Since the presence of pharmaceutical impurities in the active pharmaceutical ingredients (APIs) even in small amounts can influence the efficacy and safety of a product, impurity profiling is now getting more critical attention than any other time from regulatory authorities.
The recent report that country’s drug regulator has banned import of raw material from 10 Chinese drug companies for supplying products without having the mandatory drug manufacturing standards ,brings to focus the fact that in the recent years the regulators are getting stricter in tightening regulations and imposing stringent norms.
The European Directorate for the Quality of Medicines (EDQM) is keeping a strict vigil on API manufacturers around the world. It had suspended and withdrawn six additional certificates of suitability (CEPs) since the start of the year.
As a part of the EC's effort to curb the entrance of counterfeit medicines into the supply chain maintained in its province, a new directive on falsified medicines is also under the consideration of the European Union (EU) authorities.
To better secure the drug supply chain, the FDA is developing a risk-based model to identify APIs that may be at risk for contamination.
“We’ve actually issued assignments to the field offices to sample specific APIs we identified,” Edwin Rivera-Martinez, acting director for drug quality assurance at the Center for Devices and Radiological Health said recently at a conference. Using the same concepts, the agency is planning to expand the programme to excipients, he added.
The actions are a reminder to the pharmaceutical manufacturers for exercising more care in the selection of API suppliers and auditing and monitoring them closely to ensure substandard or adulterated materials do not end up in finished medicines.
In order to check the import of unauthorised APIs from China, India may send drug inspectors to examine certain bulk drug production units there. As a follow-up to banning the import of raw materials from 10 Chinese drug companies, the Drugs Controller General of India (DCGI) has proposed to implement overseas inspection of manufacturing sites soon. The move is to make sure that there are no incidences of regulatory lapses from any foreign drug companies who export raw materials to India.
Soon, drug inspectors will be sent to visit the manufacturing facilities in foreign countries to conduct inspections to ascertain the quality of medicines being sourced by Indian companies. DCGI Dr Surinder Singh recently told Pharmabiz that his department would be selecting a pool of 64 drug inspectors from the country and once that is done they would short-list a cluster of the best 15 to 20 inspectors who would be trained in accordance with the international standards and send for the auditing and inspection of manufacturing sites in foreign countries. The DCGI said that it was high time India too started the practice of inspecting the manufacturing sites to bring in more transparency into the drug approval system.
India imports API’s mainly from China. Indian drug companies use these API’s and other intermediates to manufacture the drugs which are sold in the domestic and international market. Some of the raw materials which were banned include clotrimazole, mefenamic acid and sulphadoxine that are used to make anti-infective and painkillers.
Indian drug companies were concerned that a single lapse in manufacturing standard can result in cancellation of their exports by foreign drug makers as India exports medicines worth Rs. 42,000 crore every year while another Rs.58, 000 crore are sold in the domestic market.
According to a senior health ministry official “We have to ensure that drugs made here are of top quality, if we are to become the pharmacy of the world in the next decade or so.”
In the past couple of decades, the market for APIs has become increasingly global, with many suppliers - particularly in Asia - now selling ingredients to pharma companies, who outsource manufacture to reduce costs. 'This is being driven by pressure on prices from both governments and competition. These pressures are particularly strong for generics companies as the profit margins on a generic with many competitor products are much lower than on a still-patented medicine. 'There is a danger as this extreme pressure on costs is very hard to combine with high levels of compliance with GMP' says an official.
There are alarming cases where criminals have substituted a cheaper ingredient to make a quick buck. In early 2008, US-based pharma firm Baxter was hit when the anticoagulant heparin they sourced from China was deliberately contaminated with as much as 30 per cent of over-sulfated chondroitin sulfate, which is cheaper than heparin to make and resembles it in analytical testing. The substitution led to the deaths of around 150 patients in the US with many hundreds of others being seriously affected.
Now the pharma customers are becoming more concerned when purchasing ingredients about the compliance position of the supplier, and there is an increasing awareness of what can go wrong.
Yet it is not always clear exactly where an ingredient has been made, and the supply chain is only as good as its weakest link - and if a link gets broken, patients could be at risk.
According some reports ,many APIs from China are made in facilities that are not authorised to make pharma-grade fine chemicals .'They have no GMP, and chemicals made there can go through a relabelling process so they appear to have a "proper" origin and penetrate the supply chain through traders. The regulators built an oversight infrastructure designed around 20th century national boundaries. But supply chains are now global and the oversight structure is obsolete. However, the regulators have finally got it, and there is now a lot of communication between regulators in the US, Europe, Japan, Australia and Canada.
In an attempt to increase API safety, last year a group of pharma companies and suppliers set up a coalition, Rx-360, with the aim of improving the safety of the supply chain. According to an expert , about 80 per cent of all medicines on the EU market are now made with ingredients sourced in Asia. But companies there are less likely to be audited than those in Europe. Rx-360's most important role, he says, involves sharing audit data. 'Whenever a member company audits a supplier, it goes into a database, and all members have access to the audits in the database for a small fee.'
Supply-chain integrity is a critical concern for the pharmaceutical industry and its suppliers, and the industry is taking a step forward by addressing these concerns as a collective whole through the formation of Rx-360. Launched in last year June, Rx-360 is a non-profit international pharmaceutical supply-chain consortium whose mission is to create and monitor a global quality system by adopting standards and best practices for the supply chain, supporting technology developments for supply-chain security, monitoring the supply chain, and developing shared audit programs.
Nearly 130 industry representatives attended the launch meeting to provide feedback on the consortium’s objectives and structure.
In the meanwhile the new directive on falsified medicines, which is under the consideration of the EU authorities, may hamper exports of API from India to the European countries, it is learnt.
The EU directive on falsified medicines seeks the exporters of APIs to get a clearance certificate for each of its consignments from the domestic drug regulators ensuring compliance of the product with the GMP requirements of EU.
The European Commission had, almost six months back, put forward a proposal to have a written declaration by the exporting country attesting the ‘equivalence of standards’ to those of the EU. The drug regulator in the exporting country should also conduct regular inspection in the relevant exporters' site to ensure compliance with the GMP standards, informed Government of India officials.
If the new directive is implemented, the API exports to at least the 37 member states of EU will have to wait for a long time to get each consignments approved by the drug regulator. Keeping constant alert on the drug regulatory and policy developments in EU following the seizure of Indian pharmaceutical consignments in its provinces, the Government of India has now acted in advance to express its concerns over the proposed regulation, according to sources from the Ministry of Commerce and Industry. The ministry has sought expert opinion from the Pharmaceuticals Export Promotion Council (Pharmexcil) on the issue.