Philip Payne

Between November 2007 and February 2008 there was an increase in the number of recorded deaths following injection of heparin.

 Investigations by FDA immediately focused on the supply of multi-dose and single-dose vials of heparin sodium produced by Baxter Healthcare Corporation (IL, USA). The company initiated a major recall of these products, as well as HEP-LOCK heparin flush products, in February 2008.  

FDA's investigation of these adverse events led to the suppliers of the API — Scientific Protein Laboratories (SPL; WI, USA) — which in turn had been supplied by Changzhou SPL (China). Subsequently, several other companies have been found to have made or handled products contaminated with a heparin-like compound, oversulfated chondroitin sulfate (OSCS). Speaking at a press conference in April, Janet Woodcock, Director of FDA Center for Drug Evaluation and Research, said: ".... we now know of at least ten Chinese firms that are in the supply chain for contaminated heparin."

  At Changzhou SPL, FDA found several breaches of cGMP and contamination of heparin, which was found to account for 5–20% of the total mass of each sample tested.  

As of May 2008, FDA was unsure how the contamination occurred and whether it was the cause of the adverse events. Whilst the agency has indicated its belief that OSCS was the likely cause, the Chinese authorities have disputed this conclusion. The UK Medicines and Healthcare Regulatory Agency (MHRA) also observed in a press release in April 2008 that "there is currently no evidence that this (i.e., OSCS) is associated with any risk to the patient."

  This release was issued after MHRA was advised by Sanofi-Aventis (France) that some batches of Clexane (enoxaparin) on the UK market contained low levels of OSCS. 

Leaving aside this debate, FDA's inspection of the Changzhou facility raised concerns regarding the lack of quality systems and highlighted wider questions about the pharmaceutical supply chain in general. 

The findings of FDA's inspection are worrying, but they serve as a useful reminder to pharmaceutical manufacturers to better control their wider supply chains. Certainly, the incident appears to have encouraged FDA to demand more investigators, and could result in tighter requirements being published in the updated Chapter 5 of the EU GMP, which is due for release later this year. Some companies have already hinted that regulatory authorities are asking more searching questions regarding their supply chain.  

Four main breaches of cGMP were highlighted in FDA's warning letter to Changzhou SPL:

There was no assurance that processing steps were capable of removing impurities. 

Systems for evaluating the suppliers of heparin crude materials, and the crude materials themselves, were inadequate.

Test methods had not been verified to ensure suitability under actual conditions of use.

Equipment used to manufacture heparin sodium USP was unsuitable for its intended use.

Regarding the first point, inspection revealed that Changzhou SPL lacked an adequate evaluation of the critical processing steps designed to remove impurities. As well as critical process parameters that were neither well defined nor controlled, an impurity profile had also not been established for the heparin sodium API. Additionally, the validation studies that were conducted failed to determine whether the process could adequately remove identified and unidentified impurities.  

The issue of identifying and testing for impurities is governed by ICH Q7A guidance.

  Changzhou SPL seemed to be of the opinion that its testing regime was consistent with a statement from ICH Q7A: "Impurity profiles are not normally necessary for APIs from herbal or animal tissue origin." FDA refuted that observation by noting that while "a full impurity profile may not be necessary as part of batch-to-batch testing of certain APIs, it is necessary that specifications for impurities be established for the production of all API and that each API batch be tested for conformance to these specifications."

  requires appropriate specifications to be established for APIs, including for control of impurities. FDA also makes it clear that the complexity of isolating and identifying impurities does not remove the responsibility to establish appropriate specifications for, and routine monitoring of, possible impurities arising from production.

The third point of FDA's warning letter highlights Changzhou SPL's failure to ensure that USP compendia test methods were verified under actual conditions of use, meaning there was no evidence that the test methods could reliably detect and quantify the presence of contaminants in the finished API.

In accordance with cGMP, analytical methods should be validated unless the methods are already included in a relevant pharmacopoeia or other recognized standard reference. If the method is a compendia method, verification of the methods should be conducted to determine that it is suitable for its intended use under actual conditions. ICH Q7A guidance also requires that all testing methods be verified under actual conditions of use and documented.

In respect of the specific contaminant identified by FDA, there are two published methods that could be used for screening. One is based on capillary electrophoresis (CE), the other on proton nuclear magnetic resonance (NMR) spectroscopy. Both tests are relatively easy to conduct and FDA now insists they be used for all heparin sodium API prior to batch release. The API material is considered contaminated if there is a doublet peak at 2.1 ppm in H-1 NMR and a shoulder peak in CE. Heparin sodium API must contain only a single peak (singlet) at 2.1 ppm in NMR and a single peak in CE. It is recommended by FDA that both screening methods (H-1 NMR and CE) be used in addition to regulatory and/or compendia specification requirements. 

Reference to the wider supply chain is made in the second point of FDA's findings. The agency identified that Changzhou SPL received material from an unacceptable workshop vendor for use in its API. Moreover, Changzhou SPL acknowledged that it received and used heparin crude materials from a workshop that the company had already designated in a "pre-audit" as "unacceptable". Changzhou SPL used this crude material in the production of API lots that were shipped to SPL in the US. 

Herein 'lies the rub' for all pharmaceutical manufacturers: how can any company be sure that the standards that suppliers might claim to operate, and might be able to demonstrate from time to time, are actually being practised all the time? Or how can pharmaceutical manufacturers have any control over the suppliers to their suppliers and so on to the furthest reaches of the supply chain? 

This is the issue that pharmaceutical manufacturers must face up to, particularly in an era when more and more APIs are being produced in countries with little history of regulation and less familiarity with the application of cGMP standards. In this respect, the issue of Good Distribution Practice (GDP) is also relevant because inadequate control of the storage and distribution of supplies may represent just as much of a risk as failing to control their production. In some countries, extreme temperatures and climates may compromise the quality and stability of supplies, and distribution failings are also frequently implicated in the production of counterfeit medicines and counterfeit APIs. 

The fourth point raised by FDA is essentially one of unsuitable equipment, which might have readily been spotted by a cursory audit. Whilst many details of the failings were left unpublished to protect proprietary and commercially sensitive information, it is still apparent that cleaning had been inadequate and volume indicators on tanks were probably inaccurate.

It seems likely that the contamination of heparin will have far reaching ramifications for pharmaceutical manufacturers and regulatory authorities. At the very least, it can be seen as a warning to industry that nothing can be taken for granted when dealing with suppliers. This is particularly true the further removed the supply chain becomes, and it is a moot point as to how far the regulators' and inspectors' reach should go. After all, it is doubtful whether the people who slaughter the pigs from which heparin is ultimately produced have even the first idea that the end point of their work is a life-saving anticoagulant drug. They will not even be aware of cGMP, let alone be in a position to practise it. 

www.fda.gov/cder/drug/infopage/heparin/adverse_events.htm

www.fda.gov/bbs/transcripts/2008/heparin_transcript_042108.pdf

www.mhra.gov.uk/NewsCentre/Pressreleases/CON014892

Good Manufacturing Practices for Active Pharmaceutical Ingredients

, section 11.2, "Laboratory Controls, Testing of Intermediates and APIs" (2001). 

, section 12.8, "Validation of Analytical Methods" (2001). 

Articles

How can any company be sure that the standards that suppliers might claim to operate, and might be able to demonstrate from time to time, are actually being practised all the time?

Is pharma's supply chain safe?

The assembly of the World Health Organisation (WHO) later this month is expected to feature counterfeit medicines as one of its important discussion points, and there is some hope that the ministers will agree on measures that will strengthen anticounterfeiting legislation and enforcement worldwide. 

Few people in the pharmaceutical industry need convincing of the danger counterfeit medicines pose to public health and commercial profit. Sadly, the world's politicians seem somewhat oblivious to the arguments, and there are many countries where counterfeit medicines are openly marketed or where the production of counterfeit medicines is either treated as no crime at all or something worthy of only minor punishment. 

The most recent meeting of the International Medical Products Anti-Counterfeiting Taskforce (IMPACT), which took place in Lisbon (Portugal) last December, endorsed a document of principles and elements that may prove to be the precursor for international cooperation in enacting national legislation against counterfeit medical products.  

IMPACT was created by WHO in 2006 from a global coalition of stakeholders, including industry, regulatory and law enforcement representatives. Its remit was to forge international collaboration in combating counterfeit medicinal products and to raise awareness of related issues. Five working groups were established to specifically examine the issues and potential approaches offered by legislation, regulatory implementation, enforcement, technology and communication.  

According to IMPACT, its stakeholders have surveyed national and international legislative instruments and, while further study is necessary, a number of key issues have been identified as contributory factors in the increasing prevalence of counterfeit pharmaceuticals:  

The definition of counterfeit medical products is absent or inadequate.

Counterfeiting medical products is not considered a serious crime or, in some cases, not even a crime.

If counterfeiting medical products is considered a crime, sanctions are sometimes more lenient than those for counterfeiters of products that have no health implications (e.g., t-shirts).

Sanctions are not applicable unless it is proven that counterfeits have resulted in injuries or death.

The responsibilities of those involved in the distribution system are not clearly defined.

There are no provisions for effective coordination and information exchange among various authorities and other stakeholders at national, regional and international levels.

There are no provisions that allow authorities to share information nationally, regionally or internationally, or to use information obtained by others in legal proceedings.

There are no provisions addressing the problem of trade in packaging and labelling materials without the obvious involvement of the companies whose name appears on these materials.

There are insufficient legal provisions concerning the confiscation and use of assets, equipment and other materials used in conjunction with the manufacture, trade and transportation of counterfeit products.

Based on these considerations, IMPACT prepared and endorsed a document of principles and elements designed to assist member states in establishing, complementing or updating national and regional legislations regarding counterfeit pharmaceuticals. In doing so, IMPACT specifically excluded some commercial considerations, such as intellectual property, parallel importation and theft of counterfeit products, to restrict its focus primarily to public and personal health implications.  

While accepting that all stakeholders can help combat counterfeit pharmaceuticals, IMPACT claims that the primary role rests with governments, and has created an extensive list of measures that governments must address to protect public health. These include recommendations on drawing up legislation and defining activity that should be seen as illegal and, additionally, suggesting sanctions for those illegal acts. A key element of IMPACT's argument is that the manufacture of counterfeit medicinal products should be punished with equal severity whether the product has damaged anyone's health or not.  

Alongside these recommendations to governments, IMPACT also outlines the key responsibilities for manufacturers and distributors — particularly in complying with existing laws, GMP and good distribution practice (GDP). Technological solutions to the problem often have a limited benefit as some jurisdictions have limited access to appropriate technology and, where it does exist, it is expected to result in increased prices. There is even an argument that technological solutions can raise more problems than they solve.  

If the recent upsurge in participation in GDP training courses is any indication, it seems that pharmaceutical professionals are realizing the importance of GDP, and are seeing that it applies to the whole supply chain rather than to an external or separate distribution channel. Advocates of GDP argue that it is a minimum requirement in helping to stem the flow of counterfeit products into legitimate distribution channels. This is because the practice of parallel distribution, and the complex interfaces between manufacturers, distributors and repackagers — particularly relating to withdrawal of product and subsequent disposal or reprocessing — are all areas of potential weakness that counterfeiters are only too willing to exploit. "All stakeholders in the pharmaceutical industry need to work together to ensure supply chain integrity, and that only 

 suppliers and customers are allowed to supply and sell," says Ciaran Brady, a GDP consultant and tutor for RSSL Pharma Training (UK)." GDP is a must to ensure patient safety and protect ourselves from the likelihood of having our products and packaging copied or misused." 

Aside from the counterfeiting issue, there are many areas that the pharmaceutical sector often falls down in when it comes to GDP. Previously, the UK's Medicines and Healthcare Products Regulatory Agency has identified deficiencies such as:  

Problems with general storage and transportation. 

Documentation and procedural deficiencies, such as a lack of written or insufficient standard operating procedures. 

Inadequate systems for dealing with returns.

Personnel issues concerning duties of key staff, including the responsible person. 

There is no reason to suppose the incidents in this list are in any way restricted to the UK as they are just as likely to relate to the rest of the world in a similar fashion.

  Worryingly, temperature control and monitoring is a recurring theme, and human error and mechanical error have both contributed to pharmaceuticals being stored and transported at inappropriate temperatures. In the context of global warming, the industry needs to address this issue. 

Returning to the forthcoming WHO assembly, Dr Amor Toumi of WHO's Medicines Regulatory Support Department of Technical Cooperation for Essential Drugs and Traditional Medicine is optimistic that the assembly will at least result in IMPACT's ideas on regulation and enforcement being adopted into national legislation.  

"Counterfeiting medicines is widespread and has escalated to such an extent that effective coordination and cooperation at the international level are necessary for regional and national strategies to achieve the ultimate goal of protecting the health of the public. We hope there will be genuine progress made at the next assembly, and that health officials in the world underline that no-one's interests are being served by allowing counterfeiters to go unchallenged and unpunished." 

is Business Development Manager at RSSL Pharma (UK) with global responsibilities. 

The assembly of the World Health Organisation (WHO) later this month is expected to feature counterfeit medicines as one of its important discussion points, and there is some hope that the ministers will agree on measures that will strengthen anticounterfeiting legislation and enforcement worldwide.

The counterfeit problem

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.

  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,

  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.

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.

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.

  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.

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:  

 Atorvastatin (a cholesterol-lowering drug). 

 Sildenafil (a drug for erectile dysfunction). 

 Dietary supplements intended for erectile dysfunction. 

 Cephalosporins (a class of antibiotics) manufactured in facilities that also manufacture noncephalosporin drugs. 

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.

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.

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,

  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.

 is business development manager at RSSL Pharma (UK) with global responsibilities.

4. Organization for Economic Co-operation and Development, "The Economic Impact of Counterfeiting and Piracy (draft)" (2007). 

www.outsourcing-pharma.com/news/ng.asp?n=82048&m-1OSPD13&c=jhqava

7. China's Business Market (November 2007). 

8. Correspondence with MHRA press office, December 2006–January 2007. 