation  Current Pharmacopoeial monograph is
reports and /or protocol is to be submitted. always applicable. Details of any
3 Batches should be of the same size and specifications additional to monograph
should be similar to the batch size should be provided.(e.g. particle size,
mentioned above in the manufacturing residual solvents)
formula.  Excipients Certificate of Analysis tested
 Formulation & Development is required against the full set of specifications.
for some countries like Russia, Ukraine, Finished product Specification and Method
Algeria, Kenya, ASEAN etc. of Analysis
Batch Analysis  If not as per Pharmacopoeia specifications
 Results of at least one batch should be should be prepared as per ICH Q6A.
given. It should be preferably of the batch Methods of Analysis should be described
of which the samples will be submitted for in details
registration. OR It can be of the latest  If based on Pharmacopoeia additional
batch, as required by the agency in the product related specifications should be
respective country. It should be given as included as in-house specifications (e.g.
certificate of analysis. Description, Hardness, Friability, Average
Excipients weight, Dimensions, Identification of
colorants, MLT). Copy of the Monograph
 For Excipients of natural origin microbial is acceptable in some countries. Methods
limits should be specified of the additional tests should be given.
 For Human or Animal origin TSE/BSE  If a test is based on a compendia
certificates from the manufacture should monograph, a copy of the monograph +
be incorporated any methods referenced in the monograph
 Information on Adventitious Agents must be submitted.
should be provided, such as Asbestos in  Details of any specifications and test
Talc methods additional to those in the
 Permitted & approved Colors and Flavors Pharmacopoeia must be submitted.
should be used.

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Jitendra et al. International Journal of Drug Regulatory Affairs; 2013, 1(2), 1-6 ISSN: 2321 - 6794

Method Validations for FP and API  Microbial limits at release and end of shelf
life. Dissolution limit should be same as
 In few countries Validation of analytical
for release.
methods is still not mandatory if the
 API used shall preferably be of different
Pharmacopoeial method is followed.
batches.
 Non-Compendial method needs to be  Stability to be performed on each
validated if required by the Agency. individual strength & container size of
Stability Data and Stability Protocol drug product, unless bracketing or
matrixing is applied.
 Ability of pharmaceutical product to retain  In conclusion Shelf life should be
its property within specified limits proposed / concluded including the storage
throughout shelf-life condition.
 The stability programme includes sample  Generally 3 batches (2 pilots, 1 smaller)
size, test interval, storage conditions, data is required to be submitted.
specific methods and container closure  A pilot scale batch is generally, one tenth
system of a full production scale or 100,000
units, whichever is larger
 Stability studies should include testing of  Recent modification of 30°C/70%RH
those attributes of the Finished product condition to 30°C/65%RH – an attempt at
that are susceptible to change during a single long-term global testing condition
storage and are likely to influence quality,  Testing frequency and storage conditions
safety and efficacy should as per the ICH guidelines
 Testing should cover the physical,  Stability data as per Zone: {Acc.: 0, 1, 2, 3
chemical, biological and microbiological & 6 months; Long term: 0, 3, 6, 9, 12, 24
attributes, preservative content and & 36 months}
functionality tests (e.g. Nebulizer).  Local stability requirements for different
countries is given below:-
Attribute Number Stability Condition Min Duration- Min Duration-
Market of Batches Long Term ACC Long Term
FWA & CA 3 Zone II 3m 3-6 m
ASEAN 3 Zone IV(b) 6m 12 m
LATAM 3 Zone IV 6m 6 m, Vene-12 m
Mid-East 3 Zone IV;Jordan-Z- 6m 12 m, SL, Jordan-
III 24m
CIS 3 Zone II 6m 6m

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Jitendra et al. International Journal of Drug Regulatory Affairs; 2013, 1(2), 1-6 ISSN: 2321 - 6794

Packing Material Other requirements

 Packing material should be suitable for  Working Standard and along with certificate
storage, transport and compatible. of analysis
 For Primary packing material detailed  Samples of API and Excipients
specifications and method of analysis  Chromatograms, Spectra of the
including Identification for material of identification tests wherever applicable
construction required.
Samples
 For Secondary packing material
specifications and method of analysis  As per the quality, it is mandatory to submit
required fresh finished product samples along with
the dossier. The quantity of the sample
 Printed packing material and PIL specimens varies as per the requirements of the Agency
and /or colored artworks Certificate of of importing country.
Analysis & Batch Packaging record
required Summary & Conclusion
Bioequivalence  Any export market demands good quality
dossier which can be generated through
 Compares the systemic exposure profile of a systematic Formulation Development.
test product (Generic) to that of a reference
product (Innovator Brand)  The proper planning and execution of
Formulation development will help in
 For the test product to be bioequivalent it quality dossier & in answering queries from
should exhibit the same rate and extent of Regulatory authorities.
absorption as the reference product
 Since the world is divided in the drug
 Required for Tablets, Capsules and Oral approval procedures with technical data as
Suspensions etc described above, it is important especially
 It can be waived for aqueous oral solutions, for the generic manufacturers, to carefully
parenteral solutions or solutions which are judge the market need, Development Cost,
locally applied and locally acting, for target regions, & regulatory requirements
example eye drops topical products before the development of drugs. Hence it is
inhalators or nasal spray products. critical to plan and co-ordinate all the
activities for successful launch of product in
 If Bioequivalence study is not available then
the market on time.
multimedia, multipoint comparative
dissolution profile data of the product with  Due to vast difference in Regulatory
innovator product should be submitted. Data requirements it is impractical to get global
should be complied the requirement for F2 marketing approval at same time and launch
factor. the product at once in all regions. Hence,
one should carefully understand and define
Pharmacological, Toxicological data
the clear regulatory strategy by looking at
 Published References on Toxicological & the target regions, different patent terms and
Pharmacology studies are attached in the its extension, various application
dossier possibilities, data requirements, potential
 Published data on clinical trials and timeline for marketing launch in different
references are attached in the dossier regions. This eliminates unnecessary
studies, minimizes the delay in drug
Registration fees- Registration fees should be approvals and subsequent launch, and
paid as per the requirements of the Agency of reduces overall cost of development.
importing country

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Jitendra et al. International Journal of Drug Regulatory Affairs; 2013, 1(2), 1-6 ISSN: 2321 - 6794

References:
1. WHO guidelines for stability testing of active
substances and pharmaceutical products
[Internet].[cited 2013 Jan] Available from:
http://apps.who.int/medicinedocs/documents/s19133en/
s19133en.pdf
2. Quality Guidelines – ICH Guidelines
[Internet].[cited 2013 March] Available from:
http://www.ich.org/products/guidelines/quality/article/q
uality-guidelines.html
3. Regulatory_affairs [Internet].[cited 2013 Jan]
Available from http://en.wikipedia.org/wiki
/Regulatory_affairs.
4. European Medicines Agency (EMA)Scientific
Guideline [Internet].[cited 2013 Jan] Available from
http://www.emea.europa.eu/docs /en_GB/document_
library/Scientific_guideline/2009/09/WC500002651.pd
f
5. Stability testing of Pharmaceutical Products in a
Global Enviornment [Internet].[cited 2013 May]
Available from http://www.who.int/medicines/
areas/quality_safety/quality_assurance/RAJ2006WHO
Stability.pdf

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