As reported recently by Phil Taylor in Securing Pharma, Leaders of the House Energy and Commerce Committee (I won't name any political parties) have written to FDA Commissioner Hamburg, demanding that FDA release documents from its prior, extensive investigations into U.S. heparin supply chain safety.

Had been checking for updates on this for so long that I missed last week's closure. 

Some of those in favor of relaxed reimportation often argue that the drug industry is fear mongering when it points to potential safety problems with drugs or ingredients sourced from abroad. "Be afraid, be very afraid. "  Well, recent events have shown that there is reason for fear....or at least for extreme caution when ensuring the pedigree of any raw materials  sourced from abroad. 

Any crime covered by the press inspires a wave of copycats.  So, it seems, the global heparin supply chain will have to be closely monitored for some time.  Both 2-D NMR and capillary electrophoresis have been recognized as the best ways to assess the purity of heparin. Both are beautiful techniques, and yield a lot of information, but they also require highly experienced analysts and expensive equipment. 

Janet Woodcock, head of FDA’s CDER, strikes me as the type of person you’d want in charge during a crisis.  And that’s exactly where FDA, and CDER, have found themselves this year, so I’m not surprised that Dr. W. was reassigned from her post of Chief Medical Officer and Deputy Commissioner to head up CDER.  Using the triage imagery of the Emergency Room, running the Critical Path initiative is important, but maintaining control of CDER, drug review and inspections, is urgent.

At the American Chemical Society national conference last weekend, Rensselaer Polytechnic researcher Dr. Robert Linhart announced that his team may have built the first fully synthetic heparin. Whether or not you believe that the possibility of another contamination crisis of natural raw heparin exists, the potential for a heparin supply independent of the whims and worries of the global supply chain, not to mention the global pig population, is certainly welcome news.

Is synthetic heparin feasible on a large scale? Yes and no, says one of Linhart's collaborators, professor Jian Liu at the University of North Carolina. The science is there to produce synthetic heparin at the milligram level, and almost there to produce it at the kilo level, Liu told me this morning. But a lack of investment and low market incentive may collude to limit the short-term outlook for engineered heparin.

"We need someone who's willing to serve as partner to expedite production," Liu says. Right now, the researchers are talking with several smaller biotech firms about development for clinical trials. They have not yet been approached by larger pharma companies.

Synthesizing heparin involves introducing sulfa groups into polysaccharides derived from E. Coli bacteria, Liu says, in order to produce an key enzyme for heparin production. The cost of this process is 10 to 100 times less than making heparin from human enzyme, Liu says.

There are a couple technical issues to be worked out before synthetic heparin could be produced at greater rates, much less at a rate to satisfy the current market demand of 30 to 40 tons per year. The first, says Liu, would be improving the yield of the starting materials. The second would be scaling up the current lab procedures to an industrial level--an "engineering problem," says Liu.

And there are financial issues. Even though heparin prices have risen this year to more than $5,000 per kilo, the cost is not prohibitive to warrant a major push towards an alternative. The incentive is not there.

Unless another crisis occurred. While Liu and colleagues certainly don't wish for this, the impetus for their research, which began in 2005, was that the heparin supply is vulnerable. Three main factors are involved in control of the supply, Liu notes: the global pig supply, the heparin harvesting and purification process, and the analytical control. While measures by FDA, other regulatory bodies, and heparin suppliers and manufacturers to establish greater control have been "pretty impressive," according to Liu, the current way of making heparin will always be vulnerable to environmental (e.g., porcine disease) and human (e.g., purposeful adulteration) factors.

Liu likens maintaining control of the heparin supply to maintaining antidoping procedures for Olympic athletes. "You have to know what you're looking for," he says. But just as athletes find ways to circumvent drug tests, there may always be heparin contaminants that will fall outside of materials inspection parameters.

Synthetic heparin created in a GMP environment from fermentation to packaging would certainly eliminate these concerns. The best-case scenario, however, is that synthetic heparin could be ready for patient use within 4-5 years, Liu says. But this is only if there are investment dollars for development and production scale-up.

Pharmaceutical Manufacturing, PharmaManufacturing.com, and On Pharma have been covering, and analyzing, the heparin case since it began. In September, we'll take a closer look at the lessons learned from the heparin crisis, and what all manufacturers must do to ensure safe and efficient supply lines.

--Paul Thomas

This just in from the Chicago Tribune: only a small number of patient deaths connected to tainted heparin could conclusively be traced to material sold by Baxter.  

How many other ticking pharma QC time bombs are out there, waiting to explode?  We'll examine this issue next month from analytical, regulatory and quality systems angles.

OK, Rockville's a long way from Miami...but the analytical detective work that FDA, MIT scientists and some companies did into potential root causes of heparin contamination makes a great whodunit.  C&EN, an outstanding publication, beat us to it by several months with this gem, published in late November. In case you missed it, here it is.

There are many lessons to be learned from "the heparin story" ---lessons in validation, risk management, due diligence, analytical method development...and we promise to bring you expert opinion on this subject for the next few months.

In the meantime, a look at the 483 for the manufacturing facility isn't too far from a GMP version of Upton Sinclair, with unlabelled materials, undocumented processes, no SOPs...

Will it truly save costs to outsource more manufacturing to a part of the world that is at such earlier stage of quality systems evolution?

"To retain respect for law and sausages, one should not see them in the making," is a quote attributed to Bismarck (it may have been said first by an Illinois politician in the 1890s).  Will it apply to pharmaceuticals?

Cut and pasted below, some of the nitty gritty from the Chinese facility 483:

Actual 483____________________________________________________________1.           There have been no critical processing steps identified for the Heparin Sodium USP [Redacted] process, and, the repeated and efficient removal of impurities, such as proteins, nucleotides, virus, endotoxin, bacteria and heavy metals at the appropriate, specified, process steps has not been evaluated.  There was no report for annual [Redacted] test results available.

The improvements offered by removal of a raw material

5. Investigations into failed lots and out of trend lots were approved as complete, but did not identify a cause for the problem. For example, Heparin Sodium USP batch [Redacted] failed the Nitrogen Determination test and was reprocessed to make [Redacted] without finding the reason for the slightly high, OOS Nitrogen result.

   Investigations into [

   Handwritten #2: cross out a word, added "OOT"] of customer [Redacted] specification @[Redacted] for Heparin Sodium USP lots [Handwritten #3: cross out word(s)] [Redacted] and [Handwritten #4: cross out word.] were performed without knowing what the failed test measurement actually represented.

Investigations into ROI out of trend results for Heparin Sodium USP lots