Situation Analysis of the Domestic Production of Essential Medicines ...

Better medicines for children in Ghana

Ministry of Health

GHANA

Situation Analysis of the Domestic Production of Essential Medicines in Paediatric Dosage Forms in Ghana

Kwasi Poku Boateng B.Pharm (Hon’s) MBA MPSGH Pharmaceutical &

Quality Management Systems Consultant

December 2011

© World Health Organization 2011

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Table of contents ABBREVIATIONS ........................................................................................................................................ II

EXECUTIVE SUMMARY ...............................................................................................................................III

ACKNOWLEDGEMENTS...............................................................................................................................III

TERMS OF REFERENCE ................................................................................................................................IV

1. INTRODUCTION ................................................................................................................................ 1

2. OBJECTIVE ........................................................................................................................................ 2

3. SCOPE ............................................................................................................................................. 2

4. METHODOLOGY ................................................................................................................................. 2

5. ANALYSIS OF FINDINGS ................................................................................................................... 3

5.1 COMPANY BACKGROUND INFORMATION.............................................................................................. 3

5.1.1 Manufacturing facilities..............................................................................................................3 5.1.2 Ownership structure..................................................................................................................3 5.1.3 Market value and main purchasers..............................................................................................3 5.1.4 Employees...............................................................................................................................3 5.1.5 cGMP and Regulation ................................................................................................................4 5.1.6 Technical/Financial assistance ....................................................................................................4 5.1.7 Production activities and research and development......................................................................4

5.2 MANUFACTURED PRODUCTS ............................................................................................................. 5

5.2.1 Percentage of companies with capacity to produce products in the targeted therapeutic categories.....5 5.2.2 Percentage of companies with capacity to produce products containing the APIs of the

26 target products ....................................................................................................................6 5.2.3 Percentage of companies producing the required dosage form and/or strength of target products.......9 5.2.4 List of the 26 targeted products that are produced locally or for which there is the capacity

to produce in the required dosage form and strength ..................................................................11

5.3 SOURCING OF RAW MATERIALS FOR MAJOR PRODUCTS ........................................................................ 13

5.4 REQUIREMENTS TO ENABLE PRODUCTION OF ADDITIONAL/ALTERNATIVE PAEDIATRIC DOSAGE FORMS........... 13

6. DISCUSSION AND CONCLUSIONS.................................................................................................... 14

6.1 DISCUSSION .............................................................................................................................. 14

6.1.2 Obstacles to the enhancement of local production capacity for child-specific medicines....................15 6.1.3 Requirements that will enable manufacturers to enhance production of child-specific medicines .......16

6.2 CONCLUSIONS ............................................................................................................................ 16

7. RECOMMENDATIONS....................................................................................................................... 16

BIBLIOGRAPHY ......................................................................................................................................... 17

ANNEX I: TARGET MEDICINES FOR PAEDIATRIC USE............................................................................. 19

ANNEX II: LIST OF 22 LOCAL PHARMACEUTICAL MANUFACTURING COMPANIES .................................... 21

ANNEX III: BETTER MEDICINES FOR CHILDREN PROJECT – DOMESTIC PRODUCTION OF ESSENTIAL MEDICINES IN PAEDIATRIC DOSAGE FORMS.......................................................................... 23

PART 1: BACKGROUND INFORMATION ON MANUFACTURER .......................................................................... 23

PART 2: PRODUCTS MANUFACTURED AND THEIR STARTING MATERIALS .......................................................... 25

PART 3: POTENTIAL TO PRODUCE ADDITIONAL/ALTERNATIVE PAEDIATRIC DOSAGE FORMS................................ 28


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ABBREVIATIONS

APIs Active Pharmaceutical Ingredients

BMC Better Medicines for Children

cGMP current Good Manufacturing Practices

DMFs Drug Master Files

EPA Environmental Protection Agency

FDA Food and Drug Administration (United States of America)

FDB Food and Drugs Board (Ghana)

GSB Ghana Standards Board

GSE Ghana Stock Exchange

ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

MDGs Millennium Development Goals

MNCs Multinational companies

NGO Non‐governmental Organization

NRA National Regulatory Authority

NSAID Non‐steroidal Anti‐inflammatory Drug

PEDs Priority Endemic Diseases

PICS Pharmaceutical Inspection Convention Scheme

PMAG Pharmaceutical Manufacturers Association of Ghana

QC Quality Control

R&D Research and Development

SHE Safety, Health and Environment

UNIDO United Nations International Development Organization

WAHO West African Health Organisation

WHO World Health Organization


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EXECUTIVE SUMMARY

A situation analysis of the domestic production of essential medicines in paediatric dosage forms was carried out as the Local Manufacturing Component of the Better Medicines for Children (BMC) project. The BMC project was initiated by the World Health Organization (WHO) with the aim of improving access to essential child‐specific medicines in countries. This project forms part of the framework and mechanism set in place to achieve Millennium Development Goals 4, 5, and 6, which set global priorities for reducing child mortality. Ghana embraced the BMC project because of its relevance to the national context with regard to access to medicines. The project seeks to address issues congruent with the existing child health policy of Ghana. This study assessed the technical capacity of pharmaceutical manufacturers in Ghana to produce generic medicines in paediatric formulations for 26 target paediatric medicines for national use. It was noted that local manufacturers either produce or have the capacity to produce medicines in most of the therapeutic categories for these child‐specific medicines. They also produce or have the capacity to produce medicines containing 20 out of the 26 active pharmaceutical ingredients (APIs) with regard to these child‐specific medicines. However, only 27% of these medicines are produced locally in the required dosage form and strength, while there is local capacity to produce a further 38%. Overall, local manufacturers have the potential to produce 65% of the targeted child‐specific medicines. If the potential to produce a majority of these medicines locally is to be realized, then constraints with regard to some facility and equipment inadequacies, regulatory and international current Good Manufacturing Practice (cGMP) compliance, low investment in research and development, limited capacity to produce some child‐friendly dosage forms, and procurement of raw materials from reliable sources need to be addressed.

ACKNOWLEDGEMENTS

I would like to express my gratitude to all of the pharmaceutical manufacturers and their staff who provided necessary data and helped in various ways during this survey. Without your input and cooperation it would not be possible to carry out this work.


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TERMS OF REFERENCE

The Local Manufacturing Component of the Better Medicines for Children project will involve a situation analysis of the domestic production of essential medicines in paediatric dosage forms. The Local Manufacturing Component would seek to:

1. Define scope of assessment and select local manufacturers of medicines for children.

2. Assess local capacity to manufacture dosage forms and pack sizes to optimize supply of medicines for children.

3. Define resources to carry‐out evaluation.

4. Identify training needs (e.g. on cGMP), depending on the results of the analysis

5. Discuss possible advocacy needs related to the production of paediatric medicines in Ghana.

6. Make recommendations for policy development and review.

7. Report to the BMC Coordination Unit and Steering Committee.


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1. INTRODUCTION

The Better Medicines for Children Initiative is an initiative of the World Health Organization (WHO) for implementation in member countries for the improvement of access to essential child‐specific medicines. This initiative forms part of the framework and mechanism set in place to achieve the Millennium Development Goals (MDGs). MDGs 4, 5 and 6 set global priorities for reducing child mortality. Availability of essential medicines for children is a pre‐condition to achieving these goals. Mortality rates in infants and children under five years of age are estimated at 50 and 80 per 1000 births, respectively. Most of these deaths are caused by diseases and could be prevented by access to safe, essential child‐specific medicines. Child‐specific medicines are those manufactured to suit the age, physical condition and body weight of the child taking them. Although flexible, solid oral dosage forms of medicines are ideal and in some cases available for children, the cost may be two to three times higher than the dosage form for adults. Health‐care workers and parents often use fractions of adult dosage forms or formulate their own prescriptions of medicines by crushing tablets or dissolving portions of capsules in water as alternatives to unavailable paediatric formulations. These are unsafe practices, because they may alter the pharmacokinetics of most formulations and thus affect the health outcomes in drug use. Manufacturing capacity is also a factor in the design of formulations appropriate for children. Ghana embraced the BMC agenda due to its relevance to the national context on access to medicines. The project seeks to address issues congruent with the existing child health policy of Ghana. The situational analysis is an aspect of the Local Manufacturing Component of the BMC project to assess the technical capacity of pharmaceutical manufacturers in Ghana to produce generic medicines in paediatric formulations of selected medicines for national use, with or without export activities. A list of 26 target paediatric medicines have been identified as the focus of the study (see Annex I). Ghana’s pharmaceutical manufacturing sector comprises approximately 34 registered firms, out of which 22 are considered to be active, according to the Pharmaceutical Manufacturers Association of Ghana. About 10 out of this number account for 80% of the total industry output with some exporting their products to countries in the West African sub‐region. A majority of the domestic manufacturing companies are owned by Ghanaian entrepreneurs; there are almost no subsidiaries of multinational companies (MNCs) manufacturing medicines locally. The production activities of local manufacturers cover mainly the secondary production of conventional dosage forms, such as tablets, capsules and oral liquids. Two companies are focused mainly on the production of large volume parenteral preparations and one company has the capacity to produce active pharmaceutical ingredients (APIs).


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2. OBJECTIVE

The objective of this report is to conduct a situation analysis of the domestic production of generic essential medicines in paediatric dosage forms, including antimalarials.

3. SCOPE

The survey assessed the technical capacity of local pharmaceutical manufacturers to produce paediatric formulations of selected target paediatric medicines (see Annex I). It did not include a complete situation analysis and in‐depth appraisal of the technical feasibility of production nor did it include a market analysis of the economic viability of the production of paediatric formulations.

4. METHODOLOGY

Local pharmaceutical manufacturers were identified from the database of the Pharmaceutical Manufacturers Association of Ghana (PMAG). Out of 34 companies, 22 were selected for the study (see Annex II). The other 12 manufacturers were not included in the survey because:

• Two of these produce mainly large volume parenteral preparations.

• Three produce just one or very few products and had limited or no capacity to produce the targeted essential paediatric medicines.

• Seven were not in production at the time or were undergoing restructuring.

A draft data collection form was reviewed and finalized (see Annex III). Data collection occurred through visits to each of the 22 pharmaceutical manufacturers, beginning in the first week of August 2010. The purpose of the study was discussed with the manufacturer’s designated contact person(s). Each contact person was interviewed and given an overview of the data collection form. The nature and extent of the information required to complete the forms was such that it could not be completed in one meeting. As a result, the forms were left with the contact person(s) to complete and were either collected by the consultant or returned to the consultant. Where necessary follow up was done by making further visits to some of the companies or by sending e‐mails or telephoning to finalize collection of the completed forms. By the last week of September 2010, 14 completed forms had been received, one company indicated that they currently did not have the capacity to produce paediatric dosage forms, and two declined to participate. The remaining six companies had previously indicated their preparedness to participate, but had not been able to complete and return the forms. Therefore, the response rate was 68%.


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5. ANALYSIS OF FINDINGS

Data and a limited set of qualitative information about manufacturers were collected on the current domestic production of the 26 targeted products and other medicines in the same therapeutic categories. The following observations were made.

5.1 Company background information

5.1.1 Manufacturing facilities

Of the respondents surveyed, 36% had production facilities built in the 1960s, but all of these had undergone some modifications and expansion between the 1990s and 2000s. In the 1980s, 14% of manufacturers built facilities and all of these have also undergone some modifications in the last decade. In the 1990s, 21% built facilities, none of which have undergone any modifications. In the first decade of the 20th century, 29% of manufacturers surveyed built production facilities and one is currently undertaking some expansion of its facility. Four of the respondents produce beta‐lactams, of which three have separate manufacturing facilities and one produces its beta‐lactams in the same facility as the other products.

5.1.2 Ownership structure

Among the respondents, 72% were private companies, 14% were public companies listed on the Ghana Stock Exchange (GSE), and 14% were a mix of jointly owned Government/public sector and private sector companies. None of them are currently subsidiaries of MNCs.

5.1.3 Market value and main purchasers

Only nine, of the respondents provided information with regards to their total market value for 2009. Using an exchange rate of US$1.00 to GH¢ 1.45, the average total market value for 2009 of the nine respondents was US$6 345 798.74 (range US$172 413.80 – 23 725 000.00). Of the companies that export products, 36% were exporting an average of about 12% of their products to other countries in West Africa, while one company supplied 20% of its products to international donors on the domestic market. The private sector accounted for an average of 73.4% of the purchases of the companies with Government accounting for an average of 31.7%.

5.1.4 Employees

The companies surveyed employed an average of 131 people with an average of 84 (64%) engaged in production and an average of 6 people (5%) engaged in quality control (QC). One company employed 6% of its staff in research and development (R&D).


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5.1.5 cGMP and Regulation

The local regulator Food and Drug Board (FDB) conducts current cGMP assessments of the various companies on the basis of WHO‐cGMP guidelines. All of the respondents were inspected by the FDB between February and May 2010. One of the respondents indicated it complies with the US Food and Drug Administration’s cGMP (FDA‐cGMP) in addition to the WHO‐cGMP. One company was inspected by the National Regulatory Authorities (NRAs) from other West African countries, such as the Republic of Benin, the Republic of Coté d’Ivoire, the Republic of Mali, the Federal Republic of Nigeria, and the Togolese Republic, and another by officials of the West African Health Organisation (WAHO). Other authorities that have inspected companies include: the Ghana Standards Board (GSB), the Environmental Protection Agency, the Department of Factories Inspectorate, the Ghana National Fire Service, and the Environmental Health Department of the Municipal Authority.

5.1.6 Technical/Financial assistance

Among the respondents, 14% received technical/financial support from external agencies, such as WAHO and the United Nations International Development Organization (UNIDO), among others, for activities such as:

• Engaging engineering expertise to redesign the facility aimed at improving GMP

compliance.

• Technical assistance towards WHO inspection and prequalification application.

• Technology transfer for the manufacture of an API.

5.1.7 Production activities and research and development

Almost all the respondent companies were engaged in secondary production of generic medicines, with one company having additional capacity for primary production. Among respondents, 43% undertake contract manufacture for other companies but none sub‐contract to other companies. Another 57% of respondents indicated that they had in‐house R&D capacity. The type of R&D activities were mainly pharmaceutical formulation development, with one company specifically indicating studies in suspension rheology, oil in water products, and water in oil products. Another company also specifically indicated that it had capacity in novel antibiotic discovery (in collaboration with a university), API process development and Phase IV b clinical studies. Only one company provided information on its annual R&D investments. Another company indicated it carried out its R&D using its regular facilities and it did not have a separate budget. The rest did not provide any figures.


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5.2 Manufactured products

5.2.1 Percentage of companies with capacity to produce products in the targeted therapeutic categories

In only two of the therapeutic categories (opiods and other beta‐lactam antibacterials), local manufacturers were either not manufacturing or were not planning to manufacture products.

Figure 1: Companies producing or planning to produce products in the target therapeutic categories

OAD: obstructive airway disease. Fe preps: iron preparations.

No. Therapeutic category Companies producing products in this

therapeutic category (%)

Companies planning to produce or have capacity

to produce products in this therapeutic category

(%) 1 Beta-lactam antibacterials, pencillin 29 7 2 Other beta-lactam antibacterials 0 0 3 Other antibacterials 43 29 4 Drugs for treatment of tuberculosis 0 7 5 Antimalarials 29 7 6 Drugs for obstructive airway disease 7 14 7 Antiepileptics 14 7 8 Psycholeptics, anxiolytics 36 7 9 Anti-inflammatory, non-steroidals 36 7 10 Other analgesics and antipyretics 93 7 11 Opioids 0 0 12 Iron preparations 21 14 13 Vitamins A and D, including combinations of the

two 7 7

14 Electrolytes with carbohydrates 14 21 15 Treatment of diarrhoea 7 21


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5.2.2 Percentage of companies with capacity to produce products containing the APIs of the 26 target products

No. API Companies producing products containing

API of the target products

(%)

Companies planning to produce or having

capacity to produce products containing API of the target products

(%) 1 Amoxicillin 29 7

2 Amoxicillin/clavulanic acid 0 7

3 Benzylpenicillin 0 0

4 Procaine penicillin 0 0

5 Ceftriaxone 0 0

6 Chloramphenicol 14 0

7 Cotrimoxazole 36 29

8 Azithromycin 0 14

9 Gentamicin 0 0

10 Isoniazid 0 7

11 Artesunate + amodiaquine 21 7

12 Artemether + lumefantrine 29 7

13 Dihydroartemisinin + piperaquine 0 14

14 Beclometasone 0 0

15 Salbutamol 7 14

16 Carbamazepine 0 7

17 Phenobarbital 14 7

18 Phenytoin 0 7

19 Diazepam 36 7

20 Ibuprofen 36 7

21 Paracetamol 93 7

22 Morphine 0 0

23 Ferrous salt 21 14

24 Vitamin A 7 7

25 Oral rehydration solution (ORS) 14 21

26 Zinc sulfate 7 21

Local manufacturers have the capacity to produce medicines that contain 20 out of the 26 APIs.


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Figures 2a and 2b: Companies with capacity to produce products containing APIs of the 26 target products

Figure 2a

Figure 2b


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5.2.3 Percentage of companies producing the required dosage form and/or strength of target products

No. Medicine Formulation Strength Companies producing required dosage

form but different strength

(%)

Companies producing required strength

but different dosage form (%)


and dosage form (%)

Companies planning to produce or

having capacity to produce the

required strength and

dosage form (%)

Suspension 125 mg/5 ml 0 0 21 7 1. Amoxicillin Dispersible tablet 250 mg dispersible tablet 0 7 0 7

Suspension 125 + 31.25 mg/5 ml 0 0 0 7 2. Amoxicillin/ clavulanic acid Dispersible tablet 250 mg + 125 mg 0 0 0 7

3. Benzylpenicillin Injection 600 mg = 1 million IU 0 0 0 0

4. Procaine penicillin Injection 1 gram = 1 million IU 0 0 0 0

5. Ceftriaxone Injection 500 mg vial 0 0 0 0

6. Chloramphenicol Injection 1 gram vial 0 0 0 0 7. Cotrimoxazole* Dispersible tablet 100 mg + 20mg 0 0 0 7 8. Azithromycin Suspension 200 mg 0 0 0 14 9. Gentamicin Injection 10 mg/ml 0 0 0 0 10. Isoniazid Scored tablet 50 mg 0 0 0 7

11. Artesunate + amodiaquine

Tablet 50 mg + 153 mg or 200 mg (as hydrochloride)

7 0 14 7

12. Artemether + lumefantrine

Dispersible tablet 20 mg + 120 mg 0 21 7 7

13. Dihydroartemisinin + piperaquin

Dispersible tablet or suspension

0 0 0 14

14. Beclometasone Inhaler 100 mcg/dose 0 0 0 0

15. Salbutamol Inhaler 100 mcg/dose 0 0 0 0

16. Carbamazepine Suspension 100 mg/5 ml 0 0 0 7

Chewable tablet 100 mg 0 0 0 7

17. Phenobarbital Injection 200 mg/ml 0 0 0 0

Oral liquid 3 mg/ml 0 7 7 0

18. Phenytoin Suspension 25 or 30 mg/5 ml 0 0 0 7

Chewable tablet 50 mg 0 0 0 7

19. Diazepam Rectal solution 2.5 mg/ml 0 0 0 0

20. Ibuprofen Tablet 200 mg 7 21 7


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No. Medicine Formulation Strength Companies producing required dosage

form but different strength

(%)


but different dosage form (%)


and dosage form (%)

Companies planning to produce or

having capacity to produce the

required strength and

dosage form (%)

21. Paracetamol Suspension 120 mg/5 ml OR 125 mg/5 ml

0 0 64 21

22. Morphine Oral solution 10 mg/5 ml 0 0 0 0

Immediate release 10 mg 0 0 0 0

23. Ferrous salt Suspension 30 mg Fe/5 ml 21 0 0 14

24. Vitamin A Capsules 100,000 IU 0 0 0 7

Sachet To make 500 ml 0 0 14 21 25.

Oral rehydration solution (ORS) Sachet To make 1 litre 0 0 0 ?

26. Zinc sulfate Dispersible tablet 10 mg or 20 mg 0 7 0 21

* Of the respondents surveyed, 36% produce Cotrimoxazole 200 +40 mg/5 ml suspension and 29% have the capacity or are planning to produce it. It is also in the Ghana Essential Medicines List.


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5.2.4 List of the 26 targeted products that are produced locally or for which there is the capacity to produce in the required dosage form and strength

No. Medicine Formulation Strength Produced locally

Total qty produced by respondents in 2009

There is capacity to produce locally

Suspension 125 mg/5 ml √ 1 202 778 x 100 ml 1 Amoxicillin Dispersible tablet 250 mg dispersible

tablet √

Suspension 125 + 31.25 mg/5 ml √ 2 Amoxicillin/ clavulanic acid Dispersible tablet 250 mg + 125 mg √

Dispersible tablet 100 mg + 20 mg √ 3 Cotrimoxazole Suspension* 200 mg + 50 mg/5ml √ 1 346 651 x 100 ml

4 Azithromycin Suspension 200 mg √ 5 Isoniazid Scored tablet 50 mg √

6 Artesunate + amodiaquine

Tablet 50 mg + 153 mg or 200 mg (as hydrochloride)

√ 5 341 460 tablets

7 Artemether + lumefantrine

Dispersible tablet 20 mg + 120 mg √

8 Dihydroartemisinin + piperaquine

Dispersible tablet or suspension

√

Suspension 100 mg/5 ml √ 9 Carbamazepine Chewable tablet 100 mg √

10 Phenobarbital Oral liquid 3 mg/ml √ 500 units


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No. Medicine Formulation Strength Produced

locally Total qty produced by respondents in 2009

There is capacity to produce locally

Suspension 25 or 30 mg/5 ml √ Chewable tablet 50 mg √ Tablet 200 mg √ 1 0 776 600 tablets Suspension 120 mg/5 ml OR √ 4 857 185 x 100 ml 125 mg/5 ml 4600 x 125 ml 125 mg/5 ml 945 x 4 L Suspension 30 mg Fe/5 ml √ Capsules 100,000 IU √ Sachet To make 500 ml √ 4 234 240 sachets

11 Phenytoin

Dispersible tablet 10 mg or 20 mg √ 12 Ibuprofen Tablet 200 mg √ 1 0 776 600 tablets 13 Paracetamol Suspension 120 mg/5 ml OR √ 4 857 185 x 100 ml 125 mg/5 ml 4600 x 125 ml 945 x 4 L

14 Ferrous salt Suspension 30 mg Fe/5 ml √ 15 Vitamin A Capsules 100,000 IU √ 16 Oral rehydration

solution (ORS) Sachet To make 500 ml √ 4 234 240 sachets

17 Zinc sulfate Dispersible tablet 10 mg or 20 mg √


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Of the targeted child‐specific essential medicines, 27% are produced locally in the required dosage form and strength; there is local capacity to produce a further 38%. In total, there is the potential to locally produce 65% of the targeted child‐specific essential medicines. With regard to the production of inhalers, injections, and rectal solutions, none of the respondents have local production capacity.

5.3 Sourcing of raw materials for major products

With regard to their sources for raw materials, 29% of respondents did not provide any information. Fifty per cent have available drug master files (DMFs), while 21% have made a request to their suppliers but have not yet received the DMFs. For those that provided information with regard to the sourcing of raw materials, about 50% of manufacturers’ raw materials came from brokers and not the original manufacturers; the other 50% was from manufacturers. Sixty per cent of these raw materials came from India, 18% from Europe (mainly the United Kingdom of Great Britain and Northern Ireland and the Federal Republic of Germany), 14% from the People’s Republic of China, and 7% from the United States of America.

5.4 Requirements to enable production of additional/alternative paediatric dosage forms

The following requirements to enable production of additional or alternative paediatric dosage forms were generally indicated by respondents:

I. Facility modification and installation of air handling units and dehumidifiers

II. Acquisition of extra equipment

a. Production equipment

i. Suppository machines

ii. Powder‐filling machines

iii. Oral liquid lines

iv. Upgrading water treatment facilities

v. Alu‐Alu blister machines for dispersible tablets packaging

vi. Micronisers

vii. Fluidised bed dryers

viii. Rapid mixer granulators

b. Laboratory equipment

i. Stability chambers

ii. Microbiology laboratory setup

iii. Analytical equipment (i.e. IR, UV/visible spectrophotometers, and high‐performance liquid chromatography [HPLC])


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III. Reformulation of some of the products into dispersible tablets or oral liquids and the redesigning of packaging materials.

IV. Technology and technical assistance

a. Technical assistance for WHO prequalification of paediatric medicines

b. Assistance with developing the capacity to formulate dispersible tablets

c. Taste‐masking technology

V. Additional human resources

a. Formulation chemists

b. Analytical chemists

c. R&D pharmacists

d. Production pharmacists

e. Microbiologists

f. Engineers

6. DISCUSSION AND CONCLUSIONS

6.1 Discussion

In the following section, issues were identified and categorized as follows.

6.1.1 Local capacity can be expanded to enhance production of child-specific medicines

Local capacity to produce child‐specific medicines can be expanded. The following steps are needed to increase production: Established local capacity: Most pharmaceutical manufacturing capacity dates back to the 1960s and is used to carry out secondary production. Currently, primary manufacturing capacity is emerging. Facility improvements: Companies have been active in modifying or expanding their facilities to keep up with changing trends. Some have obtained support from external agencies to engage engineering expertise to redesign their facilities in an effort to improve their cGMP compliance. Most companies that produce beta‐lactams have dedicated facilities for this purpose in accordance with cGMP trends. Ownership: The fact that the industry is mainly owned by local entrepreneurs could be beneficial in motivating them to support the national health‐care agenda. Exports: The industry has a relatively diversified market with export potential.


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cGMP: Some companies have sought to comply with international cGMP standards (e.g. US Food and Drug Administration standards) and also participate in the WHO Prequalification Programme. There is also an indication that the industry is subject to a more comprehensive regulation than previously. In addition to medicines regulation, companies must also comply with safety, health and environment (SHE) regulations. R&D: A fairly high percentage of respondents (57%) have in‐house R&D mainly in the area of pharmaceutical formulation development. A small percentage are involved in relatively advanced research, such as novel antibiotic discovery (in collaboration with a university), API process development and Phase IV b clinical studies. Raw materials: Efforts are made by respondents to obtain their raw materials from authentic sources with some 50% obtaining DMFs for their major starting materials. Child‐specific medicines: The respondents produce or have the capacity to produce medicines in almost all of the therapeutic categories for targeted child‐specific medicines with the exception of opiods and non‐penicillin beta‐lactams. They also produce or have capacity to produce medicines containing 20 out of the 26 APIs with regard to the targeted child‐specific medicines. Of the targeted child‐specific medicines, 27% are produced locally in the required dosage form and strength. There is local capacity to produce a further 38%. In total, there is the potential to produce 65% of targeted child‐specific medicines locally.

6.1.2 Obstacles to the enhancement of local production capacity for child-specific medicines

The following represent known obstacles to enhancing local production capacity for child‐specific medicines: Beta‐lactam facilities: Only a few manufacturers produce beta‐lactams, together with other medicines, in the same facility. Regulations: The Food and Drug Board (FDB) is not considered to be a stringent drug regulator, because it does not belong to the Pharmaceutical Inspection Convention Scheme (PICS) or the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and, due to inadequate capacity, the FBD is also unable to fully enforce compliance with WHO‐cGMP. Investment in R&D: There is inadequate investment by local manufacturers in R&D. Based on the survey, it appears not many companies allocate funds in their budgets for R&D. Lack of capacity to produce certain dosage forms: There is limited or no capacity locally to produce dosage forms such as injections and inhalers. Raw material procurement: Fifty percent of raw materials are procured through brokers, making it difficult to authenticate their original source as well as guarantee quality.


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6.1.3 Requirements that will enable manufacturers to enhance production of child-specific medicines

The following requirements will need to be met in order for manufacturers to enhance their ability to produce child‐specific medicines: • Modification of some facilities.

• Acquisition of extra equipment for both production and laboratory analysis.

• Reformulation of some products into appropriate child‐friendly dosage forms.

• Technical assistance for WHO prequalification and development of child‐specific dosage forms.

• Additional human resources in R&D, formulation, laboratory analysis, microbiology, and engineering.

6.2 Conclusions

Based on this analysis, there is domestic capacity to produce a high percentage of child‐specific medicines. The current level of production of these medicines in the required strength and dosage forms is relatively low, about 27%. Constraints with regard to some facility and equipment inadequacies, regulatory and international cGMP compliance, low investment in R&D, limited capacity to produce some child‐friendly dosage forms, and procurement of raw materials from reliable sources pose challenges that need to be addressed to enhance domestic production of child‐specific medicines.

7. RECOMMENDATIONS

The following recommendations are being made for the consideration of the stakeholders of the BMC project, policy‐makers, and members of PMAG in an effort to enhance access to child‐specific medicines. 1. Recognition of the strategic importance of local pharmaceutical manufacturers in helping

Ghana to achieve its national health‐care agenda, including access to child‐specific medicines. 2. The need for a public‐private partnership approach in supporting local manufacturers to:

a) obtain technical assistance for capacity building in the development of child‐friendly formulations and dosage forms and capacity towards cGMP compliance.

b) engage the necessary expertise to redesign some of their facilities for improved cGMP compliance.

c) comply with international cGMPs and attain WHO prequalification for products used in the treatment of priority endemic diseases.


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3. Explore the opportunity for pooled procurement by local manufacturers in order to benefit from economies of scale and possibly enhance the capacity to source quality raw material from credible suppliers.

4. Guarantee a certain level of market access to local manufacturers for a specified period on

condition that there will be a reciprocal improvement in product quality, cGMP compliance and cost reduction.

BIBLIOGRAPHY

Ghana Essential Medicines List, Edition 5. Accra, Ministry of Health, 2004. Ghana National Malaria Policy. Accra, Ministry of Health, 2009. Grupper M, Boateng F, Amporful E Binka J. Improving Access to Medicines: The Case of Local Production and Greater Access to Medicines for Ghana. London, UK Department for International Development (DFID), Health Systems Resource Centre, 2005. Harper J. The Viability of Pharmaceutical Manufacturing in Ghana to Address Priority Endemic Diseases in the West Africa Sub‐region. Eschborn, Germany, Deutsche Gesellschaft für Technische Zusammenarbeit (GTZ) GmbH, 2007. Inauguration of the Better Medicines for Children Project in Ghana: Meeting the Millennium Development Goals – The Case for Better Medicines for Children. Report. Accra, Ministry of Health and the World Health Organization, April 2010. Model List of Essential Medicines for Children, 2nd List (updated). Geneva, World Health Organization, March 2010.


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Annex I: Target medicines for paediatric use

Therapeutic category (ATC level 3)

Medicine Formulation

Suspension 27. Amoxicillin

Dispersible tablet

28. Amoxicillin/clavulanic acid Suspension

29. Benzylpenicillin Injection

Beta-lactam antibacterials, pencillin

30. Procaine penicillin Injection

Other beta-lactam antibacterials 31. Ceftriaxone Injection

32. Chloramphenicol Injection

33. Cotrimoxazole Dispersible tablet

34. Azithromycin Suspension

Other antibacterials

35. Gentamicin Injection

Drugs for treatment of tuberculosis

36. Isoniazid Scored tablet

37. Artesunate + amodiaquine Tablet

38. Artemether + lumefantrine Dispersible tablet

Antimalarials*

39. Dihydroartemisinin + piperaquine Dispersible tablet or suspension

Inhalants for obstructive airway disease

40. Beclometasone Inhaler

Adrenergics, inhalants (drugs for obstructive airway disease)

41. Salbutamol Inhaler

Antiepileptics 42. Carbamazepine Suspension 100 mg/5 ml

Chewable tablet 100 mg

43. Phenobarbital Injection 200 mg/ml

Oral liquid 3 mg/ml

44. Phenytoin Suspension 25 or 30 mg/5 ml

Chewable tablet 50 mg

Psycholeptics, Anxiolytics 45. Diazepam Rectal solution 2.5 mg/ml

Anti-inflammatory, non-steroidals

46. Ibuprofen Tablet 200 mg

Other analgesics and antipyretics 47. Paracetamol Suspension 120 mg/5 ml OR 125mg/5 ml

Opioids 48. Morphine Oral solution 10 mg/5 ml

Immediate release tablet 10 mg

Iron preparations 49. Ferrous salt Suspension 30 mg Fe/5 ml

Vitamin A and D, incl. combinations of the two

50. Vitamin A Capsules 100,000 IU

Electrolytes with carbohydrates 51. Oral rehydration solution (ORS) Sachet to make 500 ml

Sachet to make 1 litre

Treatment of diarrhoea 52. Zinc sulfate Dispersible tablet 10 mg or 20 mg

* Artesunate + mefloquine tablet 50mg + 250 mg (as hydrochloride) and artesunate +

sulfadoxine/pyrimethamine (SP) tablet 50mg + (500 mg + 25 mg) were included in the original list for antimalarials, but these are not recommended by the Ghana National Malaria Policy.


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Annex II: List of 22 local pharmaceutical manufacturing companies

No. Company Location Contact Person(s) Tel. E-mail

1. Amponsah Efah Pharma Ltd. Plot 2, Kobi ST Fumesua, Kumasi Mr. K. Amponsah Efah 020 8188977 [email protected] [email protected]/[email protected]

2. Ayrton Drugs H/No B 1/24, Tesano, Abeka Road, Accra Mr. Daniel A. Appiah 024 4026397 020 8164052

[email protected]

3. Danadams Ltd 67 Nungua Link, Spintex Rd. Baastonaa Accra Dr. Yaw Gyamfi/ Mrs.Neimatu Adjabui/ Nana Yaw Bamfo

020 8110885 0242379412 0208129137

[email protected] [email protected], [email protected]

4. Dannex ltd. 5 Dadeban Rd. North Industrial Area Mr Daniel Gordon 024 4096753 [email protected] [email protected]

5. Ernest Chemist TDC 658, 44/16 Community 17, Light Industrial Area, Tema

Mr. Mark Owiredu 024 6157612 [email protected]

6. Eskay Therapeutics 42 South Industrial Area, Accra Mr. G.G. Rao 024 4372245 [email protected] [email protected]; [email protected]

7. Geo Medicore Ltd Medie, Accra-Nsawam Rd Mr. Mulei/Mr. George Ofori Asare

027 3184685 024 4364713

[email protected]

8. Golden Tower Off Palace Link North Industrial Area, North Kaneshie Accra

Alhaji Mohamed Abubakar Baba

0208131644 [email protected]

9. GR Industries 'Plot 74, South Industrial Area, Fadama Road, Accra Mr. Dennis Agbotse 0244 793227 [email protected]

10. Kama Industries 'No. 8 Light Industrial Estate, Labone Junction, Ring Road, Accra

Nana Kofi Asiedu Appiah 024 4760653 [email protected]

11. Kanbros Chemical Industries H/No. C659/26 East Legon, Accra Mr. Kwame Kankam 0277554081 [email protected]

12. Kinapharma Ltd. Off Palace Link North Industrial Area, North Kaneshie Mr. Jonas Amponsa Asamoah

0243472110 [email protected]

13. LaGray Chemical Company Accra-Kumasi Road Opp. Nsawam Cannery, Nsawam Dr. Paul Lartey 0202010121 [email protected]

14. Letap Pharma Plot 107, South Industrial Area, Graphic Road Mr. Rama Rao Tantravahi

0302 224613 [email protected] [email protected]

15. M & G Pharma Ltd. D446/1 Bannerman Rd James Town, Accra Mr. Gopal Vaso 024 4353637 [email protected]

16. Midland Pharmaceuticals 78, Ansah Nunoo Road, Mamprobi Mr. John Arthur 0244685223 [email protected]

17. Pam Pharma Plot No.5, Sector 2, Block A, Nsawam Mr I. Lamptey 02448866658 [email protected]

18. Perfect Pharmaceuticals Limited

Spintex Road, Behind Coca-Cola Mr. Emmanuel Agyeman 0302 816004/ 0289520391

[email protected]

19. Pharma Nova Ltd. No. 1 Okodan Street, Off Accra-Osu-La Road Mr. D. Tripathi/James Awuku-Darko

0242107000 020 8173624

[email protected] [email protected] [email protected]

20. Phyto-Riker Pharma Mile 7 Dome Accra-Nsawam Rd Nana Adjoa Turkson 020 2017915 [email protected]

21. Starwin Ltd. Plot 16, South Industrial Area, Ring Road West, Accra Mr. Kwame Asante 024 380 1632 [email protected] 22. Unichem 17 Dadeban Road, North Industrial Area, Accra, Ghana Dr. Sam Gaizer 0202781025 [email protected]


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Annex III: Better Medicines for Children Project – Domestic production of essential medicines in paediatric dosage forms

Data Collection Form (Complete one form for each manufacturer) PART 1: Background information on manufacturer Name of manufacturer: ___________________

Address: ___________________

Contact person who provided information: ___________________

Phone: ___________________

Email: ___________________

Address(es) of manufacturing site(s), if different from above:

Date company was founded/established:

Year manufacturing site was built and any modifications (please specify):

Ownership structure (private, state, public, mix):

If the company is owned by another company or belongs to a group of companies, please indicate your position within the structure (and % of foreign ownership): Does your company undertake contract manufacture for other companies: Yes No Do you sub-contract to other companies: Yes No If yes, please list products and/or services:


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What was the company's total market value last year (specify currency)?

Who are the company's main purchasers (tick all that apply and provide approximate breakdown of products procured by purchaser):

Domestic:

Government: ___%

International donors: ___%

Private sector: ___%

Other (e.g. NGOs, please specify): ___%

Export: ___%

What are the company's key production activities (primary, secondary, tertiary* OR compression, packaging, etc.): (* Primary production - manufacture of active pharmaceutical ingredients (APIs) and intermediates; secondary production - finished dosage forms; tertiary production - packaging and labelling of products). How many people are employed in the company? Total: In production: ___________________

In quality control: ___________________

Do you have any in-house research and development capacity? Yes No If yes, please indicate the type of activities and annual investment:

Indicate the GMP standards (WHO, PIC/EU, FDA or other) with which the company complies:

Date of last inspection by the National Regulatory Authority: ___________________ Name authorities other than the NRA who have inspected the company:

Are you currently receiving technical/financial support from external agencies, e.g. upgrading quality certifications, technology transfer agreements; major business partnerships? Yes No If yes, please describe (including type of support and current status):


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PART 2: Products manufactured and their starting materials Do you currently manufacture the following products in either paediatric or adult formulations: Important: complete a separate row for each product with its own strength and dosage form (e.g. amoxicillin 250 mg cap/tab, 500 mg cap/tab, 125 mg/5 ml suspension, etc.)

1. Product 2. Currently manufacturing? YES/NO (If yes please complete the columns to the right. Use a separate row for each product.)

3. Planning to

manufacture if YES please

complete column 4

4. Strength

5. Dosage

form

6. Product or brand/

trade name

7. Finished product specifications:

1. British Pharmacopoeia (BP) 2. United States Pharmacopeia (USP) 3. European Pharmacopoeia (PhEur) 4. International Pharmacopoeia 5. Other - specify (e.g. "in-house")

8. Number of units

produced last year

9. Licensing status:

1. Registered and currently marketed 2. Registered but not marketed 3. Registered for export only 4. Not registered

10. List any other

countries where

product is currently registered

and marketed

Amoxicillin Amoxicillin/clavulanic acid Benzylpenicillin Ceftriaxone Procaine benzylpenicillin Any other beta-lactam antibacterials

Chloramphenicol Co-trimoxazole Gentamicin Any other antibacterial Paracetamol Any other analgesic Ibuprofen Any other NSAID Artemether + lumefantrine

Artesunate + amodiaquine Artesunate + mefloquine Artesunate + sulfadoxine/ pyrimethamine (SP)

Any other antimalarial


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1. Product 2. Currently manufacturing? YES/NO (If yes please complete the columns to the right. Use a separate row for each product.)

3. Planning to

manufacture if YES please

complete column 4

4. Strength

5. Dosage

form

6. Product or brand/

trade name

7. Finished product specifications:

1. British Pharmacopoeia (BP) 2. United States Pharmacopeia (USP) 3. European Pharmacopoeia (PhEur) 4. International Pharmacopoeia 5. Other - specify (e.g. "in-house")

8. Number of units

produced last year

9. Licensing status:

1. Registered and currently marketed 2. Registered but not marketed 3. Registered for export only 4. Not registered

10. List any other

countries where

product is currently registered

and marketed

Isoniazid Any other tuberculosis drugs

Phenobarbital Phenytoin Carbamazepine Diazepam Any other antiepileptic Morphine Any other opioid Salbutamol Beclometasone Any other antiasthmatic Oral rehydration solution Vitamin A Ferrous salt Zinc sulfate


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If your company is manufacturing penicillins or other beta-lactam products, does this production take place in a separate building provided with its own air-handling system?

Yes No Not manufacturing beta-lactam products. Are there any additional products that you are licensed to produce but are not producing? If yes, please list and explain reasons for not producing (e.g. lack of raw materials, supply chain problems, no sterile manufacturing capacity, lack of trained staff, change in recommended treatment):

Product Comment

Indicate approved starting materials' sources for the company's major products listed above:

Starting material

Are approved Drug Master Files (DMF) or Certificate of Suitability to the Monographs of

European Pharmacopoeia (CEP) available? YES/NO


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PART 3: Potential to produce additional/alternative paediatric dosage forms What, if any, additional technical requirements would be needed to add/change current production to include additional paediatric formulations and dosage forms (dispersible tables, oral dispersible tablets, suspensions and injections? For example, human resources ‐ number and skills, equipment purchase and maintenance, special storage requirements, etc. More specifically, what would be required to:

• change production from a tablet to a dispersible tablet or oral dispersible tablet (same medicine)?

• change production from a suspension of one medicine to a suspension of a different medicine?

• change production from an injection of one medicine to an injection of a different medicine?

• package and label an existing product as a paediatric product?

What additional equipment will you need in order to add paediatric medicines to your product line?

Equipment Utility

What additional technologies or technical assistance will you need to add paediatric medicines to your product line?

Technology/technical assistance Comment

What additional personnel/human resources will you need in order to add paediatric medicines to your product line?

Personnel Number Skills/education/experience

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