Safety and security requirements are paramount for the production of pharmaceutical products.
If contaminated, pharmaceutical products pose high risk to consumers. Such risks require serious legislation for quality and safety control. Rigorous product inspection is therefore necessary. Hence the regulators the world over are cracking whip on the errant manufacturers.
Various regulatory bodies like the USFDA , Council of the European Union, Central Drugs Standard Control Organisation (CDSCO) in India are now taking stiff measures to check the quality of API, or bulk drug, the actual drug in a formulation and which is the substance in a pharmaceutical drug that is biologically active.
According to a recent report, the USFDA is planning to step up regulations for drug makers that farm out their manufacturing, in an attempt to hold the companies more accountable for any product flaws.
The agency may start requiring companies to check out their contractors' facilities in person, rather than just reviewing data on paper. The agency is also mulling the prospect of issuing warning letters to drug makers as well as their contractors when manufacturing problems are found. Now, those warnings usually go only to the contractors.
Some of the Senators want the FDA to focus its microscope on pharma outsourcing. They are now insisting FDA to look more closely at outsourcing APIs for drugs made at home.
The impetus is a new report that found a large majority of APIs are made abroad. According to the report more than 80 percent of the ingredients made overseas, were mostly in plants rarely inspected by FDA. One of the most frightening example was the heparin scare of 2007, when more than 100 people died after using contaminated heparin, raw material for the blood thinner, sourced in China, were found to be tainted.
US drug makerr Baxter International has been ordered to pay compensation of $625,000 to the estate of the man who received a dose of heparin that was contaminated with over-sulfated chondroitin sulphate (OSCS).Baxter has thus lost the first lawsuit in its ongoing legal battle over the contaminated heparin scandal in 2007 and 2008.
The Council of the European Union has given its backing to the new directive on Falsified Medicines recently. The directive contains a number of clauses with implications for the day-to-day business of pharmaceutical manufacturing. In particular, it introduces a number of changes to good manufacturing and distribution practices (GMP/GDP) for APIs.
Once the directive comes into force , GMP requirements will be much more harmonised, and manufacturers will have to demonstrate greater oversight of the upstream supply chain.
For example they will have to obtain documented confirmation of compliance with EU GMP rules for imported APIs, issued by the regulatory authority of the exporting country, unless that country is on a list of countries recognised as having 'equivalent' regulatory standards, based on GMP rules, inspection and enforcement activity and communication with the EU authorities. A manufacturer should also declare in writing that API suppliers have been audited and comply with EU GMP.
In the area of APIs, registration of players in the supply chain - currently mandatory for manufacturers, distributors and importers of APIs - will be extended to include brokers which are involved in the sale or purchase of APIs indirectly, without owning and physically handling the products.
Registrations will be held in national databases held by the competent authority in each EU member state, and must be updated yearly, or when a change occurs in the business which could impact API safety or quality.
The Qualified Person (QP) at the pharmaceutical manufacturer has responsibility to verify API registrations and the safety, quality and authenticity of APIs, and also to inform the regulatory authority promptly if falsified medicines or starting materials are suspected.
API manufacturers, importers or distributors located within the EU will be inspected at a risk-based frequency, while those outside the EU may be inspected where there are grounds to suspect non-compliance, or at the request of an EU member state, competent authority or the API manufacturer itself.
Very recently Chinese active pharmaceutical ingredient manufacturer Ningbo Smart and Dr Reddy’s Laboratories received warning letters from the US regulator for GMP violations.
USFDA has issued a warning letter to the Industrias Quimicas Falcon de Mexico, a wholly owned subsidiary of Dr Reddy’s, which manufactures intermediates and APIs in Mexico.
The FDA letter cites four discrepancies pertaining to the manufacturing process at the facility. According to industry analysts, the warning letter implies that the FDA was not happy with the corrective measures put in place by the company.
Ningbo Smart Pharmaceutical Co was sent a warning letter for not properly testing batches of API before the material was shipped to customers. The company also failed to carry out identity testing of all incoming raw materials, and has not registered all APIs distributed in the US with the FDA, according to the letter.
Ningbo Smart has also fallen foul of regulators in Europe of late. The European Directorate on the Quality of Medicines & Healthcare (EDQM) recently withdrew certificates of analysis (CEPs) for two of the company's APIs, namely diclofenac sodium and mefenamic acid.
According some reports many APIs from China are made in facilities that are not authorised to make pharma-grade fine chemicals .With drug makers, of the 6000 or so companies in China that produce APIs ingredients, 33 to 50 per cent aren’t operating in compliance with good manufacturing practices, the reports add.
'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 order to ensure quality of importing pharmaceutical products into India, the Central Drugs Standard Control Organisation (CDSCO) has introduced the much-awaited auditing and inspection of manufacturing facilities in foreign countries.
The practice of sending drug inspectors to other countries before allowing them to export goods is strictly followed in developed countries where even a slight deviation from the set benchmark is not tolerated.
The first ever auditing and inspection of manufacturing facilities in foreign countries ended on a happy note as the CDSCO team led by Arvind Kukrety, assistant drug controller, CDSCO has already returned to the country after inspecting manufacturing facilities of five pharma companies in China which have been found to be in good condition. Though the Indian regulators were to inspect six companies in China in this pilot project, they could inspect only five companies as one company, Chongiqing Daxin Pharmaceutical Company, did not allow the Indian drug regulators to inspect its premises and manufacturing facility. The union health ministry is seriously contemplating to cancel the exporting licenses of this company.
The second inspection team will leave for Italy and China soon. After that, the auditing and inspection of manufacturing facilities in foreign countries by the CDSCO team will be a routine affair.
The CDSCO''s selection of China for the pilot project is significant as India is the largest importer of Chinese bulk drugs. More than 45 per cent of bulk drug exporters registered in India are from China. The number of registered Chinese bulk drug manufacturers in India is 272, and altogether 417 different drugs from the Asian giant are registered. In comparison, Italy, the second biggest supplier after China, has 55 registered bulk drug and overall 97 drugs registered, respectively.
Introduction of auditing and inspection of foreign manufacturing facilities is significant as the practice will go a long way in ensuring the quality of importing products. Even though the union health ministry had made registration of imports of drugs and pharmaceuticals into India mandatory way back in 2003, it failed to bring the desired results as the inflow of inferior raw materials into the country refused to subside.
The objective of bringing this rule in 2003 was to bring an end to the entry of poor quality APIs originating from various countries particularly from China through a scrutiny of import applications. Subsequent developments especially during the last couple of years have proved that the legislation could not alone prevent the inflow of poor quality raw materials into the country. Experts believe that the major reason for this is due to the delay in introducing the practice of auditing and inspection of foreign manufacturing sites by the Indian regulatory authorities.
In the meanwhile safety regulations covering the production of food and pharmaceuticals products in China are becoming increasingly strict. Evidence of this can be seen in new regulations approved by the Chinese Ministry of Health and the General Administration of Quality supervision. Failing one of the quality and safety inspections can be a very bad experience for a brand, a product recall minimizes business opportunities, damages brand reputation, and has a potentially serious effect on sales.
Chinese manufacturers now have to equip their factories with strong product inspection systems in order to meet demands. Manufacturers are always looking to improve and ensure the safety and quality of their products, whilst at the same time reducing costs and increasing productivity.
The Chinese Ministry of Health, currently is coordinating the law’s implementation, has drafted several extra regulations on food standards, the control of food risks and the management of new products. Supermarkets are subject to very strict standards, and manufacturers have to respect them if they want to see their products sold in store.
Up until recently Chinese food and pharmaceutical companies have not been subject to the same strict food safety laws as their European or American counterparts. To export their goods to Europe or America, industries now have to show that they follow scrupulous processes to ensure the safety of their products. Chinese manufacturers are taking this issue very seriously, especially as some countries have banned specific Chinese products until the country provides proof of inspections before exports leave the country.
It is now the responsibility of manufacturers to pay disposal costs if goods arrive in Europe or America out of probate. This has brought about an increase in the willingness of Chinese manufacturers to conduct reliable testing before offering their goods for export.