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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?
Between November 2007 and February 2008 there was an increase in the number of recorded deaths following injection of heparin.1 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."2 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."3 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 author says...
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:4
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.5 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."
ICH Q7A6 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.
5. ICH Q7A guidance, Good Manufacturing Practices for Active Pharmaceutical Ingredients, section 11.2, "Laboratory Controls, Testing of Intermediates and APIs" (2001). www.fda.gov
6. ICH Q7A guidance, Good Manufacturing Practices for Active Pharmaceutical Ingredients, section 12.8, "Validation of Analytical Methods" (2001). www.fda.gov