Philip Payne
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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.
The author says...
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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.
Learning the lessons
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.
Specific breaches
Four main breaches of cGMP were highlighted in FDA's warning letter to Changzhou SPL:4- 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.
