As part of the implementation of 2013’s Drug Quality and Security Act
(DQSA), the US Food and Drug Administration (FDA) on Friday released draft guidance explaining how it will formulate a list of bulk drug substances, known as the 503B bulks list, for which there is a clinical need, and what substances outsourcing facilities can use to compound drugs.
The 20-page draft guidance is part of FDA’s compounding policy priorities plan
and follows a fungal meningitis outbreak from 2012 that resulted in more than 60 deaths and 750 cases of infection.
The draft discusses FDA’s interpretation of the statutory phrase “bulk drug substances for which there is a clinical need,” which the agency says means that there is a clinical need for an outsourcing facility to compound a drug and that the drug must be compounded using a particular bulk drug substance.
Outsourcing facilities, which are subject to more stringent FDA oversight than traditional pharmacy compounders, can compound drugs either by altering an FDA-approved drug (i.e. by diluting the FDA-approved drug or changing the dosage form) or by starting from a bulk drug substance when an attribute of an alternative, FDA approved drug makes it inappropriate or unsafe for the patient.
FDA explains in the draft that compounding from bulk drug substances generally presents greater risk to patients than compounding from FDA-approved drugs. Compounding from bulk drug substances also involves more complex steps than compounding from approved drugs, and can introduce increased risk for compounding errors or contamination.
The agency also notes that compounding drugs using bulk drug substances (when the use of an FDA-approved drug or a drug compounded using an approved drug would meet patients’ medical needs) can undermine FDA’s approval process and reduce the incentive for manufacturers to seek approval of brand name or generic drugs.
For instance, compounder Imprimis made headlines for saying it would offer a $1 compounded version of the toxoplasmosis drug Daraprim (pyrimethamine) – the drug Martin Shkreli made famous for raising for the price of, and another compounded version of Allergan's Restasis. The company later said it would sign up as an outsourcing facility, and in December 2017, FDA issued it a warning letter
for false and misleading promotional materials related to its eye drop products.
In assessing the clinical need for a drug to be compounded from bulk substances, FDA Commissioner Scott Gottlieb said in a statement that FDA’s analysis will consider whether attributes of the approved drug may make it unsuitable to treat certain patients and whether the compounded drug is intended to address what makes it unsuitable.
FDA also said it intends to consider whether the drug product to be compounded must be produced from a bulk drug substance rather than an approved drug.
“For example, if an approved drug contains peanut oil, the FDA would consider whether there was information indicating that patients with a peanut allergy need a drug product compounded without the allergen,” Gottlieb said
. “The FDA would further consider whether there was information suggesting that the drug product needs to be compounded using a bulk drug substance, rather than the approved drug, because the type and number of manipulations necessary to remove the peanut oil from the approved product would adversely impact the overall quality of the drug.”
The agency also said it would weigh certain factors for each substance being proposed for use in a compounded drug product – “specifically, its physical and chemical characterization, possible or known safety issues, evidence or lack of thereof of effectiveness, and historical use.”
Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act Draft Guidance for Industry