Heparin Case Study

Heparin Case StudyFrancis GodwinDirector, Division of Drug Quality IIOffice of Manufacturing QualityOffice of ComplianceCenter for Drug Evaluation and ResearchSecuring Medical Product Quality Through the Supply ChainUSPMarch 29, 2017

Agenda Heparin Primer/HistorySupply Chain CharacteristicsEconomically-Motivated AdulterationBlue Ear DiseaseOSCSWhat HappenedFDA and USP ResponseImport Alert 55-03 and FDA GuidanceQuestions2

Primer Heparin is a widely-used anticoagulant Used as a drug and incorporated indevices Derived naturally from porcine (pig)intestines Is a polymer, and variants exists (lowvs. high molecular weights)3 3

Heparin HistoryKeire DA, Mulloy B, Chase C, Al-Hakim A, Cairatti D, Gray E, Hogwood E, Morris T, A.S. Mourão P, da Luz Carvalho Soares M, andSzajek A. “Diversifying the Global Heparin Supply Chain: Reintroduction of Bovine Heparin in the United States?” PharmaceuticalTechnology, 39(11), November (2015).4

RememberthisKeire DA, Mulloy B, Chase C, Al-Hakim A, Cairatti D, Gray E, Hogwood E, Morris T, A.S. Mourão P, da Luz Carvalho Soares M, andSzajek A. “Diversifying the Global Heparin Supply Chain: Reintroduction of Bovine Heparin in the United States?” PharmaceuticalTechnology, 39(11), November (2015).5

Supply Chain Characteristics It takes many animals to produce the heparinsupply– 3000 pigs for 1 kg of heparin The supply chain spreads back toslaughterhouses, crude manufacturers, andconsolidators The supply chain is intertwined; it is an olderindustry with multiple manufacturers6 6

The Heparin Supply ChainApplicationFDFAPIAPI/ConsolidatorCrude

General Crude Heparin Supply Chain (China) Risks/TraceabilityIntestinesIntestinesSlaughter Houses 25,000 (2 millions Kills/day)Casting Workshops 1,000. Buy pigs Intestines.Daily processing 1,000-20,000 kg intestines.MucosaCrude:15-300kg/month.Domestic Pharma buyersLocal Brokers: Dozens. Digestion, Resin, Elute, Precip.Crude heparin. Potency testConsolidators: Dozens. Mix crude daily output. Dissolve.Precip. Dry. Multiple tests 300-2,000 kg/month. Someconsolidators are also heparin pharma companies.Foreign buyers8

Global distributions of pigsWith estimated standing populations of 1.43 billion cattle, 1.87 billion sheep and goats,0.98 billion pigs and 19.60 billion chickens.Robinson TP, Wint GRW, Conchedda G, Van Boeckel TP, Ercoli V, et al. (2014) Mapping the Global Distribution of Livestock. PLoS ONE 9(5):e96084. os.org/plosone/article?id info:doi/10.1371/journal.pone.00960849

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Working Definition of EMA“For purposes of this public meeting, FDA proposes aworking definition of EMA as the fraudulent, intentionalsubstitution or addition of a substance in a product forthe purpose of increasing the apparent value of theproduct or reducing the cost of its production, i.e., foreconomic gain. EMA includes dilution of products withincreased quantities of an already present substance(e.g., increasing inactive ingredients of a drug with aresulting reduction in strength of the finished product, orwatering down of juice) to the extent that such dilutionposes a known or possible health risk to consumers, aswell as the addition or substitution of substances in orderto mask dilution.”Federal Register /Vol. 74, No. 64 /Monday, April 6, 2009 /NoticesDepartment of Health And Human Services/Food and Drug Administration[Docket No. ts/MeetingsConferencesWorkshops/ucm163619.htm11

Econ gsty-econ-101-8-market-equilib1.png12

Blue Ear Diseasewww.fda.gov13

Blue Ear DiseaseFatal virus that affected the pig supply in ChinaFrom the Washington Post, 9/16/2007:“Moving rapidly from one farm to the next, the virushas been devastating pig communities throughoutChina for more than a year, wiping out entire herds,driving pork prices up nearly 87% in a year andhelping push the country's inflation rate to its highestlevels since 1996. The Chinese government hasadmitted that the swine deaths amount to anepidemic ticle/2007/09/15/AR2007091501647.html14

Effects of Blue Ear Disease Supply of raw material dropsDemand for heparin stays the sameEcon 101—price increasesHigher price Higher incentive for EMAEnter over-sulfated chondroitin sulfate(OSCS)15

OSCSwww.fda.gov16

Crude Heparin PricingCrude heparin comes in various grades––––Depends on stage of purificationForm transported (resin/powder/liquid)Sophistication of crude operationsWhether brokers/middlemen consolidateTherefore price is a function of purity/potency– weight X potency– Potency confirmed via various tests2 Options for EMA– Increase the apparent potency increased price– A cheaper material with similar potency test results reduce your cost17

Heparin vs OSCSChondroitinSulfateHeparin18 html

OSCS“OSCS is not a natural product arising from animalsources. Therefore, it must be concluded that this wasnot a case of accidental contamination, but that OSCSwas intentionally added to the raw heparin product as anact of purposeful adulteration.”“The high charge density of OSCS resulted in strong antifactor IIa activity, allowing the contaminated sample lotsto pass through the anticoagulation potency screens thatwere used to determine heparin efficacy and s/PMC3015169/19

OSCS vs Heparin potencyRebecca Lever, Barbara Mulloy, Clive P. PageHeparin – A Century of Progress, ISBN 1007%2F978-3-642-23056-120

What happened?www.fda.gov21

A Perfect Storm Opaque supply chain– Many didn’t know who crude manufacturers were(bought material from brokers/consolidators)– Comingled materials hinder traceability Crude material with natural impurities Weak analytical controls– Only test for potency– Methods wouldn’t detect OSCS Supply disruption causing spike in price– Increased incentive for OSCS contaminationwww.fda.gov22

Adverse Event M11266923

FDA and USPresponsewww.fda.gov24

25 25http://www.usp.org/sites/default/files/usp pdf/EN/valueOfStandards/heparinTimeline.pdf

Import Alert 55-03Implemented in February 2012– https://www.accessdata.fda.gov/cms ia/importalert 821.html– Firms linked to historical OSCScontamination– Includes firms with violative inspections(WL, etc.)– Serves as “one stop shop” for heparinindustry to be aware of firms FDAconsiders unacceptable26

Import Alert 55-03Pass through issue– Material from these firms may not comeacross the border (internal commerce inChina)– All sponsors and API sites directly notifiedthat use of firms on the list could result intheir products being considered adulterated– API sites committed to removing listed sites,all DMF and applications were updatedaccordingly27

FDA Heparin GuidanceFinal guidance published June 2013Heparin for Drug and Medical Device Use:Monitoring Crude Heparin for 90.pdfRecommendations to better control crudeheparin that might contain over-sulfatedchondroitin sulfate (OSCS) or non-porcinematerial (ruminant material) contaminants28

Questions?29

(e.g., increasing inactive ingredients of a drug with a resulting reduction in strength of the finished product, or watering down of juice) to the extent that such dilution poses a known or possible health risk to consumers, as well as the addition