Heparin: Law, Sausages and Rockville CSI

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 [Redacted] test @ [Redacted] a batch size increase, an added [Redacted] step, a change in [Redacted] for the [Redacted] step and [Redacted] and parameter changes, approved in a 1/05 process validation report for Heparin Sodium USP, were not demonstrated.2.           There has been no impurity profile established for Heparin Sodium USP and no evaluation for degradants during stability program testing.3.           The manufacturing instructions for Heparin Sodium USP are incomplete in that they do not include a description of manual manipulations of the [Redacted] during processing steps, they do not include the actual, manually entered [Redacted] set temperatures and times and, operator observations such as level measurements, used in calculations, during the [Redacted] step are not recorded.4.       There has been no test method verification performed for the reported USP test methods, Nitrogen Determination, Protein and Total Aerobic Microbial Count, employed in testing of Heparin Sodium USP and Heparin Crude materials, to show that the methods are suitable under actual conditions of use. In addition, there is no routine test for [Redacted] residue amount at the time of release

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. [Redacted][Handwritten #5: added "and the failure of lot"][Redacted] Investigations into ROI out of trend results for Heparin Sodium USP lots [Redacted] identified both results inappropriately as outliers.
6. Heparin Crude lots [Redacted] received 8/06 from vendor [Handwritten #6: cross out word(s)] [Redacted] that included material from an unacceptable workshop vendor were used in Herapin Sodium USP [Redated] marketed to the USA.  In addition, prior to 3/06 there are no [Redacted] records from vendor [Redacted] showing the source for their crude materials.
7. The inside surface of large, "cleaned" [Redacted] tanks used in the final [Redacted] step, after both [Redacted] were very scratched, with unidentified material adhering to the insides and, the inverted handles held liquid, which spilled to the bottom of the tank when it was uprighted.  There was no written procedure showing that the tanks were dedicated to a particular process step.  There was no data collected to verify marker and tape volume markings on the outside of the tanks and, the cleaning method was not validated.  It was noted that equipment cleaning tags were made of paper and taped to the piece of equipment unprotected from liquids used in the processing room environments.
8. Raw material inventory records were incomplete in that samples removed from the containers and the status and amount of materials returned from use by the production processing department were not recorded.  For [Redacted] stored in a freezer, the amount, condition and date of return was not recorded.
9. Control of material flow in the processing area was inadequate in that waste [Redacted] was carted through a door to the outside in the processing area and not provided for by the material flow written procedure.
10. The outer foil bags containing Heparin Sodium USP lot [Redacted] manufactured and held since 5/25/07, are not labeled. The drum lid showed the only indications of the lot number.
11. There is no report or data to show that leachables for the [Redacted] bags used to hold Heparin Sodium USP lot, have been evaluated.