Document ID: FDA-2012-D-0083-0009
Agency: fda
Document Type: Notice
Title: Guidance for Industry on Heparin for Drug and Medical Device Use: Monitoring Crude Heparin for Quality; Availability
Posted Date: 2013-06-25T04:00Z

[Federal Register Volume 78, Number 122 (Tuesday, June 25, 2013)]
[Notices]
[Pages 38058-38059]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-15100]

[[Page 38058]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2012-D-0083]

Guidance for Industry on Heparin for Drug and Medical Device Use: 
Monitoring Crude Heparin for Quality; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the 
availability of a guidance for industry entitled ``Heparin for Drug and 
Medical Device Use: Monitoring Crude Heparin for Quality.'' This 
guidance was initially published as a draft guidance on February 13, 
2012. The draft was revised to clarify FDA's expectations and 
recommendations and to include references to a recently-developed assay 
for detecting ruminant contamination of crude heparin.

DATES: Submit either electronic or written comments on Agency guidances 
at any time.

ADDRESSES: Submit written requests for single copies of this guidance 
to the Division of Drug Information, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 
51, Rm. 2201, Silver Spring, MD 20993-0002. Send one self-addressed 
adhesive label to assist that office in processing your requests. See 
the SUPPLEMENTARY INFORMATION section for electronic access to the 
guidance document.
    Submit electronic comments on the guidance to http://www.regulations.gov. Submit written comments to the Division of Dockets 
Management, Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Frank W. Perrella, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 4257, Silver Spring, MD 20993-0002, 301-
796-3265; or Dennis M. Bensley, Jr., Center for Veterinary Medicine, 
Food and Drug Administration, 7519 Standish Pl., Rockville, MD 20855, 
240-276-8268; or Scott McNamee, Center for Devices and Radiological 
Health, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 
66, Rm. 3416, Silver Spring, MD 20993-0002, 301-796-5523.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a guidance for industry 
entitled ``Heparin for Drug and Medical Device Use: Monitoring Crude 
Heparin for Quality.'' This guidance provides recommendations that will 
help active pharmaceutical ingredient (API) manufacturers, 
pharmaceutical and medical device manufacturers of finished products, 
and others, to prevent the use of crude heparin that might contain 
oversulfated chondroitin sulfate (OSCS) or non-porcine material 
(especially ruminant material) contaminants. This guidance on crude 
heparin recommends strategies to test for contamination and should be 
used in addition to the United States Pharmacopeia (USP) monograph 
testing required for other forms of heparin to detect the presence of 
OSCS.
    Following reports of serious adverse events (including deaths) 
among patients injected with heparin sodium in 2008, FDA identified the 
contaminant OSCS in crude heparin sourced from China. FDA is also 
concerned about the potential for contamination of heparin with 
ruminant materials. The control of the quality of crude heparin is 
important to ensure the safety of drugs and devices and to protect 
public health. FDA developed this guidance to alert manufacturers to 
the risks of crude heparin contaminants and to recommend strategies to 
ensure that the heparin supply chain is not contaminated with OSCS or 
any non-porcine ruminant material (unless specifically approved as part 
of drug or medical device application).
    The guidance recommends that manufacturers 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 or medical device 
containing heparin. The test method should be qualified for use in 
testing crude heparin and for the identification of species origin. 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 a method entitled ``Heparin Multiplex Real-Time PCR 
Assay (hMRTA),'' on the Internet at http://www.fda.gov/AnimalVeterinary/ScienceResearch/ToolsResources/ucm350289.htm. This 
method will be updated occasionally and persons performing the assay 
should visit the Web site regularly to ensure they are using the most 
current version.
    The guidance also recommends that manufacturers test for OSCS in 
crude heparin in each lot of every shipment before use, using a 
qualified test method that is suitable for detecting low levels of OSCS 
concentrations and is based on good scientific principles. FDA has also 
made an HPLC method for testing for the presence of OSCS in crude 
heparin available on the Internet at http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM206230.pdf. Users of this method should also review the Web site 
occasionally to ensure they are employing the most current version.
    In addition to testing crude heparin for species of origin and the 
presence of OSCS in crude heparin, manufacturers should 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 or 
device application). If imported into the United States, any such crude 
heparin or heparin products in which it was used should be controlled, 
and manufacturers should notify FDA of any such finding. The guidance 
also recommends that manufacturers identify and audit crude heparin 
suppliers and heparin API suppliers to ensure conformance to 
appropriate quality standards. Manufacturers should employ the controls 
described in the guidance for industry entitled ``Q7 Good Manufacturing 
Practice Guidance for Active Pharmaceutical Ingredients'' and comply 
with the quality system regulations (as applicable).
    This guidance is being issued consistent with FDA's good guidance 
practices regulation (21 CFR 10.115). The guidance represents the 
Agency's current thinking on Heparin for Drug and Medical Device Use: 
Monitoring Crude Heparin for Quality. It does not create or confer any 
rights for or on any person and does not operate to bind FDA or the 
public. An alternative approach may be used if such approach satisfies 
the requirements of the applicable statutes and regulations.

II. Comments

    Interested persons may submit either electronic comments regarding 
this document to http://www.regulations.gov or written comments to the 
Division of Dockets Management (see ADDRESSES). It is only necessary to 
send one set of comments. Identify comments with the docket number 
found in brackets in the heading of this document. Received comments 
may be seen in the Division of Dockets Management between 9 a.m. and 4 
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.

[[Page 38059]]

III. The Paperwork Reduction Act of 1995

    This guidance refers to previously approved collections of 
information found in FDA regulations. These collections of information 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). In the 
guidance, FDA advises drug and medical device manufacturers who receive 
and use crude heparin to manufacture drugs and medical devices to 
notify the Agency of crude heparin found to contain any amount of OSCS, 
or to be derived from, in any amount, ruminant mucosa (unless approved 
in the drug or device application) (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). The collections of information in 21 CFR 
314.81(b)(1)(ii) have been approved under OMB control number 0910-0001; 
in 21 CFR 514.80(b) under OMB control number 0910-0284; and in 21 CFR 
803.50 under OMB control number 0910-0437.

IV. Electronic Access

    Persons with access to the Internet may obtain the document at 
either http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or http://www.regulations.gov.

    Dated: June 19, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-15100 Filed 6-24-13; 8:45 am]
BILLING CODE 4160-01-P