The US Food and Drug Administration (FDA) late Friday issued revised versions of two final guidance documents explaining the use of bulk drug substances in compounding and clarifying that the agency does not intend to take action against certain outsourcing facilities and compounded drugs.
The policies also clarify that the two guidance documents do not apply to inactive ingredients, which can be used in compounding without appearing on the bulk drug substances lists developed under sections 503A or 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act), if all applicable conditions are met.
Section 503A of the FD&C Act includes certain restrictions on the bulk drug substances that can be used in compounding and directs FDA to develop a list of bulk drug substances that can be used in compounding. FDA is developing such a list (see bottom of this article), known as the 503A bulks list, and one of the two guidances describes FDA’s interim regulatory policy for licensed pharmacists in state-licensed pharmacies and federal facilities and for licensed physicians that compound human drugs using bulk drug substances while the list is being further developed.
Section 503B of the FD&C Act describes the conditions that must be satisfied for human drugs compounded by an outsourcing facility to be exempt from the following three sections of the FD&C Act: section 505 (concerning the approval of drugs under new drug applications or abbreviated new drug applications); section 502(f)(1) (concerning the labeling of drugs with adequate directions for use); and section 582 (concerning drug supply chain security requirements).
Section 503B also includes certain restrictions on the bulk drug substances that outsourcing facilities can use in compounding and directs FDA to develop another list (also, see the link at bottom of this article) of bulk drug substances that can be used in compounding.
503A Interim Policy
FDA says it has received comments that its current policy could be causing unnecessary and inappropriate disruptions in patient care because there are some patients receiving compounded drugs with bulk drug substances that are not components of FDA-approved drugs, or the subject of an applicable USP or NF monograph, but that may ultimately be included on the 503A bulks list.
“FDA is issuing this interim guidance stating that it does not intend to take regulatory action for compounding drug products under section 503A using a bulk drug substance when an applicable USP or NF monograph for the substance does not exist and the substance is not a component of an FDA-approved product if, among other conditions, FDA has determined that the nomination for the bulk drug substance included adequate information for FDA to evaluate the substance and at this time, the substance does not appear to present significant safety risks,” the guidance says.
In December 2013, over 2,000 substances were nominated for the 503A bulks list, and FDA then refined the criteria for the list and about 740 unique substances were nominated. Of those, FDA says about 315 substances are already eligible for use in compounding under section 503A.
In addition, about 350 substances were nominated without sufficient supporting evidence for FDA to evaluate them, the guidance says, noting that the remaining substances may be eligible for inclusion on the 503A list and were nominated with sufficient supporting information (the complete list of the substances nominated is provided in the link at the end of this article).
FDA also says it’s considering a number of factors in prioritizing the order in which it reviews the nominated bulk drug substances, including but not limited to: Safety concerns; whether the bulk drug substance was nominated by multiple parties or by medical professional organizations; the efficiency with which the evaluation can be completed.
The agency also notes that it may group some nominated drug substances to facilitate efficient review and discussion, including those that raise similar issues (e.g., vitamins or botanicals) or have been nominated for the treatment of the same condition (e.g., warts).
503B Interim Policy
Similar to the 503A interim policy, FDA put out a call for nominations for the 503B list and received more than 2,000 substance nominations, many of which were not for substances used in compounding as active ingredients, or they did not include sufficient information to allow FDA to evaluate them.
A subsequent call for nominations in July 2014 yielded about 2,590 unique substances, FDA says, though 1,740 are biological products (all but one of these are individual allergenic extracts) which FDA notes are subject to approval in a biologics license application (BLA) (for the complete breakdown of the lists see the link at the bottom of this article).
As the latest list is being put together, FDA says it “does not intend to take action against an outsourcing facility for compounding a drug product using a bulk drug substance that is not on the 503B bulks list if the drug compounded from the bulk drug substance: (i) appeared on FDA’s drug shortage list within 60 days of distribution and dispensing, and (ii) was to fill an order that the outsourcing facility received for the drug while it was on FDA’s drug shortage list."
In addition, FDA also says it currently does not intend to take action against an outsourcing facility for compounding a drug using a bulk drug substance that does not appear on the 503B bulks list and that is not used to compound a drug that appears on the FDA drug shortage list at the time of compounding, distribution, and dispensing, provided that the following conditions are met:
1. The bulk drug substance appears on 503B Category 1 (see list below)
2. The original manufacturer and all subsequent manufacturers of the bulk drug substance are establishments that are registered under section 510 (including foreign establishments that are registered under section 510(i)) of the FD&C Act
3. The bulk drug substance is accompanied by a valid clinical outcome assessment
4. If the bulk drug substance is the subject of an applicable USP or NF monograph, the bulk drug substance complies with the monograph
5. The drug product compounded using the bulk drug substance is compounded in compliance with all other provisions of section 503B of the FD&C Act.
The agency is also providing for regular updates to the categories of bulk drug substances and FDA will determine after submissions are received whether new nominations, including re-nominations of substances with additional supporting information, have sufficient information for FDA to review them.
“After making that determination, FDA will place nominated substances in the appropriate category on FDA’s website. FDA generally intends to update the categories with any new nominations the first business day of each month. This revised policy will further minimize unnecessary disruptions to patient treatment while FDA develops the lists of bulk drug substances for use in compounding,” the agency added.
Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance for Industry
Bulk Drug Substances Nominated for Use in Compounding Under Section 503A of the Federal Food, Drug, and Cosmetic Act
Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug, and Cosmetic Act Guidance for Industry
Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act