This week, we will continue to review the DQSA and its requirements for a drug to be compounded in the U.S.

Continuing our discussion of the DQSA and the specific sections of 503A of the FD&C Act requiring rulemaking or other action by FDA, we will look at the following:

1. Withdrawn or Removed List
Already covered
2. Bulk Drug Substances List
Already covered.
3. Memorandum of Understanding Between FDA and the States
Already covered.

4. "Demonstrable Difficulties" for Compounding
EDITOR'S NOTE: This is sometimes confusing as this activity started under FDAMA97; part of which was ruled unconstitutional and so this was renewed with DQSA.

A compounded drug product would not qualify for the exemptions if it is identified by FDA through regulation as a drug product that presents demonstrable difficulties for compounding that reasonably demonstrate an adverse effect on the safety or effectiveness of the drug product. This provision is not enforceable until FDA promulgates an implementing regulation.

One of the conditions in section 503B that must be satisfied for a compounded drug to qualify for the exemptions in that section is that the drug either

(1) is not identified (directly or as part of a category of drugs) on a list published by the Secretary, of drugs or categories of drugs that present demonstrable difficulties for compounding that are reasonably likely to lead to an adverse effect on the safety or effectiveness of the drug or category of drugs, taking into account the risks and benefits to patients, or

(2) is compounded in accordance with all applicable conditions identified on the list as conditions that are necessary to prevent the drug or category of drugs from presenting such demonstrable difficulties (see section 503B(a)(6)(A) and (a)(6)(B) of the FD&C Act). Section 503B(c)(2) of the FD&C Act requires that before issuing regulations to implement section 503B(a)(6) of the FD&C Act, an advisory committee on compounding be convened and consulted.

On June 18, 2015, the PCAC reviewed and discussed FDA's proposed criteria for evaluating whether drug products or categories of drug products are demonstrably difficult to compound under sections 503A and 503B of the FD&C Act. After considering the PCAC's discussion, FDA refined the criteria and presented the changes to the PCAC on March 9, 2016. The six criteria presented to the PCAC for evaluating whether a drug product or category of drug products is demonstrably difficult to compound are the following:

(1) The complexity of the formulation;
(2) the complexity of the drug delivery mechanism;
(3) the complexity of the dosage form;
(4) the complexity of achieving bioavailability;
(5) the complexity of the compounding process; and
(6) the complexity of physicochemical or analytical testing.

It is not necessary for a previously nominated drug product or category of drug products to be renominated to this docket. Previously nominated drug products or categories of drug products may be renominated to this docket if the nominator wants to provide additional supporting information, e.g., information specific to the six questions listed above related to FDA's proposed evaluation criteria. Interested parties can also submit comments on nominated drug products or categories of drug products, or on this document, via this docket.

Previous nominations to the Difficult to Compound List or comments submitted in response to the December 4, 2013 Federal Register notice can be viewed on https://www.regulations.gov under docket number FDA-2013-N-1523, or by going to the Division of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.

Dated: July 24, 2017.

More on the "Difficult to Compound" list will be presented next week.

Loyd V. Allen, Jr., PhD, RPh
Editor-in-Chief
IJPC
Remington: The Science and Practice of Pharmacy Twenty-second edition