Pancreatic Enzymes - pancrelipase; pancreatin; lipases, proteases and amylase, porcine

Cross ref.: See the Pancrealipase and Liprotamase entries.

Status: a variety of products marketed as nutritional supplements, nutraceuticals and therapeutics

Description: Digestive enzymes extracted from bovine (cow) and porcine (pig) pancreas have long been used for treatment of pancreatic insufficiency, including marketing over-the-counter (OTC; non-prescription), but with those newly marketed since 1995 available by prescription only. Many other pancreatic enzyme products (PEPS) are now also marketed as nutritional supplements or nutraceuticals. For Biopharmaceutical Products in the U.S. and European Market, these are considered primarily natural products, not biopharmaceuticals.

PEPs aid in the digestion of meals in patients who have diseases affecting their pancreatic function, e.g., cystic fibrosis and chronic pancreatitis. PEPs contain the ingredients pancreatin and pancrelipase, both of which contain the enzymes lipase, protease, and amylase. These enzymes break down fats (lipase), proteins (protease) and complex carbohydrates (amylase) to allow absorption of these nutrients into the body.

Companies.: Current U.S. manufacturers of PEPs marketed as drugs and/or PEP active pharmaceutical ingredients (API), as reported by FDA (May 2004) include: Anabolic Inc.; Carlsbad Technology Inc.; Choongwae Pharma Corp.; Contract Pharmacal Corp.; Digestive Care Inc.; Eurand Inc.; Eurand SPA; Global Pharmaceuticals; Janssen Ortho LLC (subsidiary of Johnson & Johnson); KV Pharmaceutical Co.; Laboratories Confab Inc.; Neil Labs.; Organon USA Inc.; Patheon Inc.; PFAB LP DBA Pharmafab; Schwarz Pharma Inc.; Schwarz Pharma Manufacturing Inc.; Solvay Pharmaceuticals GMBH; Valpharma SA; Yung Shin Pharmaceutical Industries Co.; and Scientific Protein Labs. This list is likely not be fully inclusive

Scientific Protein Labs. (SPL) is reported to be the primary source for crude porcine pancreatic enzyme, supplying an estimated 65% of pancreatic enzymes used in the U.S. SPL sources is pancrease materials from pigs reared in the U.S.

Status: PEPs of porcine or bovine origin have largely been treated by FDA as grandfathered products. PEPs have been available in the U.S. as prescription and OTC drug products for the treatment of exocrine pancreatic insufficiency in children and adults with cystic fibrosis and chronic pancreatitis diseases since before the enactment of the Federal Food, Drug, and Cosmetic Act of 1938 requiring “new drugs” to be the subject of NDAs. FDA has always regulated PEPs, to the extent that it monitored the labeling and manufacturing processes. However, with the exception of one PEP (Cotazym) approved in 1996, PEPs have been marketed without NDAs. Thus, technically, no currently marketed pancreatic enzyme product has been shown to demonstrate consistent enzyme bioactivity with predictable safety and effectiveness.

Over the years, FDA received reports of problems associated with these drugs, initially involving adverse events associated with high doses. More recently, FDA has received a number of reports claiming that these products do not have the expected therapeutic effect, indicating inactive or inadequate amounts of enzymes in capsules.

In April 2004, FDA announced that all exocrine pancreatic insufficiency drug products are new drugs and various conditions for continued marketing of these drug products, including that all products must be available by prescription only. manufacturers of PEPs have four years to submit NDAs (presumably, for generic approval). These regulations do not apply to products marketed as nutritional supplements or nutraceuticals.

Pancreatic enzyme product capsules have been typically overfilled based on manufacturing standards that allowed a range of lipase content from 90% to 165% of label claims. But with the new regualations, the FDA called for a “zero overfill” target.

Only one PEP had ever received NDA approval prior to implementation of the new regulations, Cotazym from Organon Teknika, but this is no longer manufactured. Creon (see related entry) became the first approved under the new regulations.

An upcoming exclusivity battle over PEPs may concern whether each PEP is a new chemical entity eligible for 5-year exclusivity or whether 3-year “new use” exclusivity applies. An FDA determination that all PEPs are different and eligible for 5-year exclusivity is consistent with recent FDA policy conferring 5-year exclusivity “to products about which the Agency has insufficient information to know whether they contain a previously approved active moiety.” FDA has indicated that such a policy is applicable to PEPs.

As of March 1, 2012, FDA had approved five PEPs because they meet the regulatory standards for quality, safety, and effectiveness. Creon and Zenpep were approved for marketing in 2009, Pancreaze was approved in April 2010, and Ultresa and Viokace were approved in March 2012. [Also, Cotazyme was approved with a full NDA in 1996, but is not marketed].

Market: PEPs have been marketed in the U.S. for exocrine pancreatic insufficiency since before the enactment of the FDC Act in 1938 (i.e., these products were grandfathered).

FDA requirements for NDAs for PEPS are not expected to significantly alter the market or costs, with multiple manufacturers gaining NDAs.

The world market for pancreatic enzyme supplements is about $350-$400 million.

The U.S. market for pancreatic enzymes has been reported to be about 30,000 patients, the great majority with cystic fibrosis, most of whom require pancreatic enzyme to maintain proper nutrition (and their lives). However, FDA views the market much more broadly, citing an "estimated 200,000 patients in the United States who have pancreatic insufficiency" and in this context, the products do not qualify for orphan designation.