Mumbai: Last week, Cyrina van den Dam, a management student from the Netherlands who is doing some research on rural marketing in India, landed in New Delhi on her first trip to the country. She spent a night at the airport waiting for a connection. She had a cold and a headache but couldn’t find the pack of Panadol without which she usually doesn’t leave home. So she went to the airport pharmacy.
“I was happy to get a strip of Crocin 500 mg, the paracetamol brand of the same company here in India, but I don’t know why it didn’t work as well as Panadol. Is it really different in quality?” she asks.
Turns out it may be.
Lack of stringent quality controls on contract manufacturers, significant regulatory limits on packaging costs that in turn have an effect on the quality of drugs, and big differences in Indian versus overseas profit margins mean that many drug companies have two-track approach to the same drugs. One that tends to apply different—read lower—standards for drugs sold to Indian consumers and the other for drugs that are exported.
“In India, there are issues such as poor stability of drug ingredients due to inconsistency in temperature control, use of inferior quality additives that is responsible for improper dissolution of tablet in the stomach, high percentage of impurities due to poor clean-air systems, etc, all of which ultimately results in poor quality of drugs,” says Dr C.J. Shishoo, a senior pharmacologist and a trustee of Consumer Education and Research Centre (CERC), an Ahmedabad-based customer action group. adds Shishoo.
Cyrina “may not be completely wrong in her observation.”
Panadol and Crocin are the paracetamol brands of the world’s leading drug maker GlaxoSmithKline Plc. that are marketed separately in Europe and India. While Panadol is manufactured at the company’s own plant at Ermington, in Sydney, Australia, in adherence to the European drug manufacturing standards, the Indian brand is made by the company’s contract manufacturer Remidex Pharma Pvt. Ltd at its facility in the outskirts of Bangalore, in adherence to the Indian drug manufacturing standards.
A spokesperson for GlaxoSmithKline Consumer Healthcare India Ltd says the formulations of Crocin and Panadol are essentially identical, though due to regulatory reasons they are tested as per the standards of the Indian Pharmacopoeia (IP) and the British Pharmacopoeia (BP), respectively.
“Despite the different pharmacopoeial references, the key parameters of efficacy and dissolution are identical for both pharmacopoeias. Other parameters in BP and IP differ marginally, but not significantly, in terms of impurity limits and identification tests,” he says. “Crocin is manufactured at Remidex... The standards followed at Remidex are based on GSK global quality policies which are followed at all manufacturing sites globally,” he adds.
Remidex declined comment.
A senior drug inspector at the Central Drugs Standard Control Organization, India’s central drug regulator, says many contract manufacturers for large Indian and multinational pharma companies do not have the kind of quality checks they should, simply because “Indian law does not demand many such essential standards”.
The inspector, who didn’t want his name used, said multinationals that outsource manufacturing are often not very keen to insist that their vendor practise the same quality standards as prescribed by authorities in developed countries because profit “margins on drugs sold in India are comparatively low.”
According to Swati Piramal, director, Nicholas Piramal India Ltd, the country’s fourth largest drug maker, there is a clear quality difference in the drug packaging standards followed by companies for local and export markets.
“Inferior quality packaging, which the manufacturers are forced to use in India as there is a cap of 5% on packaging cost by the government, may often cause poor stability of drug ingredients,” she says.
That means that even if the drugs manufactured are of a certain quality, poor storage at most pharmacists results in patients getting products whose active ingredients may have lost efficacy.
“None of these issues are adequately addressed in the current drug regulatory law in India. Absence of regular inspections at the drug manufacturing sites and ill-equipped drug testing laboratories make things worse,” says another senior drug inspector who also didn’t want his name used.
C. Gulhati, editor of MIMS, a drug reference index for physicians, puts the blame squarely on the authorities. “Companies are getting their products manufactured at government-licensed units and that’s what the law requires of them,” says Dr. Gulhati. “The drug regulatory mechanism here is ineffective in checking double standards due to a host of reasons, including outdated law, inadequate as well as untrained staff at the regulatory departments, and political interference in the name of small scale industry and employment protection.”
Says one senior official at the drug regulator who also didn’t want to be named: “Out of the 6,000 (as per the latest statistics available in the R.A. Mashelkar committee report on pharmaceutical standards) licensed drug manufacturing units catering to local market, not even 1% maintain a regular quality assurance system while undertaking formulation development to check bio-availability (the absorption of drug in the human body), grade and quality of additives, which determines the dissolution pattern of the tablet, maximum stability period of drug ingredients (the shelf-life of the tablet or capsule).”
This is because India’s regulatory system does not have a drug master filing (DMF) system required in the US and Europe.
Under a drug master file, which is submitted by the manufacturer to the regulator while seeking permission for marketing, the manufacturer provides a fact-file of the drug. It contains the name of the drug, its safety and efficacy profile, raw material procurement details including the name and production location of the supplier, formulation process, reference standards, details of additives used, strength and bio-availability (the actual absorption of the drug in the patient’s blood stream), etc. A marketing permission is given by the developed world regulators, such as the US food and drug administration, after verifying the data submitted. Any change in the DMF, such as a different manufacturer or an altered ingredient, is only allowed with prior approval of the regulator.
India follows a two-tier drug regulatory structure with a central body—the CDSCO—approving drug imports, granting marketing approvals for new drugs, and clearing drug R&D and clinical trials in the country. A state-level drug administration then issues licences for drug manufacturing and trade (wholesale and retail) and is responsible for inspections as well.
“The central regulator, which needs at least 250 drug inspectors, is currently functioning with only 24. Though there is an already sanctioned vacancy of another 25, the posts are still lying vacant as the government is wary of increasing costs at this non-income generating department,” says the same senior CDSCO official.
The state food and drug administration departments are also facing similar problems as fresh recruitment have been frozen for several years. Gujarat, home to 1,200 manufacturing units, has only 16 drug inspectors against a minimum requirement of 42 for inspections at the manufacturing site, says a senior official of the food and drug control administration of Gujarat, who cannot be identified as he is not authorized to speak to the media.
A majority of these inspectors, too, are unaware of modern quality check or onsite inspection procedures.
The CDSCO, which was running a Drug Inspectors Training Scheme at its Mumbai zonal office till 2002, discontinued it citing financial reasons. The only institution which runs a training programme for drug inspectors in the country is National Institute of Pharmaceutical Education and Research (Niper) at Mohali in Punjab. But even there seats are limited.
CDSCO, which is also responsible for notifying drug manufacturing standards in the country, had in 2000 introduced revised good manufacturing practices (GMP) norms, which are in line with the drug manufacturing norms of the World Health Organization.
Manufacturing laws in the country fall under Schedule M of the Drugs & Cosmetics Act of India, 1959. However, with strong lobbying by the small-scale industry associations, the revised norms are yet to be implemented fully despite repeated deadlines expiring. The Central-state administerial conflicts are also often a major impediment for CDSCO in imposing strong actions against state drug departments for not implementing Central laws, say some experts.
Due to these inconsistencies in the regulatory system, drug firms often use their old facilities, which do not conform to modern quality norms, for the Indian market while setting up new facilities with international quality compliance for exports. Some other firms rely on low-standard, low-cost contract manufacturers to produce medicines sold in the domestic market at controlled prices.
“Given that many of the contract manufacturers do not adhere to the basic Schedule M norms as stipulated by the Indian regulator, the quality of the medicines produced at these facilities may be questionable,” says Gulhati.
Dilip G. Shah, secretary-general, Indian Pharmaceutical Alliance, an industry body representing around 70% of the country’s pharmaceutical production, says: “The difference in manufacturing norms of different countries do not necessarily mean difference in quality. Yes, there are small companies having ill-equipped facilities housed (in) garages that make drugs of substandard quality. At the same time, most of the big Indian companies do manufacture their products at their US food and drug administration (one of the most stringent quality manufacturing standards in the world) compliant facilities for the local market.”
“Ultimately, the reputation that a company possesses is important for its success in the market,” Shah notes. “So, no reputed companies can afford to have inferior quality products in any of its markets, whether it undertakes the manufacturing at its own facilities or at outsourced facilities.”
This isn’t always true, though.
A 2006 USFDA audit at the country’s largest pharma company Ranbaxy Laboratories Ltd’s Paonta Sahib manufacturing facility in Himachal Pradesh, which produces drugs for both domestic as well as foreign markets, found significant deviations from the specified quality manufacturing norms.
“Though the plant was reinspected by the USFDA later in 2007 , the company is awaiting a favorable outcome,” says a Ranbaxy spokesperson.
Over at Orchid Chemicals & Pharmaceuticals Ltd, a spokesperson points out that “our domestic business accounts for less than 10% of our total revenue. Hence our focus is primarily on the international market. Our own facilities, which are international quality compliant, are mainly used to cater to these markets. To meet the demands of the domestic markets we rely on contract manufacturers. While we do our best to ensure that these manufacturers adhere to high quality standards, the basic criteria required for manufacturing in India are comparatively less stringent than those prescribed by the USFDA or medicines and healthcare products regulatory agency (UK). This might not necessarily imply that there is a variation in quality but there is a chance that quality may get compromised as the Indian regulations are not as stringent as the developed world.”
According to S.A. Momin, joint commissioner at the Maharashtra state food and drug administration, many units within the state still do not comply with the amended Schedule M norms.
“Many of the units are in the process of being upgraded. The ones that do not comply will be shut down,” he says. Momin says that, to an extent, it is possible drugs sold by major pharma companies that have outsourced their manufacturing requirements to third parties may not conform to quality standards. “Such instances have happened,” he concedes, but adds that instances when there has been a significant difference in quality have been few.
Small drug makers blame the government as well.
Says Dara Patel, secretary general, Indian Drug Manufacturers Association, the industry body that represents large majority of small and medium drug firms in India: “Since the prices are too low in the country and government wants to include more and more drugs in the price control list now, it does not give the scope for the manufacturer to reinvest in the plant for upgradation.”
The small-scale industry bodies allege that a major constraint in complying with the quality norms is the additional investment.
As per the revised GMP norms, a drug unit should have at least 40 sq.m area dedicated to tablet manufacturing, which was less than 30 sq.m earlier. Similarly, the area for capsules and liquid orals has been increased to 30 sq.m from 20 sq.m, respectively.
Changes are also mandated for small volume injectibles and other parenteral drugs. The area for preparation and filtration has been substantially increased and airlocks (which control airflow in the aseptic manufacturing area) and air-handling units have been made compulsory. The bigger facilities would mean fresh investments in land and redesigning of units.
“In case no land is available for expansion, the units will be asked to close down one of the lines (either tablets, capsules or liquid orals) to meet the requirements. Also, units operating in non-industrial areas will be asked to relocate to industrial areas,” says Momin.
“Changes in infrastructure is just 25-30% of the revised Schedule M requirements and the additional finance required for these changes is insignificant,” says M. Venkateswarlu, drug controller general of India.
“The most important part in the GMP are the much-needed attitudinal changes in maintaining quality and systematic manufacturing set-up, documentation process, quality material procurement, trained personnel, clean and a controlled atmosphere for manufacturing and storage and certainly maintaining transparency while inspections. So, it is not only the responsibility of the regulator but also the industry to follow what is conducive for the common good. This holistic approach will help (in) changing the situation.”