U.S. Department of Health and Human Services,
CDRH BSE Working Group
Until February 4, 1999, comments and suggestions regarding this document should be submitted to Docket No. 98D-0924, Dockets Management Branch, Division of Management Systems and Policy, Office of Human Resources and Management Services, Food and Drug Administration, 12420 Parklawn Drive (HFA-305), Room 1-23, Rockville, MD 20857. Such comments will be considered when determining whether to amend the current guidance.
After February 4, 1999, comments and suggestions may be submitted at any time for Agency consideration to: Kiki B. Hellman, Ph. D., Office of Science and Technology (HFZ-113), Center for Devices and Radiological Health, Food and Drug Administration, 9200 Corporate Blvd., Rockville, MD 20850. Comments may not be acted upon by the Agency until the document is next revised or updated. For questions regarding the use or interpretation of this guidance contact Kiki B. Hellman, Ph. D. at (301) 443-7158 or Karen F. Warburton, Office of Device Evaluation (HFZ-460).
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 2206 to identify the guidance you are requesting.
Medical Devices Containing Materials Derived from Animal Sources (Except In Vitro Diagnostic Devices), Guidance for FDA Reviewers and Industry
Introduction and Background
Bovine Spongiform Encephalopathy (BSE) is a degenerative disease which affects the central nervous system of cattle. It is similar to other transmissible spongiform encephalopathies (TSEs) such as scrapie in sheep and Creutzfeldt-Jakob Disease (CJD) in humans. At this point in time the incubation period of BSE appears to be from 2 to 8 years. There is currently no treatment, nor is there a validated test to detect the disease in a live animal. Diagnosis is determined by microscopic examination of brain tissue. The nature of the BSE agent is widely theorized to be a prion, an abnormally folded version of a normal cellular protein. The abnormal protein then recruits additional molecules of normal protein and facilitates their conversion to the abnormal form. The agent is extremely resistant to traditional forms of disinfection and sterilization. As new information on the diagnosis, treatment and nature of the agent becomes available, this guidance will be modified as appropriate.
Epidemiologic data suggest that the BSE epidemic in Great Britain which began in 1986 occurred through feeding cattle contaminated meat and bone meal as a protein source. The BSE agent may have been present for a long time, but changes in rendering procedures in the late 70's and early 80's may have enabled the active agent to survive in the animal feeds. The agent is thought to be from scrapie-infected sheep, but cattle with a previously unidentified TSE have not been ruled out. An association between cases of variant CJD in Great Britain and BSE seems likely, although causality has not been proved. To date, there have been no cases of BSE in the United States.
The possibility of introducing the BSE agent through a medical device requires special attention on the part of manufacturers with regard to the sourcing and processing of bovine-derived material. At present this can most easily be accomplished by assuring that the source cattle are free of BSE. In 1993 and more recently, on May 9, 1996, the Food and Drug Administration (FDA) issued letters to manufacturers to request that bovine-derived materials from cattle which have resided in or originated from countries where BSE has been diagnosed not be used in the manufacture of FDA-regulated products. (Attachments 1, 2 and 3)
Since 1989, the USDA has restricted the importation of live ruminants from Great Britain. Currently the USDA restricts the importation of live ruminants from countries where BSE is known to exist, and from those countries that present a significant risk of introducing BSE into the United States. Also restricted (by USDA) from import from these countries are other ruminant-derived products such as bone meal, meat and bone meal, blood meal, offal, glands, and gelatin for animal consumption. FDA recently prohibited protein derived from mammalian tissues to be used in ruminant feed for animals in the US (Federal Register June 5, 1997; 21 CFR Part 589 "Substances Prohibited From Use in Animal Food or Feed; Animal Proteins Prohibited in Ruminant Feed").
To track medical devices which either contain or are exposed to animal-derived materials during manufacturing (e.g., human cells grown in media containing fetal calf serum), CDRH has developed the CDRH Biomaterials Database which contains an inventory of these devices, including type of material, animal species and country of origin, and target organ or tisssue for each device. Originally proposed in response to the BSE issue, the Database was expanded to include all animal-derived products (including human) in order to respond to other animal material-based sourcing concerns that may arise in the future.
Purpose of Guidance
The purpose of this document is to provide recommendations for information to be included in submissions (IDE, PMA, 510(k)) for medical devices which either contain or are exposed to animal-derived materials during manufacturing. This will reduce the liklihood of the transmission of BSE through medical devices and will provide a profile of the animal-derived materials which can be used in risk analysis of the devices.
Scope of Guidance
This guidance is applicable to all medical devices, except in vitro diagnostic devices, which either contain or are exposed to animal-derived materials during manufacturing. All animal species (e.g., human, bovine, ovine, porcine, avian (e.g., chicken), fish, etc.) are included.
Recommendations for Medical Devices Containing Materials Derived From BOVINE Sources
- All materials in a device which are derived from a bovine source should be identified. Examples are: bovine pericardium used in heart valves, bovine viscera used in gut sutures, bovine bone used in dental implants, and bovine collagen used in lacrimal plugs. These also include devices which are exposed to materials of bovine origin during manufacture (e.g., human cells grown in media containing fetal calf serum, tissue culture cells exposed to bovine trypsin.)
The bovine material should come from cattle which have not originated from or resided in a country where BSE has been diagnosed or which presents a significant risk of introducing BSE. This list of countries is maintained by the USDA and codified in 9 CFR 94.18. The countries currently identified include all countries of Europe.
Countries in which BSE exists:
Great Britain (including Northern Ireland and the Falklands)
Republic of Ireland
Countries which present significant risk:
Federal Republic of Yugoslavia
the former Yugoslav Republic of Macedonia
the Slovak Republic
- Traceable records should be maintained by the device manufacturer for each lot of bovine material and each lot of FDA-regulated product. Records should indicate the country of origin and residence of the animals. The bovine tissue source (e.g. bone, heart valve, ligament/tendon) should also be indicated.
If the manufacturer certifies that the bovine-derived material is only available from a country where BSE is known to exist, then the manufacturer should provide evidence to indicate that the BSE agent is inactivated during the manufacturing process. A detailed description of the manufacturing process should be submitted. Evidence of inactivation may be derived from one or more of the following:
a. Validation study using an appropriate model (e.g., scrapie in mice.) If a validation study protocol and/or data are submitted the reviewer should contact the Division BSE Focal Point (see below) for further guidance. Manufacturers are encouraged to consult with FDA during protocol development. Validation studies take at least 2 years to complete, are technically difficult, and may require review by experts in the TSE field. The TSE Advisory Committee will be consulted as appropriate.
b. Other valid scientific evidence (e.g., scientific literature to support specific processing methods of specific tissues (e.g, hydroxyapatite obtained from bovine bone.))
The FDA has recently changed its position with regard to the use of gelatin. A guidance document has been issued regarding the use of gelatin in FDA-regulated products for human use (Attachment 4). The guidance pertinent to medical devices reads:
"Gelatin produced from bones and hides obtained from cattle residing in, or originating from, countries reporting BSE or from countries that do not meet the latest BSE-related standards of the Office International des Epizooties (OIE) should not be used either in injectable, ophthalmic, or implanted FDA regulated products, or in their manufacture."
The guidance also states:
"At this time there does not appear to be a basis for objection to the use of gelatin produced from bovine hides and bones in FDA products for human use if the gelatin is produced in the United States from US-derived raw materials or from cattle born, raised and slaughtered in other countries that have no reported BSE cases and that meet OIE BSE standards."
- There are currently no restrictions on bovine milk and milk-derived products.
Note--Future Considerations: FDA is considering other changes in its policy concerning BSE and the safety of regulated products. Options to be considered in the future include evaluation of a country's compliance with BSE related standards of the Office International des Epizooties; and evaluating products with regard to the risk posed by the bovine tissue source and end use, in addition to the country of origin. For example, bovine neural tissue implanted in the central nervous system would pose a much greater risk than a few microliters of highly purified bovine pancreatic trypsin used in a manufacturing process to recover tissue culture cells which are further purified before use.
Experimental data with the mouse/scrapie model suggest that brain and spinal cord tissue from TSE-infected animals have high levels of infectivity; tissues such as lymph nodes and spleen are of medium infectivity; tissues such as bone marrow and liver may sometimes have low levels of infectivity. Experiments with TSE agents also indicate that the intracerebral route of inoculation is the most efficient way of transmitting the disease, followed by parenteral inoculation; the oral route is the least efficient.
Another future option might be to encourage the use of closed herds for material sources. Animals of known lineage, husbandry and medical history should provide the safest sources. Should BSE be discovered in the United States, a closed herd would become a significantly more important source for bovine material. Because the incubation time for BSE is long (2-8 years) herds would have to be closed for at least 3 years for isolation to be meaningful.
Whenever FDA changes policy on BSE, this guidance document will be revised accordingly.
Recommendations for Medical Devices Containing Materials Derived From Animal Sources OTHER Than Bovine
All materials in a device derived from any animal source, including human, should be identified by tissue type and species of origin. Some examples of materials are: porcine heart valves, porcine collagen corneal shields, porcine blood vessels used in vascular grafts, porcine collagen used in wound dressings, and hyaluronic acid from rooster combs used in viscoelastic fluids. This also includes devices exposed to materials of animal origin during manufacture (e.g. porcine trypsin used in artificial skin.)
- Country of origin/residence should be identified for all materials.
- For products derived from human tissue, refer to 21 CFR 1270, Human Tissue Intended for Transplantation, for additional requirements.
CDRH Biomaterials Database
Reviewers will evaluate submissions to identify products which contain or are exposed to animal-derived materials. Information on these products will be entered into the CDRH Biomaterials Database (Attachment 5).
The acknowledgement letter issued to manufacturers upon receipt of the IDE, PMA or 510(k) submission will prompt them to notify the reviewing Division if the device contains an animal or human derived material and such information was not provided in the original submission.
BSE Working Group:
Chair: Kiki Hellman (OST)
ODE Division Focal Points:
DGRD: David Berkowitz
DCLD: Claudia Gaffey/Gus Gonzalez
DCRND: Lisa Kennell
DOD: Karen Warburton
DRAERD: Raju Kammula
DDIGD: Pandu Soprey
Stan Brown (OST)
Ken Krell (OMS)