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FDA Implementation of the Compounding Quality Act
The new law allows an entity that compounds sterile drugs to register as an outsourcing facility. Once registered, an outsourcing facility must meet certain conditions in order to be exempt from the FDCA’s approval requirements and the requirement to label products with adequate directions for use. Under the new law, the drugs must be compounded in compliance with CGMP by or under the direct supervision of a licensed pharmacist in a registered facility (section 503B(a)). The outsourcing facility must also report specific information about the products that it compounds, including a list of all of the products it compounded during the previous six months, and information about the compounded products, such as the source of the ingredients used to compound (section 503B(3)). In addition, the outsourcing facility must meet other conditions described in the new law, including reporting adverse events and labeling its compounded products with certain information (section 503B(b)(5) and section 503B(a)(10)).
Under the new law, an outsourcing facility will not be considered registered until it has paid the applicable annual registration fee (see section 744K(g)(3)(A)). An outsourcing facility may register without paying a fee until September 30, 2014, however, because fees are not required until October 1, 2014. In addition, the new law requires that outsourcing facilities register and report their products to FDA electronically unless the Secretary grants a request for a waiver of such requirement because use of electronic means is not reasonable for the person requesting the waiver (section 503B(b)). FDA has issued draft guidances on registering and reporting for those entities that intend to register as outsourcing facilities.
Drugs produced by compounders that are not registered as outsourcing facilities must meet the conditions of section 503A to qualify for the exemptions specified in that section. Even if the conditions of section 503A are met, the compounded drugs are only exempt from those provisions of the FDCA listed above. All other applicable provisions of the FDCA remain in effect for compounded drugs, even if the conditions in section 503A are met. For example, a compounded drug cannot be contaminated or made under insanitary conditions (see sections 501(a)(1) and 501(a)(2)(A)). And if a compounded drug does not qualify for the exemptions under either section 503A or 503B of the FDCA, the compounded drug would be subject to all of the requirements of the FDCA that are applicable to drugs made by conventional manufacturers, including the new drug approval and adequate directions for use requirements.
FDA has issued for public comment a draft guidance that describes FDA’s intention with regard to the provisions of section 503A that require rulemaking or other action to implement. This draft guidance also describes the provisions of the law that are applicable to compounded drugs that do not qualify for the exemptions described above, and the other provisions of the FDCA applicable to compounded drugs regardless of whether they qualify for the exemptions under section 503A.
FDA also has announced the withdrawal of CPG 460.200, Pharmacy Compounding, issued in 2002, and the guidance “Enforcement Policy During Implementation of Section 503A of the Federal Food, Drug, and Cosmetic Act,” published in November 1998. Although we have withdrawn these guidance documents, under the DQSA, section 503A immediately applies nationwide. FDA plans to provide further information at a later date about how we intend to interpret certain provisions of section 503A.
The new law requires the Secretary to establish a mechanism to receive submissions from state boards of pharmacy concerning certain actions taken against compounding pharmacies or expressing concerns that a compounding pharmacy may be acting contrary to section 503A. This section is to be implemented in consultation with the National Association of Boards of Pharmacy (NABP). In addition, state boards of pharmacy must be notified when the Secretary receives certain state submissions or makes a determination that a compounding pharmacy is acting contrary to section 503A.
Until further information regarding how this process will work can be provided, States that wish to provide this information to FDA should submit the information by email to the following mailbox: StateCompounding@fda.hhs.gov
The agency intends to follow up with states that provide this information and to notify other states about the receipt of the information in accordance with the new law.
Sections 503A and 503B require the creation of and consultation with a Pharmacy Compounding Advisory Committee before issuance of certain regulations required by the law. FDA has published in the Federal Register notices soliciting nominations for Committee members.
Sections 503A and 503B contain various requirements for FDA to develop lists of drugs that may or may not be compounded and lists of bulk drug substances that may be used to compound. Specifically, section 503A specifies that to qualify for the exemptions under section 503A, a compounder may only use bulk drug substances to compound if:
- The bulk drug substances comply with the standards of an applicable United States Pharmacopoeia (USP) or National Formulary (NF) monograph, if one exists;
- If such a monograph does not exist, the drug substance(s) is a component of an FDA-approved human drug product; or
- If such a monograph does not exist and the drug substance is not a component of an FDA-approved human drug product, it appears on a list of bulk drug substances for use in compounding developed by FDA through regulation (section 503A(b)(1)(A)(i) of the FDCA).
Section 503B specifies that an outsourcing facility may only compound with a bulk drug substance which appears on an FDA-established list of bulk drug substances for which there is a clinical need or which are on FDA’s drug shortage list.
Sections 503A and 503B also prohibit compounding drugs that are on a list of drugs that present demonstrable difficulties for compounding, as published by FDA.
FDA has published notices requesting nominations for these three lists.
In addition, 21 CFR 216.24 contains a list of drugs that may not be compounded because they have been withdrawn or removed from the market because the drugs or components of the drugs have been found to be unsafe or not effective. Compounders may not compound any drugs that appear on this list. FDA intends to issue a proposed rule to update this list by amending section 216.24 and will apply the list to compounders seeking to qualify for the exemptions in either section 503A or section 503B. Nominations for this list can be submitted in comments on the proposed rule.
FDA intends to continue proactive and for-cause inspections of compounding pharmacies, and FDA plans to take aggressive action, including enforcement actions, as appropriate to protect the public health.
For the past year, since the fungal meningitis outbreak began, FDA has been conducting inspections of compounding pharmacies for cause (in response to serious adverse event reports and reports of quality problems) and proactively to identify pharmacies with deficient sterile compounding practices. Using a risk-based model, we identified 29 firms for priority inspections focused on their sterile processing practices. FDA identified secondary firms associated with two of these inspections, for a total of 31 firms. Between October 1, 2012 and October 31, 2013, FDA completed 42 for-cause inspections in addition to the 31 proactive inspections.
When we identified problems during any of these inspections, we issued a Form FDA-483 listing our inspection observations. We have issued a Form FDA-483 at the majority of the inspections we have conducted since the fall of 2012. As these Form FDA-483s reflect, we observed serious quality problems, including contaminated products and sterile practices that create a risk of contamination. Numerous recalls of sterile products have been conducted, and numerous pharmacies chose to stop sterile compounding after we identified problems with their sterile compounding processes. New problems continue to be identified at compounding pharmacies across the country, and FDA intends to continue its inspection and enforcement efforts to address these problems, using currently available resources. For oversight of outsourcing facilities registered under section 503B, FDA will use fees assessed and collected from those facilities in accordance with the law to supplement other agency resources.