2003D-0206 - Draft Guidance for Industry on Exocrine Pancreatic Insufficiency Drug Products--Submitting New Drug Application; Availability
FDA Comment Number : EC6
Submitter : Dr. Tibor Sipos Date & Time: 07/07/2004 05:07:47
Organization : Digestive Care, Inc.
Drug Industry
Category :
Issue Areas/Comments
GENERAL
GENERAL
PART 5 OF 10
COMMENTS SUBMITTED BY DIGESTIVE CARE, INC. (1120 WIN DRIVE, BETHLEHEM, PA 18017)
DOCKET NO. 2003D-0206 (2003N-0205)

Cost considerations are also a major concern for this section. No doubt that characterization, impurity profiling/testing and viral clearance requirements as outlined in the guidance document would add considerable cost to the drug substance. When this cost is added to the potential cost outlined for the drug product, the overall increase in cost to the patient will, in all likelihood, be at least 50%. It is therefore important to consider a value-added approach for patients who have, and will continue to use, these products for dozens of years and may have to bear these undue hardships.

DRUG PRODUCT
Identification and Characterization of Pancrelipase Drug Product:
 Enzymatic activity for key enzymes provides appropriate product identification.
 Lipase activity is an absolute criteria for product activity and identity.
 There is no practical way to impose specifications on ratios of multiple enzymes.
 IR and UV spectrophotometric methods can provide useful characterizations.

We recommend the use of IR spectrophotometric methods, employing the KBr pellet technique for the physico-chemical identification and characterizations of pancrelipase in the drug product.

We recommend the use of UV spectrophotometric analysis at 205-210 nm and 280 nm for estimating protein concentrations, respectively (Baily, JL., Techniques in Protein Chemistry, 2nd Ed., pp. 342-346, Elsevier Publishing Co., 1967).

We recommend the determination of lipase, amylase and protease to characterize the catalytic activity of the drug product per dosage unit. We would also like to point out that lipase potency is the absolute criteria for product activity and identity. Identification and characterization of pancrelipase containing products need to be based on catalytic activity; e.g. ability 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.

Stability of Digestive Enzymes in Formulations:

 Overly conservative tightening of specifications will unnecessarily reduce shelf life and increase costs without adding safety or efficacy benefits.
 Overages have been acceptable to the Agency.
 Overages of 140% are potentially acceptable for shelf life of two (2) years.

The draft guidance provides that ?primary stability data should be generated according to the guidance developed in ICH Q1A and Q5C?. While there are many sound practices to be found in these ICH guidelines, there are also stability testing requirements that are impractical or impossible to apply to Pancreatic Enzyme Products (PEPs). For instance, identification of degradation products would be difficult and unnecessary. It would be difficult because the degradation products of PEPs constitute a complex and variable population of polypeptides, peptides, and amino acids. It would be unnecessary because of the manifest safety of these degradation products, which can be viewed as digestion products of an edible organ meat. We suggest that these concerns could be resolved by amendment of the draft guidance to provide that primary stability data should be generated utilizing validated methods and procedures including those provided by ICH Q1A and Q5C, where appropriate.