Food, Medicine and Health CareAdministration and Control Authority

Strategies for Marketing Authorization ofpharmaceuticals

Executive summary

The government of Ethiopia has issued Proclamation 661/2009 in orderto protect the public health from unsafe, inefficacious and poorquality medicines and to promote healthy and productive community.Medicines safety, efficacy and quality are ensured throughstandardized premarketing evaluation of product information,manufacturing premises inspection, laboratory testing and postmarketing surveillance.The main objective of a pharmaceutical manufacturer is to producefinished products from a combination of materials including startingand packaging and labeling materials to ensure that Medicinal productsare consistently produced and controlled to the quality standardsappropriate to their intended therapeutic use and as required by themarketing authorization.

In the past few years of inspection of manufacturing facility for cGMPcompliance by the Authority, it was found that more than 60% offoreign manufacturers failed to comply for the cGMP and hence themarketing authorization. This is a remarkable risk reduction processto protect the public health from substandard and poor qualitymedicines.

The experience now a days in both developed and developing countriesis that the process of market authorization - dossier evaluation,cGMP inspection and pre-marketing quality control laboratory testingfocuses on risk based approach.

Thus in Ethiopia it means the market-authorization process-productdossier evaluation, manufacturers inspection and pre and post marketlaboratory testing should focus on risk based approach to ensure thatthe limited resources allocated are efficiently and effectivelyutilized to assess products of high risk and enhance public healthprotection and promotion in a timely and realistic manner.

The number of application for marketing authorization is increasingfrom time to time .This could be attributed to the economic growthcurrently happening in the country and the population size of thecountry as well as the attractive government investment policy.Meanwhile, the experience, skill ,qualification and educational levelof the human resource required in the medicine and food regulatoryauthorities is diversified and most of them are not readily availablein the market; moreover, the attrition rate of human resource inFMHACA is very high. Thus, using part time qualified and experiencedemployees is mandatory in order to cope up with the current demand forproduct registration and GMP inspection

Thus, this strategy points out how to deal with the current demand forthe marketing authorization, GMP inspection and laboratory testingon risk based approach and using outside experts so that safety,quality and efficacy of medicines will be ensured.

Table of Contents

Executive summary....................................................3Table of Contents....................................................4

Abbreviations........................................................5Acknowledgment.......................................................6

Definitions..........................................................7Introduction.........................................................8

Other Country Experience............................................10Marketing Authorization Strategies for FMHACA.......................11

Strategic direction.................................................11

Strategy for dossier evaluation.....................................12Dossier evaluation of low risk products..........................13

Rigorous evaluation for critical products based on the risks.....13Using Part time dossier assessors................................14

Re-registration of medicinal products............................15Strategy for Good Manufacturing Practice inspection................16

Strategy for pre-market Laboratory testing..........................17Products exempted from pre-market laboratory testing.............18

Products which require testing for selected critical parameter...18Rigorous and extensive testing...................................18

Annex I-The main elements of risk categorization for Product dossier assessment..........................................................19

Abbreviations

AMRP Abbreviated Medicine review process (AMPRP)

cGMP Current Good Manufacturing Practice

EFMHACA Ethiopian 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

Acknowledgment

The Ethiopian Food, Medicine and Healthcare Administration and ControlAuthority (EFMHACA) would like to acknowledge the U.S 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.

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 all requirements of

current ISO 17025 for the required test and whose accreditation can be

accessed on the web.

Applicant means the person or entity who submits a registration

application of product to the Authority, and responsible for the

product information

Authority Means the “Ethiopian Food, Medicine and Health Care

Administration and Control Authority or the acronym “EFMHCACA”

established in accordance with Food, Medicine & Health Care

Administration & Control Regulation No 189/ 2010.

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 document issued for the purpose

of marketing or free distribution of a product after evaluation of

safety, efficacy and quality of the product.

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 an

equipment.

Stringent Regulatory Authority mean a regulatory authority of 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) and WHO

pre-qualification program are considered to be products

registered with Stringent Regulatory Authority (SRA)

Introduction

The Authority Register 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 and local manufacturing companies have shown increased

interest to register their products. However, the increasing

demand of companies for registration and the type of products

needed from the procurement agencies are not matched with the

capacity of the Authority to provide responsive actions for

registration application and procurement request effectively and

efficiently.

Root causes of the problems are the followings:

The product registration and licensing directorate has been

mandated with responsibilities which requires specialization

of staff and separate management system : Assessment of

application for medicine marketing authorization, Assessment

of application for medical Devices/Supplies marketing

authorization, GMP inspection which include receiving

applications for GMP inspection, organizing, participating

and approval of results of GMP inspection, Assessment of

application of Clinical trial protocol and authorization of

clinical trials , Inspection of clinical trials, Handling

Food registration and local food processing manufacturing

facilities inspection, Approval of Purchase orders for

Medicine, medical devices, raw materials for Pharmaceutical

Industries and Review and approval of promotional materials

and promoters. These responsibilities require their own

respective expertise, documentation and management system.

The Authority inadequate number of staff with appropriateknowledge, experience and skills to assess dossiers. Thereis also inadequate/poor professional mix particularly toassess safety, efficacy and quality of new chemical entities

Registration is not focused on risk reduction - extensiveevaluation should be on high risk products unlike the low

risk products (e.g. OTC) which could be registered withminimum requirements

The evaluators professional capability, skill and experience

coupled with inadequate professional mix on assessment of safety,

efficacy and quality of new chemical entities and, 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 is inevitable.

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 revealed that about 60% of the manufacturers

were found to be non-compliant with the cGMP requirement.

In addition to premises GMP inspection requirement, the Authority

requests samples for quality control laboratory testing on

samples submitted by the applicant 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:

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 commercial batches and does 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 focused on samples withdrawn from

commercial batches as it appears in the market and/or from

consignment at the port of entry rather than 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.

The current revised registration guideline in CTD format demands

rigorous and thorough data.

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.

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 origin).

Based on analysis of national current situations and

international experience the Authority has come out with the

strategic options outlined below for improvement of efficiency,

effectiveness, transparency and accountability of market

authorization of pharmaceuticals.

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

Specific objective

To improve the effectiveness and efficiency of

pharmaceuticals dossier evaluation, cGMP inspection and

premarket laboratory testing

To facilitate market authorization process through

implementation of risk based marketing authorization and

fast track registration

To effectively utilize limited resources

To effectively utilize skilled manpower outside the

authority

Strategic direction1. 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. Graduated system of implementation for product safety,

efficacy and quality assessment based on priority products

and focusing on risk of products

3. Proactive risk identification, management and control

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 products

available on the local market;

Premarket evaluation of new products:

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 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 laboratory testing where applicable.

The following strategies for improving efficiency and

effectiveness of Dossier Evaluation, cGMP Inspection and Pre-

market Authorization Laboratory Testing will be implemented

during evaluation of products submitted for marketing

authorization.

The strategies for market authorization are as shown below:-

The purpose of this guidance is neither to eliminate therequirement of dossier submission nor to limit the Authority forfull assessment of the product whenever deemed to be necessary.The main purpose of this guidance is to introduce a procedurewhich will facilitate the registration and hence enhancement ofavailability of the medicines to the public.

Strategy for dossier evaluation

Dossier evaluation of medicinal products is huge task by

itself .Thus, it requires its own management or functional unit

with its own specialized , skilled and experienced

staff/assessors. Thus, segregating/or restructuring the dossier

evaluation task/activities of the authority in to separate

department/unit/directorate will solve many of the problems

currently being encountered. Furthermore, within the dossier

evaluation department/unit/directorate there should be specializedunits/teams such as ;

1. units/team for pharmaceutical products

2. units teams for biological products

3. units/teams for medical device

4. units /teams for diagnostic /reagents

After reorganizing the current product registration and licensing

directorate in the above way, the following strategies should be

applied to cope up with ever increasing demand for market

authorization.

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. Certain category of OTC, multivitamin, class I

(low risk), II (Low-moderate risk) medical devices, and Class

A (no-public health risk or low personal risk & Class B (low

public health or moderate personal risk ) IVD, and

cosmetics). For further reference and information, please see

annex I of this document.

The requirements for registration of the product 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 permanent or part time assessor)

Rigorous evaluation for critical products based on the risks

Much time of the assessors will be spent on rigorous and

extensive evaluation 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)

Biologicals and immunological;

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 requires special expertise classified

as class C and D as described in the registration guideline

for medical devices

Using Part time dossier assessors

As number of application for marketing authorization is

increasing from time to time.This could be attributed to the

economic growth currently happening in the country and the

population size of the country( it is the second populous country

in Africa which makes the it huge market for

pharmaceuticals).Meanwhile, the experience, skill ,qualification

and educational level of the human resource required in the

medicine and food regulatory authorities is diversified and most

of them are not readily available in the market; moreover, the

attrition rate of human resource in regulatory authorities is

very high.

There are only few countries (e.g. Cyprus) whose public

employees are better paid than their private counterparts. For

instance, Drug regulatory authority personnel in the Netherlands

and Australia receive remuneration comparable with that which

they would receive in the private sector. However, medical

practitioners working with the TGA are paid less than their peers

in clinical practice. The lower level of remuneration generally

leads to two problems in personnel management: difficulty in

recruiting qualified people and difficulty in retaining them

(WHO,2009).

Because of the above mentioned reasons, most of the national

regulatory authorities use skilled and qualified human resource

outside their organization. This helps them to get skilled and

experienced human resource with limited financial resource

thereby increase the safety, efficacy and quality of medicines

available in their respective countries.

Thus using skilled and qualified human resources (pharmacist and

other appropriate professionals) dossier assessment available in

academia (teaching hospitals), regional regulatory

bureaus/authorities/agencies and EFMAHAC branch offices is

mandatory to EFMHACA in order to deal with increasing demand for

marketing authorization. This will benefit the authority in the

following ways

1. Increase the efficiency of registration marketingauthorization while enhancing the reliability and assessmentresults.

2. Cope up with high attrition rate of its employees

3. Give faster response to its clients and promote goodgovernance

4. Increase access and alternatives of safe, efficacious andquality medicines to the public

5. Creat of pool of expertise who can be used whenever thereis need

To be Part time employees should be free from conflict of

interest and should sign declaration for conflict of interest and

Part time employees should not be from pharmaceutical

manufacturers, Importers, distributors, hospitals and from

retail outlet of medicines as employees of such institutions are

prone to conflict of interest directly or indirectly.

Re-registration of medicinal products

As it is indicated in the Proclamation No. 661/2009, re-registration

of medicinal products shall be done very four years. Currently the

authority is treating re-registration application as new registration

application whether there is variation /change or not. This practice

has been contributing to accumulation dossiers (backlogs).

This strategy recommends that if the manufacturer or the company

responsible for the re-registration of the medicinal product declare

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.

Strategy for Good Manufacturing Practice inspection

GMP is recognized as a vital component of the control of

pharmaceuticals. All sites of

manufacture for new marketing authorizations, and new sites for

existing products, should be

cleared with respect to GMP by the FMHACA own inspectorate or by

means of valid GMP certificate from stringent regulatory agency.

Whether local sites are given a general inspection, or whether a

separate inspection is conducted for each new marketing

authorization, is a matter for local legislation or policy. At

least finished-product manufacturing sites should be certified.

Manufacturing of pharmaceutical product requires in built quality

control and quality assurance system to produce products meeting

its marketing authorization. In other words quality of product

should be built in the process 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 consistent production and avoid

mix ups and contamination, on site audit of the manufacturing

premises to augment marketing authorization is indispensable.

This has been proven in the past few years inspection where it

was found that more than 60% of overseas manufacturers failed to

meet the requirements for cGMP which implies the risk to be posed

to the public health and scarce resource wastage on the

procurement of unsafe and substandard medicines.

FMHACA has the responsibility to inspect foreign medicine

manufacturers at least once in every four years based on the

Proclamation No. 661/2009.The number of GMP inspection

application by foreign manufacturers are increasing too. Thus,

FMHACA has no longer has the resource to fulfil this statutory

requirements;hence ,EFMHACA should have adequate manpower and

should able to use external skilled manpower in this area.

The inspection of manufacturing premises requires skilled

manpower 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.

Therefore, in order to use the scarce resource appropriately

strategic alternatives for the acceptance of a facility for cGMP

is mandatory.

Conducting GMP inspection using FMHACA staff only will not solve

the questions raised y

the stakeholder in timely manner as well as will compromise other

directorates responsibilities as they have to contribute

personnel to GMP inspection.EFMHACA will not able to respond

teimely to applicants for GMP inspection using its own human

resource. In addition ,theaddition, the attrition rate is also

high and makes it difficult to get experienced and qualified GMP

inspectors as required.

Thus, due to the factors mentioned above , using qualified and

experienced GMP inspectors outside FMHACA will be mandatory to

the authority in order to cope up with the current demand of

qualified GMP inspectors. Moreover, it increases the reliability

and credibility of the GMP inspection as GMP inspectors are

assigned based on merit .

To be Part time 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.

Part time GMP inspectors should not be from pharmaceutical

manufacturers, Importers and distributors as employees of such

institutions are prone to conflict of interest directly or

indirectly.

Both fulltime and part time GMP inspectors shall fulfil the

requirement set by the guidance on requirements for GMP inspector

qualification, training and experience requirements.

Strategy for pre-market Laboratory testing Medicine Quality Monitoring

The samples to be tested as well as the methods to be used for

analysis should rely on the risks identified during assessment.

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. There is low

tendency that an applicant will submit samples which may not

comply with the specification.

Moreover, experiences of other regulatory authorities shows that

marketing authorization is mainly based on dossier assessment and

GMP evaluation whereas the national laboratories are mainly

focused on actual consignment, PMS and addressing complaints from

public and users of the product. The current proposed strategy

does not eliminate testing when found to be necessary. It is

mandatory that when the samples tested at any time it should

comply with the approved specification as described in the

submission dossier.

The following are strategies for laboratory testing for the

purpose of marketing authorization;

Products exempted from pre-market 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 moderate risk

and complexity

Biological and immunological products that are not

registered by SRA

Rigorous and extensive testing

High risk Products not registered by SRA

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 requires special expertise classified

as class C and D as described in the registration guideline

for medical devices

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 aslow risk

The potential for

Products containing problematic API such asbioavailability, solubility, polymorphism

misuse and abuse is low

Consumer can use them for self-diagnosed condition safely and effectively

Adequately labelled Their benefit outweigh

their risk

manufacturability and stability

Orphan products(as per EFMHACA orphan drug list)

Categorized in this list areproducts 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 windowOR products with low market value such as antidotes

Orphan products containing problematic API with narrow therapeutic window

Cosmetics Any cosmetics fulfilling therequirement for guideline for cosmetics and the definitions assigned to themin the guideline

Cosmetics with an additional therapeutic label OR containing active pharmaceutical substances

Class I and II medical device and class A and BInvitro-diagnostics

Class I/II and class A/B devices as described in the registration guideline for medical devices

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

Dermatological productscontaining potent corticosteroid

considered as low risk considered as high riskAnti-inflammatory /ant allergicmedicine

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 aso High solubility and

permeability

o Wide therapeutic index

o Non-significant

effect in the event

of treatment failure

o Products full filling

SRA requirement

Products containing problematic API such as bioavailability, solubility, polymorphism manufacturability andstability

New products to the public

Products with narrow therapeutic window

Based on case by case situation and current knowledge and

understanding products categorized as low risk will be exempted

from sample testing for pre-marketing authorization. Although, in

general products categorized as low risk can be eligible for

waiver for GMP requirement this depends on the product nature. As

for example, cosmetics for the mere beauty purpose are exempted

from GMP inspection at the time of registration.