1. Draft-0
Food, Medicine and Health Care Administration and Control
Authority
Strategies for Enhancing Marketing Authorization of
Medicines
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2. Executive summary
The Government of Ethiopia has issued Proclamation N0 661/2009 in order to protect the public health
from unsafe, inefficacious and poor quality medicines and to promote healthy and productive community.
Medicines safety, efficacy and quality are ensured through standardized premarketing evaluation of
product information (safety, efficacy and quality data), manufacturing premises inspection, laboratory
testing and pharmacovigilance.
The main objective of a pharmaceutical manufacturer has to be to produce finished products from a
combination of materials including starting and packaging and labeling materials to ensure that medicinal
products are consistently produced and controlled to the quality standards appropriate to their intended
therapeutic use and as required by the marketing authorization.
Inspection of foreign manufacturing facilities carried out by the Authority in the past few years for cGMP
compliance, has shown that more than 60% of the foreign manufacturers inspected failed to comply with
the cGMP requirements and hence could not be issued marketing authorization. This is a remarkable risk
reduction process to protect the public health from substandard and poor quality medicines.
The experience now a days is that, in both developed and developing countries, medicine regulatory
authorities, in their processes of market authorization: dossier evaluation, cGMP inspection and quality
control laboratory testing, they focus on risk based approach.
The notion behind the risk based approach is nothing but to perform stringent evaluation of dossiers
application and GMP inspection on products of high risk and less stringent evaluation system to products
of low risk. Such approach is particularly important in situation where the human resource available to
perform dossiers evaluation and GMP inspection is limited and there is lack of qualified and skilled staff
within the Authority.
Thus in Ethiopia it means the market-authorization process-product dossier evaluation, manufacturers
inspection and pre and post market laboratory testing should focus on risk based approach to ensure that
the limited resources available are efficiently and effectively used to assess products of high risk and
enhance public health protection and promotion in a timely and realistic manner.
In Ethiopia, the number of applications submitted for marketing authorization is increasing from time to
time. Meanwhile, the attrition rate of staff working in the dossiers assessment and GMP inspection areas
is getting very high. Coupled with this is the problem of getting human resource having the appropriate
qualification, experience and skill, in the market; In order to address this problem it will be appropriate to
use qualified and experienced external experts in order to cope up with the current demand for product
registration and GMP inspection; Thus, the purpose of this strategy.
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3. Table of Contents
Strategies for Enhancing Marketing Authorization of Medicines............................................................ 1
Executive summary ..................................................................................................................................... 2
Table of Contents .......................................................................................................................................... 3
Abbreviations ................................................................................................................................................ 4
Acknowledgment .......................................................................................................................................... 5
Definitions ..................................................................................................................................................... 6
Introduction .................................................................................................................................................. 7
Other Country Experience ............................................................................................................................ 8
Marketing Authorization Strategies for FMHACA ......................................................................................... 9
Strategic direction ....................................................................................................................................... 9
Strategy for dossier Evaluations ................................................................................................................. 10
1. To categorize products used in the country into high risk and low risk ................................................. 10
Dossier evaluation of low risk products .............................................................................................. 10
B) Evaluation for high risk products .................................................................................................... 11
2. Using external dossier assessors ............................................................................................................. 11
3. Re-registration of medicinal products ........................................................................................ 12
II. Strategy for Good Manufacturing Practice inspection ........................................................................... 13
III. Strategy for consignment Laboratory testing ........................................................................................ 14
Products exempted from consignment laboratory testing ................................................................... 14
Products which require testing for selected critical parameter .................................................... 14
Rigorous and extensive consignment laboratory testing ............................................................... 14
Annex I-The main elements of risk categorization for Product dossier assessment .................................. 15
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4. Abbreviations
AMRP Abbreviated Medicine review process (AMPRP)
cGMP Current Good Manufacturing Practice
FMHACA Food, Medicine & Health Care Administration and Control Authority
GMP Good Manufacturing Practice
MCC Medicine Control Council
MOU Memorandum of Understanding
OTC Over the Counter
PQAD Product Quality Assessment Directorate
QA Quality Assurance
QC Quality Control
SADC South African Development Community
SRA Stringent Regulatory Authority
TGA Therapeutics Goods Administration of Australia
USFDA United States Food and Drug Administration
WHO World Health Organization
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5. Acknowledgment
The Ethiopian Food , Medicine and Healthcare Administration and Control Authority (EFMHACA) would
like to acknowledge the United States Pharmacopeial Convention's Promoting the Quality Medicines
program (USP/PQM) and U.S Agency for International Development (USAID) for their technical and
financial support in the preparation of this strategy for marketing authorization .
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6. Definitions
The definitions provided below apply to the words and phrases used in these document.
Accredited Laboratory means pharmaceutical quality control laboratory which has been accredited in
accordance with the requirements of ISO 17025 for the required test and whose accreditation can be
accessed on the web.
Applicant means the person or entity who submits application for the registration of a product to the
Authority
Authority means the “Ethiopian Food, Medicine and Health Care Administration and Control Authority
or the acronym “EFMHCACA”
Manufacture means all operations of purchase of materials and products, production, quality control,
release, storage and distribution of pharmaceutical products, and the related controls.
Manufacturer means a company that carries out operations, such as production, packaging, repackaging,
labeling and relabeling of pharmaceuticals.
Marketing Authorization means an official/legal document issued for the purpose of marketing or
distribution of a product for use after evaluation of safety, efficacy and quality of the product and other
requirements set by EFMHACA
Pharmaceutical product means any material or product intended for human use presented in its finished
dosage form or as a starting material for use in such a dosage form that is subject to control by
pharmaceutical legislation in the exporting state and/or the importing state.
Risk analysis means method to assess and characterize the critical parameters in the functionality of a
process or equipment.
Stringent Regulatory Authority means a regulatory authority that is a member of the International
Conference on Harmonisation (ICH) (as specified on www.ich.org); or an ICH observer, being the
European Free Trade Association (EFTA), as represented by Swiss Medic, and Health Canada (as may be
updated from time to time); or a regulatory authority associated with an ICH member through a legally-binding,
mutual recognition agreement including Australia, Iceland, Liechtenstein and Norway (as may
be updated from time to time). In addition WHO
pre-qualified products are considered to be similar to those products registered with Stringent Regulatory
Authority (SRA)
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7. Introduction
The Authority, EFMHACA, registers human medicines, medical devices and other health related
products as per the Ethiopian Food, Medicine and Health Care Administration and Control
Proclamation No 661/2009. As the economic development of the country is progressing overseas
companies have shown increased interest to register their products. However, the increasing
demand of companies to register their products does not match with the capacity of the Authority
The root causes of the problem are the followings:
 The Authority lacks adequate number of staff with appropriate knowledge, experience and
skills to assess dossiers and carry out the different regulatory activities.
 The type & extensiveness of the evaluation process is the same regardless of the associated
risk posed by the product/medicine.
 high attrition rate of staff
 The existing evaluators' professional capability, skill and experience and their professional
mix to assess the safety, efficacy and quality of new chemical entities and the efficacy and
quality of multisource products is very limited which hampers the efficiency of registration
process.
As a result of the above not only the efficiency of registration process is affected but also the
reliability and credibility of assessment results has been greatly questioned. Hence the call for
establishment of efficient and effective registration system based on principles of risk management
to address the nation’s public health need.
Over the past few years’ cGMP inspection was conducted on significant number of foreign
pharmaceuticals products manufacturers located mainly in Asian and African countries as part of
the fulfillment of marketing authorization. The inspection result has revealed that about 60% of the
manufacturers to be non-compliant with the cGMP requirements.
In addition to the requirement for GMP premises inspection, the Authority requests the applicant to
submit samples of the actual product to perform quality control laboratory testing as an important
element for the issuance of marketing authorization after acceptance of the dossier and the
premises for GMP. There are a number of limitations on these procedures. Testing of samples
submitted by a manufacturer has limitation in that:
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8.  It is very unlikely that the applicant will submit samples which will fail to pass the quality
specification.
 Samples submitted by the applicant may not be representative of a commercial batches and
may not represent the actual user situation. This has been reflected through trend analysis
carried out by PQAD for samples submitted for registration from the year 2007-2011. The
result shows that most of failures of samples submitted for PMS was higher (9.5%-15.5%) than
samples submitted for the purpose of pre-marketing authorization (4.7% - 10.7%). This implies
that the focus of laboratory testing should be on samples withdrawn from commercial batches
found in the market and/or from consignment at the port of entry rather than on samples
submitted by the applicant for the purpose of marketing authorization.
The requirement for testing and compliance should be in line with specification described in the
submission dossier and when tested the product should meet the specification irrespective of
whether it is at pre-marketing and/or post marketing sampling levels.
Other Country Experience
Other countries experience including South African, Australian (TGA), Malaysian, US FDA-,
Ugandan, German and Thailand market authorization processes have been reviewed during
development of these strategies of dossier evaluation, cGMP inspection and pre-market laboratory
testing for market authorization.
According to a multi country study by WHO in 2010, assessment and registration are not the same
for all categories of products. How extensive the assessment should depend on a number of factors,
for example in Australia the extensiveness of the assessment depends mainly on two factors; the
first one being the potential risks of the product and the other the availability of human resource
for assessment. These factors are taken into account in setting priorities & deciding the depth of the
review, i.e. for prescription drugs, some medical devices, some alternative products with better
efficacy and safety and these products are subjected to extensive pre marketing evaluation &
registration. Low risk products are only evaluated for safety. For some product groups,
manufacturer’s declaration of safety is accepted and the product is then subjected to more intensive
post-marketing surveillance.
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9. In addition to exemptions based on the type of product (product category) products may also be
exempted from registration on the basis of their source (country of manufacturer).
Based on analysis of national current situations and international experience the Authority has
come out with the strategic options outlined below for improvement of the efficiency, effectiveness,
transparency and accountability of the market authorization of pharmaceuticals in Ethiopia.
Marketing Authorization Strategies for FMHACA
General objectives
 To improve pharmaceuticals Market Authorization in order to promote public health
focusing on national health priorities and protect the public from substandard, unsafe,
ineffective pharmaceuticals there by increase access of safe ,efficacious and quality
medicine
Specific objective
 To improve the effectiveness and efficiency of pharmaceuticals dossier evaluation, cGMP
inspection and consignment laboratory testing
 To facilitate market authorization process through implementation of risk based
marketing authorization and fast track registration
 To effectively utilize available limited resources-human, finance and time
 To establish mechanism to effectively utilize skilled human resource available outside
the Authority
Strategic direction
1. Marketing authorization of pharmaceutical should be supported with cGMP
compliance and should focus on products essential for the promotion of key health problems
of the country and to protect the public from unsafe, ineffective & unacceptable quality
products.
2. Product safety, efficacy and quality assessment based on priority products and
focusing on risk of products
3. Proactive risk identification, management and control
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10. 4. Market authorization to be supported by regular testing of actual consignment and
samples collected through post market surveillance.
The minimum necessary activities of marketing authorization are as follows:
 Establishing and maintaining an inventory of the registered products available on the
local market Print out of the registered product should be public available containing the
minimum necessary information.
 Premarket evaluation of new products (containing new product to Ethiopian market)
 Ensuring that a complete data-set on quality is available
 Evaluating data on quality
Ensuring that newly authorized products containing well established drugs are
interchangeable with locally marketed leader products, and that the approved product
information is accurate and locally useful
 Issuing a written marketing authorization (or rejection) on completion of the assessment
process.
 Evaluating applications to make changes to product information and to pharmaceutical
aspects of existing marketing authorizations
The market authorization process also includes manufacturing premise inspection for cGMP compliance
and consignment laboratory testing where applicable.
The following strategies for improving efficiency and effectiveness of Dossier Evaluation, cGMP
Inspection and consignment laboratory testing will be implemented during evaluation of products
submitted for marketing authorization.
The strategies for market authorization are as shown below:-
Strategy for dossier Evaluations
1. To categorize products used in the country into high risk and low risk
Dossier evaluation of low risk products
 Included in the low risk categories are products which are used by small group of patients and
which don’t have high market (e.g. medicines for orphan disease and certain category of OTC
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11. (except contraceptives), multivitamin, devices, and cosmetics. For further reference and
information, please see annex I of this document.
 The requirements for registration of the products are as described in their respective guideline.
 Low risk products are characterized by their property as described in annex I of this guideline
 Low risk product will be assessed by one assessor only ( could be permanent or external
assessor)
B) Evaluation for high risk products
Much time of the assessors will be spent on rigorous and extensive evaluation of products with high
risk category. The general approach for categorization of high risk products are described in annex
I of this document. Products considered as high risk class during assessment are;
 New products (not marketed in the country before )
 Biological and immunological products;
 Generic products with poor bioavailability, complicated products etc(e.g. sterile product);
 Medicine for major public health problems of the country
o ARV, Anti- TB, Anti-Malaria etc
 Medicines with narrow therapeutic index;
 Invasive medical devices categorized as class III and IV as described in the registration
guideline for medical devices
 In-vitro devices that require special expertise classified as class C and D as described in the
registration guideline for medical devices
2. Using external dossier assessors
The number of applications submitted for marketing authorization is increasing from time to time. At the
same time there is high attrition of trained and skilled staff in EFMHACA, particularly in the Directorate
of Medicines Registration and evaluation. Moreover, as it stands now it is not easy to get from the market
professionals with the necessary qualification, skills and expertise to assess dossiers. In view of these, it
will be necessary to use external expertise to address the gap.
Thus, using outside expertise will be necessary to address the gap at least until such time that the
Authority is able to have the necessary staff in place.. This will benefit the Authority in the following
ways:
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12. 1. Increase the efficiency of the marketing authorization process and improve the quality and the
reliability of the assessment.
2. Cope up with high attrition rate of its employees
3. Give faster response to clients and promote good governance
4. Increase access and alternatives of safe, efficacious and quality medicines to the public
Experts who will be recruited as external assessors’ should be free from conflict of interest and should
sign declaration for conflict of interest.
3. Re-registration of medicinal products
As indicated in the Proclamation No. 661/2009, Article 13, all registered products are required to be re-registered
every four years by submitting applications as per the registration guidelines medicine; that is
registration is valid for four years. On the other hand, according to Article 13 of the Proclamation a
registered product shall be subject to re-registration if at any given time there is variation or change in the
information submitted in support of the registration of a product.
The requirement to re-register all products every four years has no scientific reason or value except
increasing the work load on the registration process and thus leads to accumulation of dossiers in backlog
and affecting the efficiency and effectiveness of the system.
If the manufacturer or the company responsible for the re-registration of the medicinal product declares
that there is no change/variation from the previously registered products and presents valid GMP
compliance certificate from FMHACA or stringent regulatory authority, the marketing authorization will
be renewed without further requirements of documents and evaluation. The manufacturer or company will
submit confirmatory letter indicating there has been no change from the previous registration condition.
If variation is declared during the re-registration application, the re-registration process will be treated by
the variation handling guideline of the authority.
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13. II. Strategy for Good Manufacturing Practice inspection
GMP is a vital component of the control of pharmaceuticals. All sites of manufacturer for new marketing
authorizations, and new sites for existing products, should be cleared with respect to GMP by the
FMHACA's own inspectorate or by means of valid GMP certificate from stringent regulatory agency.
Manufacturing of pharmaceutical product requires inbuilt quality control and quality assurance
system to produce products that meet marketing authorization requirements. In other words
quality of product should be built in the process of product design and manufacture rather than
testing on the end products. Moreover, there are several quality requirements that can’t be tested in
the product such as processing conditions, systems and manufacturing premises. Thus, inspection
of manufacturing premises to assure consistency in production and avoid mix ups and
contamination, on site audit of the manufacturing premises is indispensable..
The inspection of manufacturing premises requires skilled human resource and adequate financial
resources. An audit of one particular manufacturing premise requires a minimum of three expertise
and sufficient days for audit and report writing.
FMHACA at present has limited number of “qualified GMP inspectors”. In addition the Authority
experiences high attrition of inspectors which makes it difficult to fulfil its mandate.
Thus, to address the problem of shortage GMP inspectors this strategy suggests that FMHACA
should use external qualified GMP experts to serve as inspectors. For this FMHACA has to develop
guideline defining the minimum requirements that should be required to be met in order to serve
as GMP inspectors.
To be external GMP inspector for the authority one should be free from conflict of interest and
should sign declaration for conflict of interest and TOR prepared by FMHACA for this purpose.
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14. III. Strategy for consignment Laboratory testing
At present EFMAHACA's marketing authorization process involves three parameters:
 Assessment of safety, efficacy and quality data submitted by the manufacturer
 GMP inspection of the manufacturing site
 Testing of samples of the product submitted together with the dossiers.
While assessment of dossiers and GMP inspection are essential and necessary, testing of sample
submitted by the manufacturer is not considered the best approach; there is low tendency that an applicant
will submit samples which do not comply with the specification. Rather the strategy should be to test
samples taken from commercial batches or from consignments at the ports of entry or market.
Thus, in order to realize the proposed strategic dossier assessment and registration process discussed
above the current sample testing based on ‘sample requisition’ from the applicant should be shifted to
representative sampling from commercial batches withdrawn from consignment and/or market..
The following are strategies for consignment laboratory testing:
Products exempted from consignment laboratory testing
 Product registered by stringent regulatory Authorities in SRA region,
 Commercial batch Products tested by accredited Quality Control Lab in SRA region
 Low risk products
Products which require testing for selected critical parameter
 Products registered by SRA but manufacturer located in non- SRA region
 Product that are not registered by SRA with high risk and complexity
 Biological and immunological products that are not registered by SRA
Rigorous and extensive consignment laboratory testing
 High risk Products not registered by SRA
 Generic products with poor bioavailability, high risk products etc.(e.g. sterile product);
 Medicine for major public health problems of the country
o ARV, Anti- TB, Anti-Malaria etc
 Medicines with narrow therapeutic index;
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15. Annex I-The main elements of risk categorization for Product dossier
assessment
Each product will be categorized and in of two risk categories for the subsequent dossier
assessment, laboratory testing and premises requirement for cGMP.
Parameters Low Risk High Risk
Over the counter
product
Products which have the following
characteristics are in general
considered as low risk
 The potential for misuse and
abuse is low
 Consumer can use them for
self-diagnosed condition safely
and effectively
 Adequately labelled
 Their benefit outweigh their
risk
Products containing problematic
API such as bioavailability,
solubility, polymorphism
manufacturability and stability
Orphan products
Categorized in this list are products
intended to be marketed for small
group of subjects not more than 200,
000 population and the product
contains non-problematic drug
substance with wide therapeutic
window OR products with low market
value such as antidotes
Orphan products containing
problematic API with narrow
therapeutic window
Cosmetics Any cosmetics fulfilling the
requirement for guideline for
cosmetics and the definitions assigned
to them in the guideline
Cosmetics with an additional
therapeutic label OR containing
active pharmaceutical substances
Multivitamin and
minerals
Multivitamin and minerals under the
category of OTC drugs as listed in the
OTC drug list issued by the Authority
Prescription only vitamins
Antihelmentics Antihelmentics having local action
generally considered as low risk
products.
Narrow therapeutic index
Antihelmentics
Dermatological
products
Dermatological products having local
action having wider therapeutic index
considered as low risk
Dermatological products containing
potent corticosteroid considered as
high risk
Anti-inflammatory
/ant allergic
medicine
Non steroidal and antihistaminic
having wide therapeutic index
Narrow therapeutic product and
product having potential for causing
dependence are considered a high
risk product.
Other Products  Products containing drug
substances with the property such
 Products containing
problematic API such as
bioavailability, solubility,
polymorphism
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16. as
o High solubility and permeability
o Wide therapeutic index
o Non-significant effect in the
event of treatment failure
o Products full filling SRA
requirement
manufacturability and stability
 New products to the public
 Products with narrow
therapeutic window
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