Contains Nonbinding Recommendations 
 
 
Heparin-Containing Medical Devices 
and Combination Products: 
Recommendations for Labeling and 
Safety Testing 
Guidance for Industry and 
Food and Drug Administration Staff  
Document issued on: September 20, 2018. 
The draft of this document was issued on July 9, 2015. 
 
For questions about this document, contact the CDRH Product Jurisdiction Officer at 
CDRHProductJurisdiction@fda.hhs.gov. 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Devices and Radiological Health 
 
  Contains Nonbinding Recommendations 
Preface 
Public Comment
 
You may submit electronic comments and suggestions at any time for Agency consideration to 
https://www.regulations.gov. Submit written comments to the Dockets Management Staff, Food 
and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 20852. 
Identify all comments with the docket number FDA-2015-D-2167. Comments may not be acted 
upon by the Agency until the document is next revised or updated. 
Additional Copies 
Additional copies are available from the Internet.  You may also send an e-mail request to CDRH-
Guidance@fda.hhs.gov to receive a copy of the guidance. Please use the document number 1817 
to identify the guidance you are requesting.   
Heparin-Containing Medical Devices 
and Combination Products: 
Recommendations for Labeling and 
Safety Testing 
Guidance for Industry and 
Food and Drug Administration Staff  
This guidance represents the current thinking of the Food and Drug Administration (FDA or 
Agency) on this topic.  It does not establish any rights for any person and is not binding on 
FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff 
or Office responsible for this guidance as listed on the title page.  
1. Introduction1 
The United States Pharmacopeia (USP)2 drug substance monograph for Heparin Sodium, and 
drug product monographs for Heparin Lock Flush Solution and Heparin Sodium Injection, 
recently have undergone several revisions following serious and fatal events related to the use of 
heparin sodium products.3 Investigation of heparin product overdose errors identified the 
expression of drug strength in the labels as a major contributing factor in these errors. This 
guidance document addresses these safety concerns by clarifying new expectations for labeling 
with regard to the revised heparin USP monographs,4 as well as outlining safety testing 
recommendations. 
                                                 
1 The Office of Combination Products (OCP) and the Center for Drug Evaluation and Research (CDER) were 
consulted in the preparation of this guidance. 
2 The United States Pharmacopeial Convention is a scientific nonprofit organization that develops standards for the 
identity, strength, quality, and purity of drugs and drug ingredients marketed in the United States. These standards 
are published in the compendia, U.S. Pharmacopeia and National Formulary (USP-NF). The Federal Food, Drug, 
and Cosmetic Act (FD&C Act) recognizes the USP-NF as official compendia. Section 201(j) of the FD&C Act. 
3 USP Monograph: Heparin Sodium, USP Monograph: Heparin Sodium Injection, USP Monograph: Heparin Lock 
Flush Solution. The FD&C Act generally requires a drug product to conform with an applicable official USP drug 
product monograph. Sections 501(b) and 502(g) of the FD&C Act. 
4 See also FDA Drug Safety Communication: Important change to heparin container labels to clearly state the total 
drug strength (available at https://www.fda.gov/Drugs/DrugSafety/ucm330695.htm). 
 
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In addition, the outbreak of serious and often fatal events due to heparin contamination with 
oversulfated chondroitin sulfate (OSCS) in 2008 led the USP to include in its drug substance 
monograph additional testing of heparin sodium to ensure its quality and purity. This guidance 
also outlines use of conformance to the monographs in premarket submissions, namely testing 
specified in the current USP monographs and testing and documentation recommendations 
contained in the guidance document Heparin for Drug and Medical Device Use: Monitoring 
Crude Heparin for Quality.5,6 
Note that recommendations made in this guidance reflect FDAs current position on this issue 
and may change in the future as new scientific information or new detection methods become 
available. FDA intends to revise this guidance document as needed to reflect any additional 
revisions to these USP heparin monographs. 
For the current edition of the FDA-recognized standard(s) referenced in this document, see the 
FDA Recognized Consensus Standards Database Web site at 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm. 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agency's 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 guidances means that something is suggested or 
recommended, but not required. 
2. Scope 
This guidance provides labeling and safety testing recommendations for medical devices and for 
combination products that include heparin sodium or low molecular weight heparin that have a 
device primary mode of action (PMOA) or are otherwise assigned to CDRH for regulation.7 
Note that some devices for in vitro diagnostic uses include heparin. Such products can be 
classified as devices if the heparin would not come into contact with the body when the product 
is used as intended. Products that include a device and heparin for in vivo use are combination 
products.8 Products that include only bonded coatings of heparin sodium or low molecular 
weight heparins with a fixed total dose of heparin are unlikely to pose a risk of heparin overdose 
and recommendations in this guidance may not be warranted; however, recommendations in this 
guidance may be appropriate for these types of products in certain instances, such as in cases 
where significant amounts of heparin are found to be released.  
                                                 
5 Available at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291390.  
6 The Agency updates guidances periodically. To make sure you have the most recent version of this guidance, 
check the FDA guidance page at 
https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
7 Center assignment for combination products is based on which constituent part (the drug or device in this case) 
provides the PMOA, i.e., makes the greatest contribution to the overall intended therapeutic effects of the 
combination product. See section 503(g)(1)(C) of the FD&C Act; 21 CFR 3.2(m). If PMOA cannot be determined 
with reasonable certainty, Center assignment is based on application of the criteria at 21 CFR 3.4(b). 
8 For additional information on combination products, please visit 
https://www.fda.gov/CombinationProducts/default.htm. 
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3. Background
 
Heparin has been identified as a high-alert medication by the Institute for Safe Medication 
Practices (ISMP) due to a heightened risk of patient harm when dosed incorrectly. In 2003, the 
USP's Safe Medication Use Expert Committee recognized a recurring trend of medication errors 
related to misinterpretation of the expression of concentration on the labeling of injectable 
products, resulting in serious consequences to patients, including death. Heparin products span a 
wide range of doses and concentrations based on the indication for use for the product as well as 
the intended patient population. Heparin administration for systemic anticoagulation is provided 
as final concentrations ranging from 50-100 units/mL. The source vials from which these 
dilutions are prepared contain concentrations ranging from 1,000-20,000 units/mL. When 
heparin sodium is only intended to maintain patency of an indwelling intravascular catheter, the 
heparin lock flush solution (which is regulated by FDA as a drug-device combination product 
with a device PMOA (see 71 FR 47499 (August 17, 2006)), typically includes heparin 
concentrations ranging from 1-100 units/mL packaged in 1-30 mL vials with total drug content 
ranging from 1 unit to 1,000 units or a variety of fill volumes in prefilled syringes with total drug 
amounts per syringe ranging from 1 unit to 500 units.  
In 2007, the USP Parenteral Products-Industrial Expert Committee recommended revisions to the 
new "Strength and Total Volume for Single- and Multiple-Dose Injectable Drug Products" 
section of USP General Chapter <1> Injections. These revisions became official in 2009 and this 
information was subsequently relocated to General Chapter <7> Labeling in 2016. This chapter 
directs that for single- and multiple-dose injectable drug products, the strength per total volume 
should be the primary and prominent expression on the principal display panel of the label, 
followed in close proximity by strength per mL enclosed by parentheses. Following these 
changes, FDA and ISMP expressed concern that the labeling prescribed in the Heparin Lock 
Flush Solution monograph (and in the Heparin Sodium Injection monograph) was inconsistent 
with General Chapter <7> Labeling. USPs Expert Committees, including the committee 
responsible for these Heparin monographs at that time, Monographs-Biologics and 
Biotechnology 1, proposed revisions to the labeling sections of the heparin monographs that 
would incorporate the USP standards for labeling for injectable medications, specifically, USP 
General Chapter <1> Injections, Strength and Total Volume for Single- and Multiple-Dose 
Injectable Drug Products (which now appears in <7> Labeling). Those revisions became 
official May 1, 2013. 
4. Labeling Statements 
 
A.  For Heparin Lock Flush Solution Products 
The USP monograph for Heparin Lock Flush Solution requires the product labels9 express 
strength per total container volume as the primary expression of strength, followed in close 
                                                 
9 Under section 201(k) of the FD&C Act, The term label means a display of written, printed, or graphic matter 
upon the immediate container of any article; and a requirement made by or under authority of this Act that any word, 
statement, or other information appear on the label shall not be considered to be complied with unless such word, 
 
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proximity by strength per mL enclosed by parentheses, for single- and multiple-dose injectable 
drug products. The strength per total volume should be the primary and prominent expression on 
the principal display panel of the label.10 For example: 
Total strength/total volume:   100   Units/10 mL 
USP
                        Strength/mL:       (10   Units/mL) 
USP
For products containing a volume of less than 1 mL, the strength per fraction of an mL should be 
the only expression of strength.11 For example; 
Strength/mL:       100   Units/0.5 mL 
USP
For products containing a volume equal to 1 mL, the strength should be expressed as strength per 
mL, not strength/1 mL. 
    Strength/mL:      100   Units/mL 
USP
The Agency further recommends that the above information be included in the instructions for 
use as part of the device/combination product description. Consistent with the monograph, the 
label must identify the organ (e.g., intestinal mucosa) and the animal species (e.g., porcine) from 
which the heparin sodium is derived.12 
B.  For HeparinBonded Products 
Specific labeling for the amount and strength of heparin for heparin-bonded products is not 
generally needed. However, there may be additional labeling considerations based on the specific 
device type and review of the product. For example, the Agency may recommend that the 
amount and strength of heparin be included in the label if significant amounts of heparin were 
found to be leaching from a product. In such cases, the total amount of heparin per total surface 
area should be displayed on the primary package label followed by the concentration per area 
unit in parentheses. For example: 
Total amount of heparin/total surface area:  100   Units/total surface area2 
USP
  Strength/area unit:         (10   Units/unit of surface area2) 
USP
The Agency further recommends that the above information, if requested, be included in the 
instructions for use as part of the device/combination product description. For all heparin-bonded 
products, the Agency recommends the labeling identify the tissue (e.g., intestinal mucosa) and 
the animal species (e.g., porcine) from which the heparin sodium is derived. 
                                                 
statement, or other information also appears on the outside container or wrapper, if any there be, of the retail 
package of such article, or is easily legible through the outside container or wrapper.  
10 USP Monograph: Heparin Lock Flush Solution. 
11 Id. 
12 Id. 
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5. Safety Testing for Heparin-Containing Products 
Manufacturers of heparin lock flush solutions must comply with the current USP monograph for 
that product, as well as the USP drug substance monograph for Heparin Sodium. Manufacturers 
of heparin sodium injections must comply with the current USP monograph for that product, as 
well as the USP drug substance monograph for Heparin Sodium. See sections 501(b) and 502(g) 
of the FD&C Act. Firms are also recommended to follow the guidance document, Heparin for 
Drug and Medical Device use: Monitoring Crude Heparin for Quality, mentioned above. 13,14  In 
addition, we recommend that manufacturers who receive heparin sodium drug substance or 
active pharmaceutical ingredient (API) that is represented to be USP to produce a combination 
product or an in vitro diagnostic medical device that includes heparin sodium or low molecular 
weight heparin ensure and document that the heparin has been tested according to the current 
USP drug substance monograph, and that it is manufactured and/or tested consistent with 
applicable guidance documents on heparin. Manufacturers of medical devices and combination 
products containing heparin must comply with the elements of safety testing that are required to 
be performed and documented as part of compliance with the Quality System (QS) regulation for 
devices (21 CFR 820), and with both the QS regulation and current good manufacturing practice 
requirements for drugs if the product is a combination product (see 21 CFR Part 4).  
Premarket submissions to CDRH  premarket notification (510(k)) submissions, premarket 
approval (PMA) applications, De Novo requests, and humanitarian device exemption (HDE) 
applications  should describe the heparin product in detail and document compliance with 
heparin safety testing. Please note, however, that heparin testing data and records should be 
maintained on file with the medical device or combination product manufacturer, but do not need 
to be included in premarket submissions. See Appendix A for more details. The premarket 
submission should include the following information: 
  Heparin source-tissue and confirmation of species origin (e.g., porcine intestinal 
mucosa); 
  Identification of the actual manufacturer (i.e., name, address, and contact information) of 
the heparin sodium API and any repackagers and distributors who handle the heparin 
sodium before receipt. 
The premarket submission should also provide the following to indicate the manufacturers 
conformance with testing parameters from the guidance Heparin for Drug and Medical Device 
Use: Monitoring Crude Heparin for Quality. 
  Testing for OSCS using methods that are qualified and suitable for detecting low levels 
of OSCS concentrations (e.g., strong anion exchange high-pressure liquid 
chromatography and 1H Nuclear Magnetic Resonance). 
                                                 
13 Available at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291390.  
14 In addition, the Center for Drug Evaluation and Research (CDER) has issued a guidance for industry, 
Immunogenicity-Related Considerations for Low Molecular Weight Heparin, available at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM392194.  
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  Heparin-containing combination products and medical devices should also comply with 
the contaminant safety testing recommendations in the USP monograph on Heparin 
Sodium and the Center for Drug Evaluation and Researchs (CDERs) guidance 
recommendations15 to detect OSCS contamination of heparin and to identify of the 
animal origin of the heparin.
                                                 
15 Heparin for Drug and Medical Device Use: Monitoring Crude Heparin for Quality, available at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291390. 
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Appendix A - Documentation of Heparin Safety Testing 
FDA recommends that the following Heparin Safety Controls testing data and records of crude 
heparin, heparin API, and heparin product be maintained on file: 
  Heparin crude: 
  Procedure(s) followed to reject, control, and properly dispose of any crude 
heparin found to contain any amount of OSCS or ruminant material contaminant 
and notify the local FDA district office of the finding, as well as documentation of 
all related actions taken. 
  Heparin sodium (including heparin sodium used to make low molecular weight heparin): 
  Description of controls used to prevent the use of heparin containing OSCS or any 
other contaminants (e.g., USP monograph tests, ICH Q7, Good Manufacturing 
Practice Guide for Active Pharmaceutical Ingredients). 
  Description of how the manufacturer followed CDERs heparin guidance, 
Heparin for Drug and Medical Device Use: Monitoring Crude Heparin for 
Quality.16  
  Although batches of heparin sodium that have deviated from specifications, have 
failed testing, or that are contaminated should be rejected and not enter the supply 
chain, all procedure(s) followed to fully and promptly investigate and resolve 
deviations and failure of quality or document that the heparin sodium has been in 
compliance, as well as documentation of all related actions taken should be 
maintained on file. 
  Heparin product: 
  If further manipulation of the USP heparin product in your manufacturing 
activities is required, documentation that this additional manipulation will not 
interfere with product purity or effectiveness.  
 
                                                 
16 Available at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291390. 
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