Has The FDA Put The USP Monograph Process “Under The Bus”?


  • August 11, 2015

By Nicholas Fleischer, R.Ph., Ph.D.

In the August 3, 2015 issue of the Federal Register, the Food and Drug Administration announced the availability of the following draft guidance: Dissolution Testing and Specification Criteria for Immediate-Release Solid Oral Dosage Forms Containing Biopharmaceutics Classification System Class 1 and 3 Drugs. The new guidance is intended to replace an 18-year old guidance entitled Dissolution Testing of Immediate Release Solid Oral Dosage Forms, which the author of this blog helped prepare. We applaud the Agency’s effort to simplify and standardize the dissolution methods and specifications that currently exist in the United States Pharmacopoeia (USP) and in the Agency’s Dissolution Methods Database.

In reviewing the proposed draft guidance, several changes should be highlighted. However, before discussing the changes, it is important to note that the Agency reiterates that the guidance is only a recommendation and not a requirement.

The draft guidance defines a highly soluble drug substance as one where the highest dose strength is soluble in 250 mL or less of aqueous media over the pH range of 1 to 6.8. This is in contrast to the 1997 guidance which stated that solubility should be determined in a buffer adjusted between pH 1.0 and 8.0. In addition, there is a new recommendation that the drug substance should be chemically stable for 24 hours over the pH range of 1 to 6.8.

While the 1997 guidance was silent on this topic, the draft guidance excludes adoption of the dissolution standards proposed in the guidance to products where the labeling claim of the drug products includes early or rapid onset of action. This exclusion seems puzzling as the concept of the Biopharmaceutics Classification System (BCS) was based on the premise that a highly soluble, rapidly dissolving drug product is similar to a solution drug product which in many cases is eligible for a waiver from conducting in vivo studies as per 21 § CFR 320.22(3). It is hoped that the Agency identifies those products where the time to achieve the maximum plasma concentration is critical to the intended use of that product.

The draft guidance proposes only two standard dissolution test conditions as below:

A.  Basket Method (USP apparatus 1)

  • Stirring rate = 100 RPM
  • 500 mL of 0.01M HCl aqueous media
  • No surfactant in media
  • 37±0.5°C

B.  Paddle Method (USP apparatus 2)

  • Stirring rate = 75 RPM
  • 500 mL of 0.01M HCl aqueous media
  • No surfactant in media
  • 37±0.5°C

While having only two standard dissolution test conditions may be welcomed by the industry, it is hoped that the Agency arrived at this recommendation based on data.

The draft guidance states that for drug products where the method described in a USP drug monograph differs from the recommendation of the guidance, ANDA applicants may use the standard dissolution test conditions and seek revision of the relevant monograph. This recommendation appears to reject the recommendation of the previous guidance which stated that all approved new ANDA products should meet current USP dissolution requirements, if they exist. The USP dissolution requirements are based on data which is evaluated by an expert working committee and then proposed for public comment before inclusion as the compendial method and specification. The Agency’s suggestion that ANDA applicants seek revision of the relevant monograph does not appear to be well thought out.

The draft guidance recommends a single point dissolution specification of Q=80% in 30 minutes for BCS class 1 products and Q=80% in 15 minutes for BCS class 3 products.

Before the draft guidance is finalized, it is hoped that the Agency explores the impact the recommendations in the guidance may have on currently marketed drug products. Highlighted below are examples of some drug products that may be impacted:

Atenolol tablets, a BCS class 3 drug, has the following dissolution test in the USP monograph:

  • Paddle (Apparatus 2)
  • Stirring rate = 50 RPM
  • 900 mL of 0.1 N acetate buffer, pH 4.6
  • Q=80% in 30 minutes

Ranitidine tablets, a BCS class 3 drug, has the following test in the USP monograph:

  • Paddle (Apparatus 2)
  • Stirring rate = 50 RPM
  • 900 mL of water
  • Q=80% in 45 minutes

Diltiazem Hydrochloride Tablets, a BCS class 1 drug, has the following test in the USP monograph:

  • Paddle (Apparatus 2)
  • Stirring rate = 75 RPM
  • 900 mL of water
  • NMT 60% (Q) in 30 minutes and NLT 75% (Q) in 3 hours.

The draft guidance may simplify and standardize the dissolution testing methods and specifications for immediate-release solid oral dosage forms. However, it is hoped that it will be more of help than a hindrance to the pharmaceutical industry. The Weinberg Group can provide assistance in responding to the recommendations in the draft guidance.

Written by Nick Fleischer, R.Ph., Ph.D., Vice President, Clinical Pharmacology & Biopharmaceutics at The Weinberg Group, the world’s leading food and drug consulting firm. If you have any questions or thoughts on this blog post or others, please contact us.