A Big Year Ahead For API Regulations

Last year was a notable one for API regulatory guidelines, as the measures passed in 2005 are sure to have a major impact on the market this year.

By Ambrose Stafford
Sandoz Pharmaceuticals, Inc.

Two thousand five is history and we are already well into 2006. It is worthwhile to take a quick look back at the past year and review some highlights of the year for active pharmaceutical ingredients (API) regulatory guidance in the U.S.

While it was actually published in December 2004, it wasn’t until 2005 that most of us started to familiarize ourselves with the draft guidance document titled “ANDAs: Pharmaceutical Solid Polymorphism—Chemistry, Manufacturing and Controls Information.”

While some may have considered it anti-climatic, the expectations are almost always too high when anticipating a guidance on such a topical subject. It isn’t reasonable to expect the guidance to provide answers to every possible question or solutions to every possible problem that may arise. This document does, however, provide some clear direction on a number of important issues.

Regarding the influence of polymorphism on solubility, dissolution and bioequivalence the guidance clearly points to the Biopharmaceutical Classification System (BCS) as the recommended framework for regulatory decisions regarding polymorphism and the impact on bioavailability and bioequivalence. In cases where absorption is strongly related to intestinal permeability, then differences in polymorphism and solubility are expected to have little influence on bioavailability. Therefore, starting with a look at the biopharmaceutics of the drug, an ANDA applicant can potentially establish if the issue of polymorphism will be of major or minor significance.

The guidance is less specific regarding the influence of polymorphism on manufacturing of drug products, focusing on underlining the importance of consistency from batch to batch. Polymorph conversion during manufacturing can be a source of anxiety for formulators. The guidance points out that conversion is acceptable if it can be shown that the conversion is consistent from batch to batch. Clear instruction, however, is an objective that will require the application of the sharpest scientific minds at the ANDA applicant company.

The most specific guidance in the document is in the form of three decision trees. Decision Tree I addresses the requirement for polymorph specifications if it is known that polymorphs exist and have varying solubilities that have varying bioavailability based on the BCS.

Decision Tree II provides a process for setting specifications for polymorphs when different forms are known to have different bioavailability. 

Decision Tree III provides a process for deciding if specifications are required for polymorphism in the drug product. 

Perhaps the most welcome guidance appears in a footnote quoted here:

“A drug substance can exist in many polymorphic forms, but some forms may be rare and not likely to form. For example, in one approved drug product, the drug substance can exist in at least twenty polymorphic forms, but in reality only a subset of polymorphic forms has the potential to develop under the process conditions used to manufacture the drug product. Therefore, we recommend that you consider only those polymorphs that are likely to form during manufacture of the drug substance, manufacture of the drug product or while the drug substance or the drug product is in storage.”

Considering the plethora of literature being published describing an ever increasing number of polymorphic forms for almost every drug substance under the sun, this advice from FDA must come as a welcome relief to most in the industry.

Impurities in Drug Substances

The other significant draft guidance related to generic APIs published in 2005 was titled, “ANDAs: Impurities in Drug Substances.” This draft guidance formally proposes updating the previous 1999 document to contain the recommendations made in the ICH document Q3A “Impurities in Drug Substances.” While not specifically mentioned, but incorporated by reference, the most notable part of the guidance is the specification of thresholds for identification and qualification of impurities.  

While the guidance is a draft document, it would be most prudent of API manufacturers and ANDA applicants to strive for compliance with these thresholds during the product development process. Generic pharma and API process developers would do well to apply the thresholds universally for all their small molecule project.  Despite the fact that both ICH Q3A and the draft guidance from FDA specifically exclude fermentation products from their scope it is clear that the thresholds will be applied across the full range of products.  If it is found during development that it is not possible to manufacture the product with all impurities below the identification level,  the guidance provides a convenient decision tree for developers to use planning a course of action to deal with the impurities of concern (see Decision Tree IV).

With publication of drafts addressing two key issues in API development, 2005 was a notable year. What can we expect in 2006?  Many, if not all, in the industry are waiting for guidance on “bio-similar” products but I’d rather not speculate on whether this will be completed by the end of the year.  n

The views of Mr. Stafford do not necessarily reflect the views or policies of Sandoz Pharmaceuticals.

Footnotes on Decision Tree IV

a. Lower thresholds can be appropriate if the impurity is unusually toxic.

b. For example, do known safety data for this impurity or its structural class preclude human exposure at the observed level?

c. In this context, an FDA-approved human drug product generally refers to the reference listed drug. It may also include a different drug product with the same route of administration and similar characteristics such as tablet versus capsule.

d. An impurity is considered qualified for ANDAs when one or more of the following conditions are met:

• When the observed level and proposed acceptance criterion for the impurity do not exceed the level justified by an FDA-approved human drug product.

• When the impurity is a significant metabolite of the drug substance.

• When the observed level and the proposed acceptance criterion for the impurity are adequately justified by the scientific literature.

• When the observed level and proposed acceptance criterion for the impurity do not exceed the level that has been adequately evaluated in comparative in vitro genotoxicity studies.

e. If appropriate, a minimum screen (e.g., genotoxic potential) should be conducted. A study to detect point mutations and one to detect chromosomal aberrations, both in vitro, are considered an appropriate minimum screen.

f. If general toxicity studies are appropriate, one or more studies should be designed to allow comparison of unqualified to qualified material.  The study duration should be based on available relevant information and performed in the species most likely to maximize the potential for detecting the toxicity of an impurity. On a case-by-case basis, single dose studies can be appropriate, especially for single dose drugs. In general, a minimum duration of 14 days and a maximum duration of 90 days would be considered appropriate.

About the Author

Ambrose Stafford is director of API sourcing at Sandoz Pharmaceuticals, Inc. located in Wilson, NC, U.S. Mr. Stafford has over 15 years experience in the API industry. He began his career in API manufacturing with Bristol-Myers Squibb in Ireland and progressed through roles of increasing responsibility with BMS in Ireland and the U.S. before joining Sandoz in 2001.