New Compounding and Outsourcing Facility Guidance Issued Just in Time for July 4th Holidays

By Karla L. Palmer – 

Yesterday FDA provided drug compounders some pre-Fourth of July fireworks by issuing a slew of “policy documents” as part of the Agency’s implementation of the Compounding Quality Act (“CQA”) (Title I of the Drug Quality and Security Act (“DQSA”)), which was enacted November 27, 2013.  The policy documents include a draft interim guidance, a proposed rule, a Final Guidance, and two revised requests for nominations for the bulk drug substance lists for both Section 503A and Section 503B compounders.  FDA stated in its press release that these “actions are essential next steps in providing the compounding industry with the appropriate tools to comply with the law and advancing the FDA’s efforts to continue protecting patients.”

More specifically, the policy documents include the following: 

• cGMP for Section 503B:  Draft interim guidance describing FDA’s expectations for compliance with current good manufacturing practice (“cGMP”) for voluntarily registered outsourcing facilities under Section 503B of the FDC Act. The draft guidance focuses on cGMP requirements related to sterility assurance of sterile drug products and the general safety of compounded drug products.  (More details are included in our separate blog post, and i the Federal Register announcement).
• Drugs Withdrawn for Safety/Effectiveness; proposed additions: A proposed rule that would revise FDA’s list of drug products that may not be compounded because they have been withdrawn or removed from the market for reasons of safety or effectiveness.  The proposed rule seeks to modify the description of one drug product on the current list and add 25 drug products to this list.  The list applies to both compounders under 503A and outsourcing facilities under 503B. 
• Final Guidance for Section 503A Compounders: Final Guidance for individuals or pharmacies that intend to compound drugs under Section 503A.  The non-binding Guidance generally sets forth and restates the provisions of Section 503A, addresses FDA’s interim policies concerning certain provisions that require implementing regulations or other actions, and includes a non-exhaustive list of potential enforcement actions against individuals or pharmacies that compound human drug products in violation of the FDC Act.   

            Some further points on the Final 503A Guidance:

• FDA states that until a bulk drug substances list is published as a final rule, human drug products should be compounded using only bulk drug substances that are components of drugs approved under FDC Act Section 505, or are the subject of United States Pharmacopeia or National Formulary monographs.
• FDA does not intend to enforce the 5% limit on interstate distribution until after FDA has finalized a Memorandum of Understanding (“MOU”) and made it available to the states for their consideration and signature.   FDA will announce the availability of the MOU and specify a time period during which the MOU will be made available for states to sign.  After the time period expires, FDA intends to begin enforcing the 5% limit in states that have not signed the MOU.  Notably, FDA retreated from its position in draft guidance on Section 503A, which required states to sign the MOU within 90 days after presentation to them.  The 90-day deadline had attracted a number of negative comments.
• FDA expects to employ a “risk-based enforcement approach” concerning violative compounded drugs.  It will give “highest enforcement priority” to compounded drugs that pose the greatest risks to public health.  FDA emphasizes that it does not need to identify a particular safety problem before pursuing enforcement action.  Based on recent actions, we expect FDA to pay particular attention to whether a pharmacy may not have “adequate assurance of sterility.”
• The Guidance is silent concerning the permissibility of office use compounding – even for non-sterile drug preparations – which several industry groups and members of Congress have continued to stress should be permitted, at least for low-risk, non-sterile products, under Section 503A.  Section 503B expressly addresses and permits only sterile compounding for office use, although there is no apparent reason that outsourcing facilities capable of compounding sterile drugs could not also be permitted to compound nonsterile products.
• Bulk Drug Nomination Process; Sections 503A and B:  FDA issued Notices advising that it is “reopening” the nomination process for the two bulk substance lists (specifically, active pharmaceutical ingredients) that may be used to compound drug preparations. The Notices are available here and here. 
• Bulk Substances for Section 503B Outsourcing Facilities:  The Agency says it is requiring the nomination “do-over” because many of the 753 comments received from interested parties included nominations that were not for bulk drug substances used in compounding as “active ingredients,” and “none included sufficient information to justify inclusion of the nominated substances on the list.”  (This may reflect insufficient clarity as to what data FDA expected to see.)  Some nominations were “en bloc” nominations of thousands of substances and entire compendia.  FDA noted that such bulk nominations provided “no justification” for inclusion on the positive list.  Of further note:   
• To improve the efficiency of the process for developing the list of bulk drug substances that may be used to compound drug products under Section 503B, FDA is providing more detailed information on what it needs to evaluate a nomination, and providing an additional 90-day period to receive nominations from interested persons.   
• Importantly, bulk substances that were previously nominated will not be further considered, unless they are re-nominated and “adequately supported.”  Substances that are not adequately supported will not be placed on the bulk substances list.
• Details Needed for Nominated Products: FDA is providing more detail on what information is needed to evaluate the nominations.  All nominations must demonstrate how the ingredient is used as an active ingredient in a particular compounded drug product.  To qualify for placement on the 503B list, the nominated bulk substance must be required to compound a drug product for which there is a clinical need.  The Agency has decided that the clinical need only exists where there is a clinical need for the specific drug product, in other words, that there are no acceptable substitutes.”  (Notice at page 5-6).  (Notice at page 5-6).   
• Clinical Need: To the extent information about the clinical need was provided for individual nominations, FDA noted many comments included a statement about the need for the use of bulk drug substances in compounding generally, rather than information about the “specific clinical need for drug products compounded using a particular bulk drug substance.  For example, many nominations included the following standardized language as the explanation of clinical need for compounding with the bulk drug substance: ‘Prescribed dosage forms and strengths not available commercially. Manufacturer backorders. Possible patient sensitivities to manufactured product dyes, fillers, preservatives and other excipients.’” (Notice at page 7).  A full description of clinical need is at 9 to 11.  FDA also includes the format for interested parties to use for submissions. (Notice at 11-13).
• Inactive Ingredients:  The Agency also clarified that inactive ingredients used in compounded drug products, which typically include flavorings, dyes, diluents, or other excipients, need not and will not be included on the list.
• Bulk Substances for Section 503A Compounders:  The Agency says it is similarly scrapping all of the prior Section 503A nominations because many of the 110 comments received from interested parties included nominations that also were not bulk drug active ingredients, included en block nominations, and did not include substances used in compounding as “active ingredients.” 
• Section 503A Submission Criteria: FDA will examine the following four criteria for proposed Section 503A bulk substances: (1) The physical and chemical characterization of the substance; (2) any safety issues raised by the use of the substance in compounded drug products; (3) historical use of the substance in compounded drug  products, including information about the medical condition(s) the substance has been used to treat and any references in peer-reviewed medical literature; and (4) the available evidence of effectiveness or lack of effectiveness of a drug product compounded with the substance, if any such evidence exists.
• To qualify for placement on the list, it is necessary to identify the above information about the nominated substances.  FDA will evaluate the nominated substances in consultation with the Pharmacy Compounding Advisory Committee. Submission criteria for bulk substances under Section 503A is set forth at pages 8-10 of the Notice.  The new, explicit criteria will substantially reduce the number of nominees and probably exclude many nominees from being listed.

The draft interim guidance for cGMP and the proposed rule for drugs withdrawn for reasons of safety or effectiveness are available for public comment for 60 days, and the dockets are open for the public to nominate bulk drug substances for compounding under Section 503A or 503B for 90 days.