2003D-0206 - Draft Guidance for Industry on Exocrine Pancreatic Insufficiency Drug Products--Submitting New Drug Application; Availability
FDA Comment Number : EC12
Submitter : Dr. Tibor Sipos Date & Time: 07/12/2004 12:07:22
Organization : Digestive Care, Inc.
Drug Industry
Category :
Issue Areas/Comments
PART 10 OF 10
DOCKET NO. 2003D-0206 (2003N-0205)


In conclusion, DCI comments and recommendations are as follows.

Chemistry, Manufacturing, and Controls Section of the Application:

 We recommend the determination of lipase, amylase, and protease to characterize the catalytic activity of the drug product per dosage unit. Lipase potency is the absolute criteria for product activity and identity. Identification and characterization of pancrelipase containing product needs to be based on catalytic activity; e.g. able to hydrolyze lipid substrate (triglycerides) into free fatty acids and monoacyl glycerol, proteins into peptides and amino acids, and starches into dextrins and maltose as determined by official USP test methods.

 Establishing lipase, amylase, and protease enzyme ratio specification for the finished drug product is impractical and unachievable.

 Isoelectric focusing, SDS-PAGE electrophoresis or HPLC techniques are not suitable for the identification and characterization of pancrelipase extracts.

 The IR spectrophotometric method, employing the KBr pellet technique, is useful for the physico-chemical identification and characterization of pancrelipase drug substance and drug product.

 Excessive tightening of specifications will result in a short shelf life that will significantly increase costs without adding safety benefits. The overall economic impact of a short shelf life is that the cost of PEPs will approach the cost of other short shelf-life medications, such as vaccines.

 Based on our extensive experience of 30(+) years with these pancrelipase products, allowing for overages of at least 140% would provide a two-year shelf life and satisfy a lower stability limit of 90% and still safely meet the needs of patients within the normal prescribing practice and use.

Human Pharmacokinetics and Bioavailability Section:

 Intubation procedures to demonstrate delivery of exogenous enzymes into the intestine in their biologically active state is unjustified and unnecessary in the light of readily available PD markers of efficacy. These procedures are complex, time consuming, invasive, uncomfortable, painful, and prohibitively expensive. They can damage the lining of the esophagus and stimulate the gagging reflex and, thus, compromise interpretations of data.

 We urge the Agency to waive this requirement.

Clinical Studies for New PEPs:

 Dose-response relationship in clinical trials is probably unachievable, impractical, and should not be required since the patients are normally titrated by physicians.

 A 72-hour stool analysis is one established and valid quantitative measure of steatorrhea. Stool markers can more suitably establish baseline.

 Efficacy of product line extensions should be based on clinical signs and symptoms.

Pediatric Studies for PEPs:

 We would like to encourage the FDA to include pediatric subgroup analysis for clinical trials in their guidelines.

Miscellaneous Items:

We would like to advocate the assembly of an expert panel to discuss many of the issues and concerns expressed by manufacturers and end users of pancreatic enzyme products in a public forum.

If you have any questions concerning these recommendations, please contact me by telephone at (610) 882-5950 or by e-mail at tibsipos@fast.net. Digestive Care, Inc. is pleased to send representatives of the company to the FDA to discuss concerns and recommendations with the Agency, if the need should arise, in the Fall of 2004. Your cooperation concerning this matter is greatly appreciated.