Elevated anti-collagen antibody levels have been detected in patients treated with clinical doses of injectable collagen, even in the absence of adverse cutaneous reactions ^A32697. Antibodies to both native type I bovine and human collagen can lead to a variety of symptoms including joint inflammation, edema at the injection site of bovine collagen implant and fever, as late as 6 months after injection ^A32702, ^A32703.

Products derived from bovine tissues, especially gelatine, tallow and dicalcium phosphate have been studied in relation to bovine spongiform encephalopathy (BSE) and Creutzfeld-Jacob disease (CJD) ^A32698. The risk of BSE and CJD is dependent on many factors, including the country of origin of the bovine collagen, the health of the cattle from which the collagen is obtained, and practices during processing. Denaturation temperature is a particularly important parameter, depending on the collagen origin and hydration level ^A32699. According to the World Health Organization (WHO), prolonged alkaline treatment, filtration, and heat sterilization (? 138o C for ? 4 sec) or an equivalent process on gelatin is a safe practice in preventing BSE ^L2497.

The collagen manufacturing process may have some steps in common with the manufacture of gelatin such as alkaline and sodium sulfate treatment, calcium hydroxide and sodium hydroxide treatments or enzyme treatment. These common steps can, however, differ in duration and pH condition which can result in significant differences in their prion inactivation capacity. Manufacturers should at least conduct a process evaluation based on the similarities of the collagen processing steps, as compared to known inactivation steps in the manu­facture of gelatin, to support the safety of the product. Outside of the processing steps, differences also exist in the final use of the material and, as a result, in their risk assessment, while gelatin is widely used for oral administration, many collagen applications are in the form of implants. This should be considered in the final risk assessment of type I bovine collagen products ^L2498.

According to the EMA (European medicines agency), collagen produced from tissues such as hides, skins, tendons, and sinews do not usually present a measurable TSE risk provided that contamination with potentially infected materials, for example, spillage of blood and/or central nervous tissues, is avoided during procurement. Hides represent a safer raw material for human implants derived from collagen. However, cross-contamination with brain material released during the slaughtering process, possibly dried on the surface of hides is difficult to eliminate. This is another aspect to consider in the evaluation of the safety of bovine type I collagen ^L2497.