Guidance for Industry 
 
Heparin for Drug and Medical 
Device Use: Monitoring Crude 
Heparin for Quality 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Veterinary Medicine (CVM) 
Center for Devices and Radiological Health (CDRH) 
 
June 2013 
 
Current Good Manufacturing Practice (CGMP)   
 
Guidance for Industry 
 
Heparin for Drug and Medical Device 
Use: Monitoring Crude Heparin for 
Quality 
 
Additional copies are available from:  
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Division of Drug Information, WO51, Room 2201 
 Center for Drug Evaluation and Research 
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Phone: 301-796-3400; Fax: 301-847-8714  
druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm  
and/or 
Communications Staff, HFV-12 
Center for Veterinary Medicine  
Food and Drug Administration 
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Rockville, MD  20855 
Phone: 240-276-9300 
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm 
and/or 
Division of Small Manufacturers, International, and Consumer Assistance 
Center for Devices and Radiological Health 
Food and Drug Administration 
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Phone: 301-796-5680 or 1-800-638-2041 
Fax: 301-847-8149 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm 
dsmica@fda.hhs.gov 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Veterinary Medicine (CVM) 
Center for Devices and Radiological Health (CDRH) 
 
June 2013 
 
Current Good Manufacturing Practice (CGMP) 
  Contains Nonbinding Recommendations 
 
 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION .......................................................................... 1 
II.  BACKGROUND ............................................................................. 2 
A.  Heparin Contamination .................................................................................................................. 2 
B.  Regulatory Authority....................................................................................................................... 3 
III.  Recommendations .......................................................................... 5 
 
  Contains Nonbinding Recommendations 
 
 
1
Guidance for Industry  
 
Heparin for Drug and Medical Device Use: Monitoring Crude 
Heparin for Quality 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
I.  INTRODUCTION  
 
This guidance is intended to alert manufacturers of active pharmaceutical ingredients (APIs), 
pharmaceutical and medical device manufacturers of finished products, repackers, and others to 
the potential risk of crude heparin contamination.2  
 
This guidance provides recommendations that will help API manufacturers, pharmaceutical and 
medical device manufacturers of finished products, repackers, and others, to better prevent the 
use of crude heparin that might contain over-sulfated chondroitin sulfate (OSCS)3 or non-porcine 
ruminant material contaminants.  It is important to monitor the use or development of test 
methods for crude heparin in addition to those set forth for heparin sodium API in the United 
States Pharmacopeia (USP). It is also important to identify and control the animal origin of crude 
heparin and confirm the species origin of heparin.  This is consistent with the current USP 
                                                 
1 This guidance was developed by the Center for Drug Evaluation and Research (CDER) in cooperation with the 
Center for Veterinary Medicine (CVM) and the Center for Devices and Radiological Health (CDRH) at the Food 
and Drug Administration. 
2 For the purpose of this guidance, we use the term crude heparin to mean an unrefined mixture of heterogeneous 
linear polysaccharides mainly composed of repeating units of highly sulfated disaccharides containing uronic acid, 
either D-glucuronic acid or L-iduronic acid, and D-glucosamine, and including various impurities extracted from 
mammalian tissues that requires further purification and processing before clinical use.  
3 Over-sulfated chondroitin sulfate (OSCS) is an over-sulfated form of chondroitin sulfate (CS) that contains an 
unusual type of sulfation not found in any natural source of CS.  Glycosaminoglycans are polysaccharides 
containing repeating disaccharide units composed of alternating sulfated residues of N-acetylgalactosamine and D-
glucuronic acid.  Although CS is a naturally occurring glycosaminoglycan (e.g., derived from cartilage byproducts), 
OSCS is a semi-synthetic derivative of CS made by the chemical sulfonation of native CS.  Thus, OSCS typically 
contains two to three additional sulfate groups per disaccharide unit compared to chondroitin sulfate.  For the 
purpose of this guidance, we use the term OSCS to mean over-sulfated chondroitin sulfate and related over-sulfated 
glycosaminoglycan analogs. 
1 
  Contains Nonbinding Recommendations 
 
monograph for heparin sodium (USP33-NF28 Supplement 1 Reissue), which states:  Label [the 
heparin sodium] to indicate the tissue and the animal species from which it is derived.  The 
identification of the animal origin of heparin has been studied by physico-chemical, 
immunological, and polymerase chain reaction (PCR) methods.  Notwithstanding certain 
limitations, these methods have the potential to detect ruminant material contaminants in porcine 
heparin.  Some of these methods (e.g., PCR, immunochemical) could be used to detect ruminant 
contamination in the raw materials intended for use in quality heparin production.4,5  This 
guidance outlines the importance of testing for contamination in crude heparin  testing that 
should be performed in addition to the USP monograph tests set forth for heparin sodium API 
(used to make unfractionated and low molecular-weight heparin) to detect OSCS.6 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidance describes the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited.  The use of the word should in Agency guidance means that something is suggested or 
recommended, but not required. 
 
 
II.  BACKGROUND  
 
A.  Heparin Contamination 
 
In early 2008, FDA received reports of serious acute hypersensitivity reactions (including some 
resulting in death) in patients undergoing dialysis.7  Further investigation as well as the sudden 
onset of adverse events suggested the contamination of heparin sodium for injection as a 
common factor among the cases.  In April 2008, after extensive analysis and screening, FDA 
identified the contaminant OSCS in heparin API manufactured in China.  (A large proportion of 
the heparin supply was then and is now imported into the United States from foreign facilities, 
and manufactured with crude heparin sourced from China.)  In addition to the United States, at 
least 10 other countries reported the presence of contaminated heparin within their supply chains.  
OSCS contamination of heparin appears to be an example of intentional adulteration and has also 
been referred to as economically motivated adulterationi.e., heparin appeared to be 
intentionally contaminated with OSCS to reduce the cost of production.  
                                                 
4 For the specificity of the tests, see J.Pharm. Biomed. Anal. 27: 305-313 (2002); J.Pharm. Biomed. Anal. 29: 431-
441 (2002); Molecular and Cellular Probes 20: 250-258 (2006); J. Food Protection 75: 1107-1112 (2012); Anal. 
Bianal. Chem. 404: 43-50 (2012). 
5 See Heparin Multiplex Real-Time PCR Assay (hMRTA). This analytical method for crude heparin is available 
at http://www.fda.gov/AnimalVeterinary/ScienceResearch/ToolsResources/ucm350289.htm. 
6 Such testing should also include steps to monitor and confirm the species origin of heparin, as discussed above in 
note 4 and throughout this guidance.  See discussion in section III and note 11. 
7 For further details, see Kishimoto, T., Viswanathan, K., Ganguly, T., et al., Contaminated Heparin Associated with 
Adverse Clinical Events and Activation of the Contact System, N. Engl. J. Med. 2008; 358:2457-2467; McMahon, 
A.W., Pratt, R.G., Hammad, T.A., et al., Description of Hypersensitivity Adverse Events Following Administration 
of Heparin that was Potentially Contaminated with Oversulfated Chondroitin Sulfate in early 2008, 
Pharmacoepidemiology and Drug Safety 2010; 19: 921-923. 
2   Contains Nonbinding Recommendations 
 
 
Beyond OSCS contamination, the complexity and global nature of the heparin supply chain 
provide other opportunities for intentional adulteration.  In particular, substitution of non-porcine 
sources of crude heparin for porcine heparin generally raises concerns, unless specifically 
approved in a drug or medical device application.  The potential for bovine heparin substitution, 
for example, could pose a risk because of possible contamination with the bovine spongiform 
encephalopathy (BSE)8 agent derived from ruminant materials.9  The control of the animal origin 
of crude heparin is important for ensuring the safety of drugs and devices that contain heparin 
and to protect public health. 
 
The reported incidents of OSCS contamination, FDAs past discovery of OSCS in both heparin 
API and crude heparin, and the ruminant substitution scenario illustrate the potential risk of 
contamination for FDA-regulated products derived from heparin.  Therefore, it is important for 
drug and medical device manufacturers to be diligent in ensuring that no component used in the 
manufacture of any drug or medical device containing heparin is contaminated with OSCS or 
non-porcine material. 
 
FDA has issued a health information advisory to make the public aware of FDAs ongoing effort 
to monitor the safety and quality of the heparin supply.10 
 
B.  Regulatory Authority 
 
As previously discussed, the manufacture of heparin generally involves the extraction and 
isolation of crude heparin from porcine intestinal mucosa and further purification of heparin.  
Crude heparin is often intended for use as a component of other drugs, including heparin sodium 
for injection and low molecular weight heparins. 
 
FDA considers the presence of OSCS or use of any non-porcine origin material, especially 
ruminant material (unless specifically approved in the drug application) in crude heparin, or any 
other form of heparin, to render that drug adulterated under section 501 of the Federal Food, 
Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 351).   
 
Medical devices may also contain drug components such as heparin.  For example, certain 
medical devices may be coated with heparin.  FDA also considers the presence of OSCS or any 
non-porcine origin material, especially ruminant material (unless specifically approved in the 
device application) in a device containing heparin to render that product adulterated under 
                                                 
8
 Butler, D., British BSE Reckoning Tells a Dismal Tale, Nature 1998, 392: 532-533. 
9 Scientific Opinion on BSE Risk in Bovine Intestines, EFSA Panel on Biological Hazards, European Food Safety 
Authority, EFSA Journal 2009, (1317): 1-19. 
10 Public Health Update: Recall of Heparin Sodium for Injection (2/28/2008), 
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm112665.htm;  
Follow-up Notice to Heparin Device Manufacturers and Initial Distributors (4/8/2009), 
http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm135352.htm. 
3   Contains Nonbinding Recommendations 
 
section 501 of the FD&C Act (21 U.S.C. 351).11  Under 21 CFR 820.50 and 820.80, medical 
device manufacturers are required to have purchasing controls and acceptance activities to ensure 
that devices containing heparin meet specified requirements.   
 
FDA requires manufacturers of drugs to ensure the identity, strength, quality, and purity of their 
products.  (See, e.g., 21 CFR 211.84 and 211.100 for finished pharmaceuticals.)  FDAs 
guidance for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical 
Ingredients (ICH Q7)12 provides guidance on proper material control in the manufacture of APIs 
and use of API starting materials, including, but not limited to, a supplier management program 
that ensures use of only qualified material suppliers.13  Also, FDAs guidance for industry Q9 
Quality Risk Management (ICH Q9) provides guidance regarding the application of risk 
management principles to the manufacture of drugs.  It is critical that a firms quality control 
program ensure the safety and quality of crude heparin used to make FDA-regulated products.  It 
is equally important that firms engage in business only with appropriately qualified suppliers. 
 
For medical devices, the control of suppliers is addressed in the Quality System Regulation 
under purchasing controls (21 CFR 820.50).  The relationship between purchasing controls and 
acceptance activities (21 CFR 820.80) is vital and directly related to design controls, especially 
the output of risk analyses and other risk management activities (21 CFR 820.30(g)) to support 
better decision-making and establish the type and extent of controls commensurate to the risk.14 
 
 
                                                 
11
 The presence of OSCS or any non-porcine origin material, especially ruminant material, in products containing 
heparin may also implicate other violations of the FD&C Act. 
12 In November 2005, ICH renamed Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical 
Ingredients (ICH Q7A) as Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (ICH 
Q7).  We update guidances periodically.  To make sure you have the most recent version of a guidance, check the 
CDER guidance page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
13 See ICH Q7 section VII, Materials Management. 
14
 In addition to purchasing controls, acceptance activities, and design controls, there are other requirements under 
21 CFR Part 820.  For example, manufacturers must have procedures to control and evaluate nonconforming 
products (21 CFR 820.90) and implement any actions necessary to correct and prevent recurrence of nonconforming 
product and other quality problems escalated to corrective and preventive actions (21 CFR 820.100).  Ultimately, 
manufacturers of devices containing heparin must comply with all applicable requirements under 21 CFR Part 820. 
4   Contains Nonbinding Recommendations 
 
III.  Recommendations 
 
Because of the risk of potential heparin contamination in the future, it is important that 
manufacturers take steps to ensure that the heparin supply chain is not contaminated with OSCS 
or any non-porcine origin material, especially ruminant material, unless specifically approved in 
the drug or medical device application.  FDA recommends that drug establishments that receive 
or use crude heparin to manufacture drug products or heparin components for use in medical 
devices do the following: 
 
1.  Test and confirm the species origin of crude heparin in each lot of every shipment before use 
in the manufacture or preparation of a drug (including APIs, drug products, and heparin 
components for use in a medical device).   
 
The test method should be qualified for use in testing crude heparin and for the detection and 
identification of the species origin of ruminant material. The method should be based on good 
scientific principles (e.g., sufficient accuracy and specificity) and possess a level of sensitivity 
commensurate with the current state of scientific knowledge and risk.  FDA has posted an assay 
method for measuring ruminant contamination in crude heparin using real-time polymerase chain 
reaction (PCR, hMRTA).15  This method has been evaluated for suitability using crude heparin 
of porcine origin and bovine reference materials.  An alternative method or methods can also be 
qualified for use (i.e., sufficiently validated for the degree of precision/accuracy required for its 
use) in screening crude heparin for the presence of ruminant material.  
 
2.  Test for OSCS in crude heparin in each lot of every shipment before use in the manufacture 
or preparation of a drug (including APIs, drug products, and heparin components for use in a 
medical device).   
 
The test method should be qualified for use in testing crude heparin and suitable for detecting 
low levels of OSCS.  The method should be based on good scientific principles (e.g., sufficient 
accuracy and specificity) and possess a level of sensitivity commensurate with the current state 
of scientific knowledge and risk.  FDA has published an assay method for measuring OSCS 
contamination in crude heparin using strong anion exchange (SAX) high-pressure liquid 
chromatography (HPLC).16,17  This method has been evaluated using crude heparin of porcine 
origin and OSCS reference materials.  An alternative method or methods can also be qualified 
                                                 
15 See Heparin Multiplex Real-Time PCR Assay (hMRTA). This analytical method for crude heparin is available 
at http://www.fda.gov/AnimalVeterinary/ScienceResearch/ToolsResources/ucm350289.htm. 
16 See Analysis of crude heparin by 1H-NMR, capillary electrophoresis, and strong-anion-exchange-HPLC for 
contamination by over sulfated chondroitin sulfate, J. Pharm. Biomed. Anal. 51: 921-926 (2010).  This HPLC 
method has a limit of detection for OSCS of less than 0.1 percent.  This analytical method for crude heparin is 
available at  
http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM2062
30.pdf. 
17 For another assay method for detecting OSCS in crude heparin, see, Sommers, C.D., D.J. Mans, L.C. Mecker, and 
D.A. Keire. 2011. Sensitive Detection of Oversulfated Chondroitin Sulfate in Heparin Sodium or Crude Heparin 
with a Colorimetric Microplate Based Assay.  Anal. Chem. 83: 3422-3430. 
5   Contains Nonbinding Recommendations 
 
for use (i.e., sufficiently validated for the degree of precision/accuracy required for its use) in 
screening crude heparin for the presence of OSCS.  
 
3.  Know the identity and role of the actual manufacturer of crude heparin and any repackers and 
distributors who handle crude heparin before receipt and use.   
 
Manufacturers of APIs, finished drug products, and heparin components for use in medical 
devices should sufficiently audit18 and qualify their crude heparin suppliers to ensure 
conformance to appropriate quality standards.   
 
4.  Employ the controls described in ICH Q7 to prevent the use of crude heparin containing 
OSCS or ruminant or unlabeled sources of crude heparin and to fully and promptly 
investigate and resolve deviations and failures of quality, especially identity and purity. 
 
5.  Reject for use any crude heparin found to contain any amount of OSCS, or to be derived 
from, in any amount, ruminant mucosa (unless approved in the drug application).  If 
imported into the United States, control and properly dispose of any such crude heparin or 
heparin products in which it was used and notify the local FDA district office of the 
finding.19 
 
                                                 
18 See, e.g., CDRH Quality System Audits Medical Device Quality Systems Manual, available at 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequirements/QualitySystemsRegul
ations/MedicalDeviceQualitySystemsManual/ucm122726.htm. 
19 Applicants and/or manufacturers must comply with relevant postmarket requirements (e.g., for human drugs, 21 
CFR 314.81(b)(1)(ii); for animal drugs, 21 CFR 514.80(b); for medical devices, 21 CFR 803.50). 
 
6