2003D-0206 - Draft Guidance for Industry on Exocrine Pancreatic Insufficiency Drug Products--Submitting New Drug Application; Availability
FDA Comment Number : EC7
Submitter : Dr. Tibor Sipos Date & Time: 07/07/2004 05:07:55
Organization : Digestive Care, Inc.
Drug Industry
Category :
Issue Areas/Comments
PART 6 OF 10
DOCKET NO. 2003D-0206 (2003N-0205)

The requirements of performing stability testing at 100% of the label claim potency, and not allowing for a range wide enough to support a reasonable overage and shelf life, will lead to an extremely short shelf life (less than one year) and this will have profound economic consequences throughout the chain of distribution. It could also adversely affect the clinical outcome of patients using these drugs. Shorter shelf life will result in more expired, returned, and wasted product. Manufacturing campaigns for different dosage strengths will have to be shorter or campaigning may have to be abandoned and parallel manufacturing lines established at increased capital and labor cost. Three major chain wholesalers account for approximately 90% of the distribution of pharmaceutical products to retailers and hospitals. Each of these wholesalers has strict requirements regarding the acceptance and handling of products based on the expiration dating. All three remove products from their shelves months ahead of expiration, which further shortens potential time in the distribution chain. Thus, distributors and pharmacies will have increased inventory management costs. The patient?s risk of running out of supply will be increased because any disruption in production or transportation will cause an almost immediate shortage, since inventories will necessarily be kept low to minimize the costs of out-of-date returns. The overall economical impact of the short shelf life is that the cost of PEPs will approach the cost of other short shelf-life medications, such as vaccines.

Testing at 100% of the label claim potency and having a proposed shelf life that does not depend on a stability overage will not result in physicians being able to more accurately prescribe PEPs. The variability represented by the stability overage is overshadowed by the variability associated with varying fat content and amounts of meal and patient digestive differences. Physicians will still have to titrate patients to achieve optimal dosage. We also note that labeled potency of PEPs is only indicative of their biological potency in actual use. Lipase activity is pH dependent. The hydrolysis of triglycerides at pHs of 8.0, 7.0, and 6.0 proceed at approximately 70%, 24% and <1%, respectively, of the activity measured at the optimal pH of 9.0 Label potency of PEPs is determined at pH 9.0, whereas the pH in the small intestine is approximately 7.5-6.5 or lower, depending on meal and patient factors, which results in 49% to 97% less enzyme activity at the site of action than label claim.

It has also been our experience over the past 30(+) years that lipase activity degrades at a rate of about 8-12% per year in the pancrelipase drug substance due to several issues, some of which are difficult to control such as inherent protease activity and moisture. Present USP standards for PEPs have been set to 90-165%, presumably to account for these issues. Based on our extensive experience with these pancrelipase products, tightening the upper limit for overages to 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.

This proposed range would be in line with some of the other classical biologicals as indicated in the examples above for chorionic gonadotropins
and menotropins. Physicians have safely and effectively used these products with 45% variability (80-125%) despite the fact that ovarian hyper stimulation, in the case of menotropins, occurs much more frequently than fibrosing colonopathy in cystic fibrosis.