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Pharmaceutical Technology Europe
On 11 December 2007, the US Department of Health and Human Services (HHS) and the State Food and Drug Administration (SFDA) of the People's Republic of China signed a Memorandum of Agreement (MOA) to enhance the safety of drugs, excipients and medical devices exported to the US from China.1 The agreement was signed in Beijing by HHS secretary Mike Leavitt and SFDA commissioner Shao Mingli, and was just one of a broader series of trade agreements that was reached between the two countries.
The official line from the HHS press release is that President Bush appointed Leavitt to chair a Cabinet-level working group on import safety,1 made up of 12 federal departments and agencies. Members of the group visited ports, border crossings, supermarkets, retailers, processing facilities and wholesalers across the US to gain a better understanding of the vast import process. Leavitt also met with his counterparts from Mexico and the European Commission (EC) to discuss common import-safety challenges. On 6 November 2007, the working group presented an action plan to the President made up of short- and long-term recommendations to bolster the safety of the increasing volume of imports entering the US.
With regard to pharmaceutical imports, the second session of the US–China Strategic Economic Dialogue in May 2007 saw FDA and SFDA launch negotiations on a binding MOA on the safety of drugs and medical devices exported from China to the US. The negotiations resulted from a growing concern regarding ensuring the safety, quality and effectiveness of many Chinese products.
It would be very wrong to label the Chinese pharmaceutical industry as 'all bad'. The country exports numerous APIs globally, including approximately 70% of the world's penicillin (making it the largest worldwide producer), 50% of its aspirin and 35% of its paracetamol (acetaminophen). Similarly, Chinese bulk drugs are sold worldwide. The EU, US, India and Japan are the biggest trade partners and make up 60% of China's export markets. China also exports bulk drugs such as vitamins, amino acids and sweetners to the US; vitamins and antibiotics to Europe; enzymes and primary amino acids to Japan; and antibiotics and hormone intermediates to India.2
However, there have been major concerns regarding the quality of pharmaceutical products and APIs exported from China. Institutional corruption and failure to properly regulate and inspect pharmaceutical production has blighted China's reputation and, in 2007, led to the execution of Zheng Xiaoyu, the former head of SFDA.3
A separate case involving Cao Wenzhuang, the administration's former pharmaceutical registration department director, also resulted in imposing the death penalty, though this was suspended for 2 years, which is likely to result in the penalty being commuted to a life sentence.
Despite attempts to clean up its industry, China is well-known as a key supplier of counterfeit drugs. An Organization for Economic Co-operation and Development (OECD) report issued in November 2007 highlighted the problems arising from counterfeit products sourced in India and China, with one company quoted as saying that counterfeits of its pharmaceutical products sourced in China had been detected in 42 countries.4 Independent reports from the EC claim that the main source for counterfeit drugs entering the EU is India, closely followed by the United Arab Emirates and China. These three accounted for more than 80% of the fake medicines entering Europe in 2007.5
At the request of the Chinese Government, the recent MOA includes an agreement from the US to enhance the technical capacity of China's regulatory agencies to help ensure exports to the US meet US safety standards.
Specifically, the two countries are establishing a bilateral mechanism to help ensure these imported products meet standards for safety and effectiveness by building quality into the process from the start. SFDA will require firms that manufacture certain products intended for export to the US to register with them. It will also work towards a system that will enable it to certify that firms manufacturing medicines and medical devices, and the products themselves, meet FDA requirements.
However, this agreement is relatively limited. It only covers:
To support these registration and certification programmes, the two countries will conduct joint training programmes and activities covering topics such as inspection methods, clinical trials to ensure safety, and the development of technical guidance documents, laws and regulations.
FDA and SFDA also intend to exchange information on drugs and devices to ensure better product safety. For example, SFDA will notify FDA within 24 h of any discovery that a product sent to the US could cause serious adverse health consequences, and provide the tracking information necessary to identify the shipment and supplier. Previously, there was no formal system of notification between regulators in the two countries.
Other aspects at the MOA include giving FDA officials increased access to production facilities, establishing a comprehensive electronic tracking system as a protection against counterfeiting, and encouraging China's involvement in international regulatory and public-health bodies.
The Chinese authorities are taking their own responsibilities seriously. In June 2007, China's top administrative body, the State Council, announced a series of regulatory reforms that vowed to place new controls on drug (and food) imports and exports by 2010. There was also a pledge to increase the proportion of such products that are subject to random inspections to 80%.
Aside from the corruption convictions noted above, SFDA recently revoked the manufacturing licence of a factory belonging to Hualian Pharmaceutical in Shanghai after initially forcing it to stop all production at the facility in September. Hualian had been found guilty of making contaminated medicines (leukaemia drugs, methotrexate and cytarabine hydrochloride) that caused paralysis in more than 100 patients.6
In September 2007, SFDA released a draft recall plan that would require manufacturers to recall drugs as early as 24 hours after they were discovered to be unsafe. From January 2008, China will also change procedures for issuing GMP certification.7
Under the previous arrangements, if less than three defined 'severe defects' were discovered in the drug making process, manufacturers could still obtain a certificate as long as they rectified the problem within a prescribed time limit. However, the new standards will allow no 'severe defects', such as falsifying application documents. The new standards have strengthened supervision over weak links in quality control such as technological requirements on management including personnel qualifications, production process, quality control and document verification to ensure drug quality. This move can be seen as part of an ongoing process of raising the standards and scope of GMP certification in China since it was made mandatory in 2004. Although GMP certification was introduced in 1998, adherence had been voluntary until 2004.
Many would argue that an agreement of the kind recently signed between the US and China is long overdue, even though it only covers a fraction of the APIs that China produces. There is clearly scope to expand the agreement to include other APIs, and potential for countries to enter into similar agreements.
The UK signed a Memorandum of Understanding with SFDA in September 2007,8 creating no legal obligations on the part of either authority, but intending to facilitate the exchange of information on medicines and medical device regulation — with particular emphasis on traditional chinese medicines. According to the UK's Medicines and Healthcare products Regulatory Agency (MHRA) the key issue will be discussions on safety information relating to traditional Chinese medicines and the herbal products they contain, including the authentication of herbal reference materials. Officials will also be discussing the fight against counterfeit products and exchange of good practice on manufacturing inspections.
As far as inspections are concerned, when an applicant marketing authorization holder of a given product wants to introduce it to the UK from any country outside the MHRA's jurisdiction, they must sign a declaration granting MHRA permission to go and inspect that facility. If permission was refused on attendance (a situation that has never happened, to date) MHRA would refuse the entire application and suggest they nominate another site. To date, MHRA has only had the need to inspect four Chinese manufacturing sites.
There is nothing equivalent to the FDA/SFDA MOA in preparation at present in Europe as a whole. Whether that situation will change remains to be seen, as it remains to be seen whether the MOA has any real impact on improving standards of legitimate products and reducing the numbers of counterfeit products emerging from China.
Philip Payne is business development manager at RSSL Pharma (UK) with global responsibilities.
2. C.E. Young, European Pharmaceutical Manufacturer 6(5) (2006).www.pharm-europe.com
3. China Daily, (July 2007). www.chinadaily.com.cn
4. Organization for Economic Co-operation and Development, "The Economic Impact of Counterfeiting and Piracy (draft)" (2007). www.oecd.org
5. J.Sheridan and E.Norman, Laboratory News (November 2007). www.labnews.co.uk
7. China's Business Market (November 2007). www.china-business-market.com
8. Correspondence with MHRA press office, December 2006–January 2007.