Issues with GMP implementation in Nepal
a)
Rules are subject to local discretion and regulatory capacity and not updated in line with WHO standards
The rules and standards themselves are subject to a great deal of local discretion and interpretation and this in itself depends on the role of the enforcers and the staff who are employed.
Senior DDA officials told us they have developed regulations in the following areas: Drug registration regulations, Drug standard regulations, Drug Inquiry and Inspection Regulation and Drug manufacturing code.
Drug manufacturing code of 1984 is written in Nepali and published along with the WHO GMP code of practice (in English). Despite the WHO revising their GMP codes in 1998 and 2003, this part has not been updated in the DDA’s publication. We were told by a senior drug administrator that the DDA is in the process of publishing a new code as the 1984 DDA code does not explain certain things clearly; for example, it is written in the code that “fresh air” is necessary while producing drugs but it does not explain what is meant by this. When asked about overlap between the DDA code and WHO GMP code, he replied in vague terms, saying that most of the WHO GMP standards are incorporated in the DDA code (Interview, Senior Drug Administrator, DDA, June 2007).
From the 1990s the DDA made the upgrading of facilities to WHO GMP standards mandatory. The deadline was set for April 2007, but by the end of the data collection period in 2008 only eight companies had managed this. The then director of the DDA described that the WHO GMP certification for Nepali companies remained “optional”, with the DDA’s own Code on Manufacturing of Drugs the only legally binding requirement. As of 2013 26 of the 58 Nepali companies were compliant with the WHO GMP (personal communication, 2013).
GMP certification was described by the DDA as necessary only for export [
43], although the WHO does inspect for drugs and products linked to their “own purposes” (for example vaccination programmes, TB drugs for DOTS, and ARVs). The WHO role is mainly indirect, through the DDA. While the Association of Pharmaceutical Producers of Nepal (APPON) are supposed to be assisting with this process, and doing trainings around GMP they are deemed by many to be of little help (as one company director stated: “they take our money and drink whisky”!). During the fieldwork period, they had a volunteer pharmacist from Japan helping them with this process of developing guidelines and trainings. APPON was more involved in lobbying for dollar rates for imports from India and for non-tariff barriers such as labelling of all foreign imports in Nepali.
b)
GMP training and capacity
The Director of the DDA described the GMP certification process as part of the Essential Drugs and Medicines Programme. The DDA conducted the initial training in country, with support from the WHO which is “technical and financial”. However, the difficulties they face in implementing the GMP process were described to us as three fold. Firstly, regulatory capacity relating to the staff issues and their lack of expertise; this is not only DDA staffing problems (they had only five staff members who checked that rules were being followed), but the lack of expertise in the company staff. While there are increasing numbers of graduates now coming out of the universities, to date they have little experience. Pharmacy is a relatively new discipline in Nepal (Kathmandu University started their Pharmacist training course in 1994; the Institute of Medicine set up their School of Pharmaceutical and Biomedical Sciences in 1997; Pokhara University started in 2000; and Purbanchal University in 2005). By March 2014 there were 1400 pharmacy graduates registered with Nepal Pharmacy Council (personal communication) while the DDA register, in addition to the existing quality control laboratories and producers, reported 1688 wholesalers and 8800 retailers of allopathic medicines [
44].
Secondly there are difficulties with understanding the concept. Some manufacturers say that they already sell well, so why do they need GMP? They have a “market perspective”, and as their drugs pass their own tests, why do they need it? They complain about the investments required for upgrading when they see little benefit. Thirdly, the GMP concepts themselves are changing and becoming more stringent.
c)
Regulatory requirements and associated costs
An interview with a senior member of the of the quality control division of Nepal Drug Limited, the state run pharmaceutical company, which was struggling to remain in competition with the new private companies, reveals the issues they face with GMP (Interview notes, May 2007). He stated that they did not have the infrastructure to fulfil GMP standards; that the laboratory was not well equipped; there was not enough physical space; human resources were inadequate; there was no R&D budget; little administrative support; and that the location of the factory was wrong, due to the poor air quality in Kathmandu.
“If we have to go to GMP, we need the budget to improve some of the existing facilities, update them, and establish a new department to fulfil the requirement of WHO-GMP…. We have been discussing to hire consultants from outside to do feasibility study for focusing on IV Fluid (saline) WHO-GMP certificate”.
One group of senior management workers for one of the GMP certified companies described the sheer production of paperwork required for monitoring as overwhelming, besides the prohibitive costs. In addition, the director of one of Nepal’s largest pharmaceutical companies said that initially their production dropped after implementing GMP standards. They used to have “quality control”, but now this has shifted to “quality assurance” with greater stringency. This shift was described to us by another company’s senior manager as follows:
“Quality control is not in common use now. We call it quality assurance. Before while checking quality, they used to check at the end. But now they say that if we check it right from the beginning then quality is assured right from the beginning. The quality of excipient, whether the raw material is mixed properly or not, whether it is weighed properly or not, coating, punching, if everything is done properly, all this is checked. This is called SOP (Standard Operating Procedure)” (Interview, Kathmandu, April 2007).
One of the larger more established pharmaceutical companies had recently upgraded to GMP certification standards. The director of the company told us that the initial cost outlay had been 4 crore rupees (That is 40 million rupees, or a little over £300,000 at 2007 exchange rates). This had spun them from a profit making business into one with large debts. An ex-employee of Royal Drugs Nepal, stated that there was no way that this company could afford to upgrade to GMP standards. One particular complaint was that despite this initial outlay, the Nepal market was small and it would be difficult to recoup costs (the size of the Nepal market is stated to us a particular difficulty for Nepal to develop its own injectables; the market is just too small). Not one person we interviewed in the business thought of export as a possibility, and all were concentrating on the Nepal market.
A senior pharmacology professor referred to the problem in Nepal as one of quality versus cost. He referred to amoxicillin, which is now produced by nearly all the Nepali companies. It costs around 4–5 rupees, but if you find it for less than this then in his opinion the quality must be compromised. He reckoned that the then director at the DDA was good at his job, and working hard at trying to keep prices low while maintaining quality; he was working at trying to get GMP certification implemented. It was difficult, he said, as smaller companies used to send “goondas” around to him to ask why GMP was being put into place, claiming that it was driving up their costs and the prices of affordable medicines.
We were further told that the concepts themselves have changed a lot. An employee at one company explained to us how they had shifted to the AHU (air handling units) which are stricter, and of the use of “reverse osmosis” having replaced “demineralisers” for the water they use. The costs to run these new units had increased as well, and the size of the backup generators required to keep manufacturing standards up with the regular power cuts have increased. This was a particular problem in Kathmandu where during the time of the research power cuts of up to sixteen hours a day were frequent.
The GMP process was described to us by senior staff at one company where we were shown around the production site, and they bemoaned the sheer volume of recording necessary at every level of production. GMP certification considers many elements: the premises; personnel; quality control; production; sanitation and hygiene and finally, documentation. As they phrased it all the GMP process “should be done per documentation and documented”. Each and every activity is prescribed in detail through Standard Operating Procedures (SOPs), which are strategically displayed in Nepali and English throughout the site. The DDA was described as responsible for the guidelines that are set up for this end, and then responsible for their implantation (Interview, Kathmandu, April 2007).
d)
Impact on local industry and market
Less than half of currently operating companies achieved the WHO-GMP certification, perhaps due to the rise in costs. Stricter measures taken in the case of imported products have resulted in some Indian companies being unable to import their products, and their products not being re-registered by the DDA (Interview, wholesaler, April 2007). The producer of “strepsils” (BOOTS) entered into a contract with a Nepali company to make this in Nepal, but because the company does not have GMP certification Strepsils are no longer available on the Nepal market.
Aid conditionalities and GMP
Although health expenditure from the general government has been steadily increasing the foreign aid remains a significant source of health care financing in Nepal (19 % of total health expenditure in 2008/09). The dependence is more pronounced in certain areas such as safe motherhood, immunisation, family health and planning, TB and leprosy control and STDs [
45].
Government regulation currently states that any tender for the government procurement of drugs must be accompanied by the appropriate paperwork, which includes GMP certification. Despite the old state run Nepal Drugs (ND) not having GMP certification, contracts for public procurement are awarded as a priority to ND.
In the 1990’s ND was formulating rifampicin and supplying the National Tuberculosis Programme with about 1.1 million capsules annually (Interview, ND, February 2007). This was prior to the development of the WHO prequalification and the GDF), through which Nepal and other developing countries are currently supplied anti-TB drugs paid for by the Global Fund and other donors. After several years ND lost the contract and although it was not possible to ascertain the key reasons it was suggested that change in management and bribery caused the loss of contract (Interview, ND, February 2007). In addition, donors and conditions for international procurement of medicines changed. Currently, even with the capacity, ND would not be able to supply rifampicin to the national programme without WHO prequalification or other international GMP certificate.
During an interview with a senior advisor to the Ministry of Health and Population, we were told that the J-Vaccine (for Japanese Encephalitis) for Nepal was paid for by Japan and procured by the Nepal government from a company in China. The Chinese company was not GMP certified but the Japan government was happy with the quality and willing to give money. In 2007 the money for the vaccine was no longer given directly to Nepal but to UNICEF. Since the WHO, and other UN agencies, cannot procure any drugs without GMP certification the Chinese company, which had not applied for GMP by then, could not supply the product.
In 2005 MoHP launched a zinc programme in the public health sector procuring zinc from Nutriset in France. Local producers were also interested in supplying zinc. The POUNZ project introducing the zinc programme in the private sector assisted three local manufacturers with achieving the GMP audit and the three producers started supplying zinc in 2009. This would not be possible without the government commitment to this large scale programme and technical assistance offered by POUNZ. MoHP is planning to change procurement to the local suppliers who continued working with US Pharmacopeia representatives towards WHO prequalification with the view of reaching to international markets [
46,
47]. As of May 2015 no Nepali manufacturer has achieved WHO prequalification [
34].
These examples show some of the issues that arise from GMP certification in a heavily aid dependent state like Nepal.
Getting around registration: drugs and therapeutics committees?
Some (private) hospitals have established Drugs and Therapeutics Committees (DTCs) to get around market registration. One private hospital director explained that their committee – established in February 2006 - allows them to procure from any part of the world, even if that drug is not licensed in Nepal with the DDA. He explained that the DTC formation has been encouraged by the DDA who “don’t have physicians”, although the government says what the makeup of the committee should be. The DTC then can “import” medicines not registered, for example important drugs for their hospital cardiac medicines (the hospital specialised initially in cardiology – and has expanded from that). They have to produce “documents” – studies and outcomes from these drugs. Thus they are able to provide data for later registration.
A communication in the Kathmandu University Medical Journal suggested that these committees have a supportive function for the DDA:
“In developing countries like Nepal, where the pharmacovigilance programs are in its primitive stage, the DTC has immense responsibility in ensuring drug safety. This committee can also act as an advisory committee to the policy makers and drug regulatory authority of Nepal for drug safety matters based on their experiences” [
48].
GMP and export
By 2012 no Nepali company had yet exported any pharmaceutical product [
38]. However, GMP certification is also required for Ayurvedic products. Shakya documents the experience of a Nepali Ayurvedic company (Gorkha Ayurved Co.) with exporting medicinal herbs. The company had no idea that GMP certification was necessary (or that buyers could also ask for other internationally harmonised standard of Sanitary and Phytosanitary Measures (SPS). When the company set about the process of heading towards GMP certification, they found the RDRL (and the Department for Food Technology and Quality Control) “without any plan of policy regarding SPS standards, including GMP certification procedures”, particularly for Ayurvedic products [
49]. Shakya is critical that the DDA had not prepared itself for accreditation processes, nor determined the basic mechanisms that companies should take. Businesses were pretty much on their own, suggested the author, with the company having huge outlays, including hiring a foreign expert to assist in the process.
It seems apparent that one consequence of attempting to harmonise its regulatory capacity will be a greater dependence on foreign assistance (both technical and financial) for this process.