eac gmp inspection manual

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EAC/TF-MED/GMP/PD/N1R0

EAST AFRICAN COMMUNITY

INSPECTION MANUAL FOR GOOD MANUFACTURING PRACTICE

APPROVED BY THE ….. TH ORDINARY MEETING OF THE EAC COUNCIL OF

MINISTERS

(REF: EAC/CM …./DECISION------/DD/MM/YY)

Sept 2013, Version

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EAST AFRICAN COMMUNITY SECRETARIAT

EAC CLOSE

P.O.BOX 1096 ARUSHA, TANZANIA

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TABLE OF CONTENTS

1. ACKNOWLEDGMENTS.................................................................................2

2. PREFACE......................................................................................................3

3. RESPONSIBILITY FOR IMPLEMENTATION AND LEGAL FRAMEWORK.........5

4. INTRODUCTION...........................................................................................5

5. SCOPE.........................................................................................................6

6. TYPES OF INSPECTIONS..............................................................................6

6.1. Routine inspection..................................................................................6

6.2. Concise (Abbreviated) inspection.............................................................7

6.3. Follow-up inspection...............................................................................7

6.4. Special inspection...................................................................................8

7. FREQUENCY OF INSPECTIONS...................................................................8

8. PLANNING FOR GMP INSPECTIONS.............................................................8

9. PREPARATION FOR GMP INSPECTION.........................................................9

10. JOINT GMP INSPECTION..........................................................................10

11. QUALIFICATION OF GMP INSPECTOR.....................................................10

12. CODE OF ETHICS AND CONDUCT FOR GMP INSPECTORS.....................10

13. DECLARATION OF CONFLICT OF INTERESTS.........................................10

14. CONDUCTING GMP INSPECTION.............................................................10

15. SAMPLE COLLECTION AND TESTING......................................................10

16. INSPECTION REPORT..............................................................................11

17. CLASSIFICATION OF GMP INSPECTION OBSERVATIONS........................11

18. RECOMMENDED REGULATORY ACTION(S).............................................12

19. PRODUCT RECALL...................................................................................12

20. APPEAL....................................................................................................12

21. REFERENCES..........................................................................................13

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22. AUTHORS/CONTRIBUTORS.....................................................................13

23. ANNEXES.................................................................................................14

1. ACKNOWLEDGMENTS

This manual has been developed to provide guidance to Good Manufacturing

Practices (GMP) inspectors when conducting inspection of pharmaceutical

manufacturing facilities.

The Manual has been drafted by the East African Community (EAC) Technical

Working Group (TWG) on GMP. The team relied on their experiences and

knowledge on pharmaceutical manufacturing including GMP provisions

highlighted in their individual Countries, World Health Organization (WHO)

and Pharmaceutical Inspection Convention Scheme (PIC/S) Guidelines for GMP

and other available literature.

EAC is highly indebted to development partners and more specifically to WHO

for their technical support; the World Bank and Bill and Melinda Gates

Foundation (BMGF) for their financial assistance and African Union New

Partnership for African Development (AU-NEPAD) Planning and Coordinating

Agency for high level advocacy and technical support.

I wish to also thank the EAC Secretariat staff for their hard work and

coordination of the EAC Medicines Regulatory Harmonization (MRH)

Programme implementation. The oversight role of the EAC MRH Steering

Committee is also acknowledged.

I also acknowledge the EAC esteemed stakeholders; the Ministries responsible

for the EAC Affairs and Health, the EAC pharmaceutical industry and

associations and the academia for their inputs in this manual.To be

incorporated after national/regional stakeholders consultation meetings.

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Secretary General

EAC Secretariat

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2. PREFACE

This manual has been prepared to enable effective implementation of GMP

inspection activities done under EAC Regional Regulatory HarmonizationProgramme. The manual has been prepared to guide EAC GMP inspectors in

preparing for and performing GMP inspection activities of Active

Pharmaceutical Ingredients (APIs) and Finished Pharmaceutical Products

(FPP). It also serves as reference document for EAC inspectors prior and during

GMP inspection and it shall be applicable in the region.

The manual highlights general conditions and other pertinent requirements

that are necessary for carrying out GMP inspections. It is divided into varioussections which amongst other things outline different types of inspections,

qualifications, training and experience required for inspectors as well as code of

ethics and conduct to be observed by inspectors when engaged in inspection

activities. In addition, the manual defines procedures to be followed when

preparing and planning for joint inspection, reporting requirements including

format and classification system adopted for non-compliances observed during

GMP inspection.

Various working documents are annexed to this manual to help inspectors to

comprehend matters related to GMP. It is also expected that the manual shall

help inspectors to conduct GMP inspection with integrity and diligence.

The Code of Ethics and Conduct for Inspectors and confidentiality agreement

for performance have also been outlined with the objective to remind inspectors

on their ethical and moral obligations when engaged in GMP inspection

activities.

NMRAs specifically GMP inspectors, are the target group for this manual and

they are expected to follow what has been described in the document.

Adherence to requirements outlined will enable consistent conduct of GMP

inspections including uniform reporting and consequently amicable decision

making that minimizes complaints from manufacturers. It is therefore

anticipated that the EAC GMP inspectors shall read this manual and diligently

apply what has been documented.

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............................

.

..........................

.

..........................

.

.........................

.

.........................

.

Ministry of East

African

Community

Affairs

REPUBLIC OF

UGANDA

Ministry of East

African

Community

Affairs and

Regional

Integration

REPUBLIC OF

BURUNDI

Ministry of East

African Affairs,

Commerce and

Tourism

REPUBLIC OF

KENYA

Ministry of East

African

Community

Affairs

REPUBLIC OF

RWANDA

Ministry of East

African

Cooperation

UNITED

REPUBLIC OF TANZANIA

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3. RESPONSIBILITY FOR IMPLEMENTATION AND LEGAL

FRAMEWORK

This manual will be implemented by the EAC NMRAs GMP inspectors in

accordance with the relevant policies, laws, cooperation, guidelines,

manuals and procedures existing at national and regional level.

4. INTRODUCTION

The EAC-MRH Programme was established to improve public health through

harmonization of medicines regulation and all matters related to improved

access to medicines of acceptable quality, efficacy and safety in the EAC region.

Regulation of medicinal products involves among other things, inspection of

pharmaceutical plants to verify compliance to GMP. GMP is that part of quality

assurance which ensures that products are consistently produced and

controlled to meet quality standards appropriate for the intended use and as

required by marketing authorization. It is designed to minimize the risks

involved in any pharmaceutical production that cannot be eliminated through

testing the final product.

GMP inspections are conducted as one of the requirements for registration of

medicinal products in the EAC. Such inspections are also conducted for

operating as well as new pharmaceutical plants so as to verify compliance with

GMP standards. Inspection involves review of documents, records, facilities and

any other resources to assess their conformity to the requirements of EAC GMPof medicinal products.

Consistency in conducting GMP inspection activities is very important in

ensuring quality assurance of pharmaceuticals by the NMRA. This results into

common decision making by different EAC GMP inspectors at the end of

inspections and thus avoiding complaints from manufacturers. In order to

achieve that goal, EAC GMP inspectors need to be provided with this manual

which contains sufficient working tools needed for observing, investigating and

reaching conclusions in a particular inspection.

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The manual highlights general conditions and other pertinent requirements

that are necessary for carrying out GMP inspections. It is divided into various

sections which amongst other things outline different types of inspections,

qualifications, training and experience required for inspectors as well as code of

ethics and conduct to be observed by inspectors when engaged in inspection

activities. Moreover, the manual defines procedures to be followed when

preparing and planning for inspection, reporting requirements including format

and classification system adopted for non-compliances observed during GMP

inspection.

Various working documents are annexed to this manual to help inspectors to

comprehend matters related to GMP. It is also expected that the manual shall

help inspectors to conduct GMP inspection with integrity and diligence.

5. SCOPE

The manual is applicable for all types of GMP inspections for pharmaceutical

manufacturing plants of API and FPP in the EAC Partner States NMRAs. This

manual serves as a guide to EAC GMP inspectors in preparing for and

performing GMP inspection activities. It also serves as reference document forinspectors prior and during GMP inspection.

6. TYPES OF INSPECTIONS

There are four types of inspection as indicated below;

i.Routine inspection

ii.Concise inspection

iii.Follow-up inspection

iv.Special inspection

6.1. ROUTINE INSPECTION

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Routine inspection is a full review of all aspects and components of GMP within

a facility. Routine inspection is conducted under the following circumstances:

i.To a newly established manufacturing facility or a manufacturer who has

expressed interest of expanding manufacturing activities e.g.introduction of new products.

ii.When there is modification to manufacturing methods or processes; or

changes in key personnel, premises and/or equipment.

iii.When GMP certification has expired.

This type of inspection should be announced.

6.2. CONCISE (ABBREVIATED)INSPECTION

Concise inspection is the evaluation of limited aspects relating to GMP

compliance within a facility. A limited number of GMP requirements are

selected by the inspector to serve as indicators of the overall GMP compliance

by the manufacturer. The inspector also has to identify and evaluate any

significant changes that could have been introduced by the manufacturer since

the last inspection.

Collectively, the selected indicators and the changes identified indicate the

manufacturer’s attitude toward GMP.

A concise inspection is conducted under the following circumstances:

i.Where a manufacturer has a consistent record of compliance with GMP

through routine inspections in the past.

ii.Where a sample of aspects can be taken as a good indication of the

overall level of compliance with GMP.

However, if the concise inspection uncovers evidence that the level of GMP

compliance has fallen, a more comprehensive or full GMP inspection should be

performed soon after the concise inspection.

These inspections can be announced or unannounced.

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6.3. FOLLOW-UP INSPECTION

A follow up inspection is also referred to as a re-inspection or a reassessment of

the manufacturing facilities. It is performed specifically to monitor the result of

corrective actions of the manufacturer following a previous inspection.

Depending on the nature of the defects and the work required, the follow-up

inspection could be carried out within the agreed timeframe after the previous

inspection.

The follow-up inspection is limited to specified GMP non compliances that have

been observed. There are number of circumstances in which special visits or

inspections may be necessary (Refer to Annex…). A follow up inspection shall

be unannounced.

6.4. SPECIAL INSPECTION

A special inspection is undertaken to do spot checks which could focus on one

product, a group of related products, or specific operations e.g. mixing, or

labeling.

Special inspection is conducted under the following circumstances:

i. When there are complaints about a specific product that suggest there

may be defects.

ii. When there is a product recall due to events such as adverse drug

reactions.

iii. To gather specific information, or to investigate specific operations of

the manufacturing processes.

The inspection shall be unannounced.

7. FREQUENCY OF INSPECTIONS

The frequency of inspection of local and foreign manufacturers shall be as

follows:

7.1 Local pharmaceutical manufacturers

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Local manufacturers shall be inspected once a year or after 2 years depending

on the type of inspection to be performed.

7.2 Foreign pharmaceutical manufacturers

Foreign manufacturers shall be inspected once after 3 years. A manufacturer

may be inspected more than once within 3 years, depending on the type of

inspection to be performed.

8. PLANNING FOR GMP INSPECTIONS

The planning for GMP inspection shall be as per EAC Standard Operating

Procedure for Planning of Inspection (refer to Annex…)

While planning for GMP inspection, the following categories of manufacturers

should be considered;

a)Facilities located within the EAC Region

All applicants with their ownandcontracted manufacturing sites shall

be inspected at regular intervals in accordance with the EAC NMRAs

recommendation - at least annually for routine GMP inspection.

b)Facilities located in foreign countries

All facilities located in countries outside the EAC region shall be subject

to GMP Inspection once every three years unless otherwise notified.

Facilities located in countries with stringent NMRAs shall be subject toa first inspection and thereafter may be assessed using document

review unless otherwise required.

c) Manufacturers of APIs

Manufacturers of APIs shall be inspected on a risk-based basis. For the

purpose of this manual, high risk categories shall include, but not be

limited, to the following:

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i. Manufacturers of sterile APIs who do not have approval of

stringent regulatory authorities.

ii. Manufacturers of APIs for anti-retroviral, anti-malarial and anti-

tuberculosis medicinal products who do not have approval ofstringent regulatory authorities.

iii. Manufacturers of relatively unstable APIs who do not have

approval of stringent regulatory authorities.

iv. Manufacturers of APIs for which market complaints have been

received

9. PREPARATION FOR GMP INSPECTION

The preparation for GMP inspection shall be as per EAC Standard Operating

Procedure for Preparation for Inspection of Pharmaceutical Manufacturing

Facilities (ref to Annex…)

10. JOINT GMP INSPECTION

GMP inspection within the EAC shall be conducted as per EAC Standard

Operating Procedure for joint GMP inspection (ref to Annex…)

11. QUALIFICATION OF GMP INSPECTOR

EAC NMRAs shall appoint inspectors to inspect domestic and overseas

manufacturing facilities where medicines used in EAC are manufactured. GMP

inspectors should have the necessary qualification in order to effectively take

part in inspection of pharmaceutical manufacturing facilities.

The qualification of GMP inspectors should be in line with EAC GMP guidelines

(ref No.....) and SOP for training and qualification of GMP inspectors (Refer to

Annex…..)

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12. CODE OF ETHICS AND CONDUCT FOR GMP INSPECTORS

The code of ethics and conduct for GMP inspectors should be in line with EAC

code of ethics (ref to Annex IV)

13. DECLARATION OF CONFLICT OF INTERESTS

The declaration of conflict of interests should be done as per the guidelines for

declaration of conflict of interests EAC NMRAs GMP inspectors (ref to Annex V)

14. CONDUCTING GMP INSPECTION

GMP inspection shall be conducted as per EAC Standard Operating Procedure

for Conducting Inspection of Pharmaceutical Manufacturing Facilities (ref to

Annex…)

15. SAMPLE COLLECTION AND TESTING

The inspection may include the collection of samples for verification of quality

parameter as deemed necessary by the inspectors as per the SOP on sampling

(Annex…). Normally, the sample size should be sufficient to carry out the test

for investigated parameter(s). Unless otherwise indicated by the laboratory,

samples of the following sizes may be taken, depending on the dosage form of

the product:

i. tablets and capsules: 100 units per batch;

ii. injections (single component): 20 units per batch;

iii. injections (combination): 20 units per batch;

iv. oral powders for reconstitution: 10 units per batch;

v. liquid formulations: 5 bottles/units per batch.

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16. INSPECTION REPORT

Inspection report should be written immediately after completing the

inspection. The compiled report shall be shared within the NMRA and membersof the EAC GMP TWG within fourteen (14) calendar days upon completion of

inspection. The EAC GMP TWG shall make sure that GMP inspection report is

sent to the inspected facility within thirty (30) calendar days after receiving the

inspection report.

GMP inspection report shall be written according to Standard Operating

Procedures for preparing and reviewing GMP Inspection Report (ref to Annex…).

Sufficient details should be provided to allow for an independent assessment,

comprehension and easy decision making.

Observations made that are considered to be non-compliance with EAC GMP

requirements should be listed and cross referenced. Where observations are

included in the report, clear distinction should be made between “compliances”

and “non-compliances”. Non-compliance observations should be classified as

“critical”, “major” and “minor”. These classes are detailed below.

17. CLASSIFICATION OF GMP INSPECTION OBSERVATIONS

The intention of this part is to help classify the non-compliances observed

during GMP inspection. Overall, the evaluation should commensurate with the

nature and extent of the deviations (i.e. severity). Situations involving fraud,

misrepresentation or falsification of source data or records linked with

pharmaceutical manufacturing will result in a non-compliance rating.

Non-compliances should be noted by Inspectors and classified as critical, major

and minor (refer to guide to risk classification of GMP deficiencies): Annex III

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18. RECOMMENDED REGULATORY ACTION(S)

Below is a table showing a set of regulatory actions that can be recommended

by inspectors when making decisions on the outcome of inspections.

S/N Category of non-

compliances

Regulatory action(s)

1. Minor • Recommend corrective action within a

given timeframe

• Request for compliance report

2. Major • Issue warning letter

• Recommend corrective action within a

given timeframe

• Recommend temporary withdrawal or

suspension of marketing authorization

• Request for comprehensive compliance

report

• Follow-up inspection to verify

implementation if necessary

3. Critical • Recommend permanent withdrawal of

marketing authorization incase of

registered products

• Recommend suspension of marketing

authorization incase of registered

products

• Recommend not to grant marketing

authorization for new application.

19. PRODUCT RECALL

The product recalls should be conducted as per EAC SOP on product recalls

(ref to Annex…………)

20. APPEAL

Any manufacturer may appeal against any decision of the NMRA.

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When a manufacturer appeals against a decision of NMRA, the written

submission by the manufacturer will be evaluated by the NMRA. The NMRA

will then decide whether to accede to the appeal of the manufacturer after

evaluating the submitted motivation, reason and appeal. The NMRA may

consider the appeal and motivation, and accept or reject the appeal according

to the national regulations.

21. REFERENCES

i. WHO Prequalification Programme documents:

http://apps.who.int/prequal/

ii. The Pharmaceutical Inspection Convention and Pharmaceutical

Inspection Co-operation Scheme ( PIC/S) guidance documents oninspection: www.picscheme.org

22. REVISION HISTORY

Revision

No:

Date Author(s) Section(s)

revised

Description

of change

Approvals

00 Septem

ber

2013

EAC TWG

GMP

Members

All First

approved

version to be

issued

REF:

EAC/CM...../DECISION-

-----/dd/mm/yy

23. AUTHORS/CONTRIBUTORS

Members of the Technical Working Group (TWG) on medicinal products Good

Manufacturing Practice (GMP)

National Drug Authority - Uganda

1.Kate Kikule

2.David Nahamya

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http://www.picscheme.org/


http://www.picscheme.org/



3.Apollo Angole

4.Denis Mwesigwa

5.Conrad Mark Mbabazi

DPML/MOH – Burundi

6.Mpawenimana Servilien

7.Mudasigana Marie Louise

8.Niyungeko Vanis

9.Nyabenda Bonaventure

10.Ghislaine Mukamisha

Pharmacy and Poisons Board - Kenya

11.Dr. Jacinta N. Wasike

12.Dr. Shaban Sifuma

13.Dr. Felista Chepwogen

14.Dr. Katatha Wanza

15.Dr. Sichei Cheworei

16.Dr. Sarah Chesaro

Pharmacy Task Force - Rwanda

17.Joseph Kabatende

18.Gladys Akimana

19.Alex Gisagara

20.John Patrick Mwesigye

21.Clarisse Irasabwa

Tanzania Food and Drugs Authority (TFDA)

22.Adonis Bitegeko

23.Kissa W. Mwamwitwa

24.David R. Matle

Zanzibar Food and Drugs Board (ZFDB)

25.Mohammed Omar Mohammed

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26.Zahran Ali Hamad

27.Hidaya Juma Hamad

World Health Organization

28.Dr. Alain Prat

World Bank

29.Apollo Edson Muhairwe

EAC Secretariat

30.Dr. Stanley Sonoiya

31.Ms. Jane Mashingia

32.Ms. Angela Msuya

Steering Committee(To be incorporated after Steering Committee meeting)

Stakeholders (To be incorporated after national/regional stakeholders

consultation meetings)

23. ANNEXES

I. Declaration of Conflict of Interest Form for East African Community -

National Medicines Regulatory Authorities (NMRAs) GMP Inspectors

II. Confidentiality Agreement for Performance of Work for GMP Inspector

(Team Member Participating in Inspections of PharmaceuticalManufacturers) within the Scope of The East African Community

Medicines Regulatory Harmonization (EAC MRH) Programme

III. Code of Ethics and Conduct for GMP Inspectors

IV. Guidelines for Declaration of Conflict of Interests for EAC-NMRAs GMP

Inspectors

V. Guidelines on Good Manufacturing Practice for Medicinal Products

within the EAC and its annexes

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VI. Guidelines on Training and Qualifications of GMP Inspectors within The

East African Community

VII. SOPs

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