2003D-0206 - Draft Guidance for Industry on Exocrine Pancreatic Insufficiency Drug Products--Submitting New Drug Application; Availability
FDA Comment Number : EC3
Submitter : Dr. Tibor Sipos Date & Time: 07/07/2004 05:07:20
Organization : Digestive Care, Inc.
Drug Industry
Category :
Issue Areas/Comments
PART 2 OF 10
DOCKET NO. 2003D-0206 (2003N-0205)

Recognition of the complexity inherent in the quality of these classical biologicals can be seen in present guidelines as per the examples indicated below.

1.3 Scope

The principles adopted and explained in this document apply to proteins and polypeptides, their derivatives, and products of which they are components (e.g., conjugates). These proteins and polypeptides are produced from recombinant or non-recombinant cell-culture expression systems and can be highly purified and characterized using an appropriate set of analytical procedures.

The principles outlined in this document may also apply to other product types such as proteins and polypeptides isolated from tissues and body fluids. To determine applicability, manufacturers should consult with the appropriate regulatory authorities.

This document does not cover antibiotics, synthetic peptides and polypeptides, heparins, vitamins, conventional vaccines, cells, whole blood, and cellular blood components.


- Historically, the relative purity of biological products has been expressed in terms of specific activity

- Impurity profiles are normally not necessary for APIs from herbal or animal tissue origin.?

No doubt these conclusions arose from insights into the difficulties associated with applying conventional standards and controls for purity, stability, and specifications used for chemically synthesized drugs to classical biologicals. As an example, the USP specifications for chorionic gonadotropins and menotropins are 80% - 125% for both drug substance and drug product (USP 27, pg. 882 and 1158), a much wider range than expected for synthesized drugs. The USP recognizes lipase specification for Pancrelipase Delayed-Release Capsules of not less than 90% and not
more than 165% of the label claim (USP 27, pg. 1402).


While we shall leave much of the detailed response for the drug substance to the Active Pharmaceutical Ingredients (API) manufacturers, we wish to address certain items in this section since manufacturers must confirm specifications prior to formulation.

Identification and Characterization of Pancrelipase Drug Substance:

- Lipase activity is an absolute criteria for product activity and identity.
- Enzymatic activity for other key enzymes are useful characterizations but there is no practical way to impose or force specifications on ratios of multiple enzymes.
- Advanced biochemical techniques (e.g. HPLC, SDS-PAGE electrophoresis, Isoelectric-focusing) are good research tools but are unsuitable for routine characterizations of such a complex biological extract as pancrelipase. Pancrelipase drug substance contains water-soluble and non-soluble forms of activity which will not be adequately addressed by numerous analytical assays.
- IR and UV methods could be useful characterization methods.