Out of Africa: the pharma challenge
Pharmaceutical Technology Europe
Manufacturing facilities must be inspected by members of regulatory bodies. However… these bodies are woefully inadequate at performing the task.
Traditionally, African countries have imported drugs from countries where the prices are cheaper, such as India and China. However, the tightening of regulatory and patent laws in these countries means this source will no longer be an option. Coupled with the escalation in the number of people suffering from tuberculosis, malaria and HIV, the local manufacture of cheap, essential medicines that are independent of supplies from overseas pharmaceutical companies is imperative.
Pharmaceutical companies operating in countries such as South Africa, Uganda, Tanzania, the Democratic Republic of Congo and Ethiopia are investing in new or upgraded facilities that can manufacture these drugs. Some African companies have been granted licences from large multinationals to manufacture specific drugs, but these local companies have to ensure their facilities comply with both local and international standards. This has led to a dramatic advance in regulatory requirements for African pharmaceutical manufacturing facilities. Previously, there was neither official nor locally developed standards, but now the general trend is to adopt international principles, such as those of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S), World Health Organization (WHO) or the EU.
During 2007, the African Union drafted the Pharmaceutical Manufacturing Plan for Africa, but to implement this, several obstacles must be overcome:
- Technical expertise is a critical prerequisite, but to produce adequate numbers of graduates in biology, chemistry, biochemistry, and process and pharmaceutical engineering, a substantial investment in education is required.
- The legislative framework needs to be conducive to local drug production, which extends beyond legislation, ensuring good manufacturing practice (GMP), good clinical practice, good distribution practice and good laboratory practice. Legislation regarding the regulation of related duties and taxes on imported raw materials and intermediates, as well as internal procurement legislation and pricing policies, is likely to require amendment.
- Reliable, sustainable and reasonably priced electricity and water supplies, as well as other essential infrastructure, must be ensured. For example, a fully compliant facility in Zimbabwe, which was recently completed using donor funding, struggles to operate because of the inability of the government to supply sufficient electricity, diesel fuel and other essential supplies.
- Adequate funding must be located. While some companies manufacturing essential medicines such as antiretrovirals (ARVs) have been well-supported by donor funds, others that manufacture a variety of basic medicines struggle to raise the funding necessary to comply with required standards.
Digging deep
Engineers faced with the dilemma of designing facilities that must comply with global standards, without adequate funding, frequently 'dig deep' and exhibit a considerable amount of ingenuity. In most cases, upgrading old, noncompliant facilities results in compromises in layout, product flow, staff flow, air pressures and airflow. The engineer must devise acceptable layouts within the confines of the existing structure. Usually, companies have grown and expanded their facilities haphazardly into whatever space is available, which seldom results in logical staff and product flow. Rectifying such a layout without expensive radical changes makes the task of creating a GMP-compliant design far more difficult than planning a new facility.
Clients are frequently unfamiliar with the regulatory requirements and do not fully grasp some of the concepts of product and staff flow, and what packing materials, shippers and pallets are allowed in the different areas. For instance, once zones are segregated, such as primary and secondary packing areas, there is often a necessity for double handling of products. This includes moving materials from wooden pallets to GMP pallets; double-bagging bottles to avoid taking shippers into primary packing areas; and creating wipe-down airlocks for primary packing materials, as well as other activities. These tasks are time consuming and the manufacturer is usually resistant to changes that affect productivity, but these steps are mandatory to ensure GMP-compliant production.
Conflicting rules
Many local players in the African pharmaceutical industry are ignorant of the various regulatory standards or are faced with apparently conflicting requirements. For example, the South African National Medicines Regulatory Authority (SANMRA) guideline requires 20 air changes/h to achieve a Grade D condition, whereas the PIC/S GMP guideline stipulates that air changes should be related to the room configuration and function. Another example is in the permissible levels of 5 μm/m3 of air stipulated by the various guidelines, such as PIC/s, SANMRA, EU and WHO, for Grade A and B areas: PIC/S allows 1 particle/m3 , whereas the SANMRA states it should be zero. This discrepancy is also evident in other national medicines regulatory authorities (MRAs), and was a topic of discussion at the Global Regulatory GMP Conference in Prague (Czech Republic) in September 2005. Attending conferences of this nature in Europe and the US is costly because of the remote location of countries in sub-Saharan Africa, resulting in companies being unable to keep up with the changing trends. Therefore, a manufacturing facility that was considered to be state of the art 10 years ago is now no longer GMP-compliant. This demonstrates the importance of staying abreast of the constantly evolving standards.
Africa needs to find a way to balance its health and trade objectives with the manufacturers' need to make a profit. It is laudable to assume that the main objective of a country's health department is to improve access to affordable medicines, but the imposition of stringent quality standards on the factories comes at a price. A further obstacle that manufacturers in South Africa face is the government's imposed single pricing exit policy on pharmaceutical products, which has forced manufacturers to seriously consider the viability of continuing manufacturing. Ironically, there is currently a boom in the growth of the manufacturing industry in South Africa.
Manufacturing facilities must be inspected by members of regulatory bodies. However, as the recently released WHO document Medicines Regulatory Authorities: Current Status And The Way Forward shows, these bodies are woefully inadequate at performing the task. Surveys conducted in African countries highlight some of the problems encountered:
- 90% of MRAs lack the capacity to conduct medicines regulatory functions and, therefore, cannot guarantee the quality, efficacy and safety of medicines.
- 84% of MRAs have inadequately qualified staff. In addition, the staff lack the qualifications and experience needed to perform all MRA functions.
- External expertise is solicited in 58% of the cases.
- 42% of MRAs issue or renew licences for various practitioners without checking or referring to the records of inspection reports.
- 63% of MRAs are unable to evaluate new medicines because of inadequate resources. In the case of vaccines, 87% of MRAs are incapable of evaluating them.
Searching for solutions
Remedial steps are required and the WHO document emphasises the need to have clearly defined missions, training, funding, organizational structures, adequate documentation and resources.
In South Africa, the SANMRA is a member of PIC/S and has thoroughly trained their inspectors in all aspects of the industry. They are one of approximately 29 other member countries that benefit from operating with an international standard. Most national standards basically have the same intent: ensuring good quality pharmaceutical products, but the interpretation of these standards by inspectors often varies. The advantage of being a PIC/S member is that common training is provided, which should result in an uniform interpretation of guidelines. This should make life easier for the manufacturers too, as they will be graded on a common standard. When conducting an inspection, one often hears the manufacturer claiming regulatory bodies A and B have approved their facility, while regulatory body C finds fault All regulatory bodies have the same standards in their guidelines, but the application of these standards may differ from inspector to inspector. Adopting international standards would go far in alleviating this sort of problem, but inspectors' application of these standards would need to be harmonized. Different interpretations of standards frequently leave a lot to be desired, making the training of inspectors of paramount importance.
Local pharmaceutical manufacturers in South Africa must now comply with the PIC/S standard. In some cases, other international standards need to be considered for these companies to manufacture under license from large international players — especially if they intend to export to Europe and the US. Consequently, the industry in Southern Africa, and in Africa as a whole, is being pressured into raising standards.
Bodies such as WHO have undertaken to train pharmaceutical inspectors in developing countries, and have developed training guides and presentations that regulatory bodies can source and use in further training. The training includes:
- Modules on clean room criteria and standards.
- Environmental control systems (heating, ventilation and air conditioning (HVAC)).
- Building layout, facility finishes and materials.
- Water for pharmaceutical facilities and validation of these water generation systems.
African success
Donor funds are being channelled into African countries, such as South Africa, Nigeria and Uganda, to finance essential medical research, such as vaccines. Typical of this approach is the new quality control laboratories facility at Biovac in Cape Town (South Africa), where a partnership with an overseas company has made the project economically viable. This type of facility requires bio-safety laboratories (BSL) of varying levels to contain the pathogens. A new BSL 4 laboratory for research into haemorrhagic fevers is currently being erected in Johannesburg (South Africa). Strict validation procedures and documentation will be locally prepared.
Although Africa now has an increasing number of facilities of a very high standard, it is difficult to compare these with facilities in First World countries where funding is more readily accessible. However, certainly in South Africa, many of the upgraded facilities are comparable with international standards with regards to product flow, staff flow, air handling plant and building finishes. The cost of erecting these facilities in South Africa is significantly lower than in Europe and the US because of lower labour costs and the use of local rather than imported materials.
Africa's companies may still have a way to go, but their own cheaper medicines are on the horizon.
Bibliography
1. World Health Organization, Supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning (HVAC) systems for non-sterile pharmaceutical dosage forms (May 2005).
2. World Health Organization, Medicines regulatory authorities: Current status and the way forward (June 2006).
3. BBC News (June 2006).
4. WHO Expert Committee on Specifications for Pharmaceutical Preparations, Fortieth Report (World Health Organization, 2006).
5. Ministers Meeting of the Third Session of the African Union Conference of Ministers of Health, Draft: Pharmaceutical Manufacturing for Africa (April 2007).
6. Pharmaceutical Inspection Convention, Guide to Good Manufacturing Practices for Medicinal Products (2007)
7. SA Guide to GMP — Version MCC2003/1, (PMA, PO Box 12123, Vorna Valley, 1686, South Africa).
8. ISPE Global Regulatory GMP Conference, New Regulatory Initiatives and Achieving International Harmonisation (September 2005).
9. Eli Lily Pharmaceutical Company, News release (November 2006).
Deryck Smith is a registered consulting engineer, with 40 years' experience in ventilation and air conditioning. During the last 16 years, Deryck has been devoted exclusively to clean room technology. He has on occasion worked as a consultant for WHO, attending related meetings of experts in Geneva (Switzerland). Deryck has led training on their behalf for pharmaceutical inspectors from developing countries, and has assisted with inspections. In addition, he has assisted with the preparation of an HVAC Guide for pharmaceutical inspectors. He qualified as a mechanical engineer at the University of Pretoria (South Africa) and is a registered professional engineer with the Engineering Council of South Africa.
