On January 16th, 2018, FDA Commissioner, Scott Gottlieb, M.D. issued the 2018 Compounding Policy Priorities Plan. This document outlines, what the commissioner describes as, key priorities the agency will pursue to implement the federal law on compounding and to advance the FDA’s public health mission.
At a very high level, this plan signals some major changes in compounding regulation that will certainly impact the operations of both 503A and 503B compounding facilities. Below, we have provided a brief synopsis of the key elements, stratified by how it may 503Bfacilities. Click here to read the original FDA plan.
Risk-Based Approach to Manufacturing Standards for Outsourcing Facilities
The FDA plans to issue proposed regulations on the cGMP requirements 503B Outsourcing Facilities are required to meet, through a revision to the current draft guidance.
- The proposed regulations will be structured to make it more efficient and cost-effective for 503A compounders to voluntarily register as a 503B.
- Regulations will be “flexible” and take a risk-based approach to enforcement of cGMPs. These regulations will be based more on the size and scope of an outsourcing facility’s operation.
- The FDA’s goal is for more compounders to register as outsourcing facilities, with the understanding that they CAN still meet the FDA’s core requirements and increased patient access to medically necessary compounds.
- The revised draft guidance will also outline circumstances in which the FDA does not intend to take action against a 503B facility, and provides exemptions from certain cGMP requirements.
The revised draft guidance will provide more clear guidelines on the Agency’s intent to enforce regulations using a risk-based approach. This may allow smaller 503B facilities, which pose a relatively low risk to public health regarding the scope and scale of their operations, to be exempt from certain cGMP requirements. However, 503B entities should keep in mind that reducing the cGMP requirements remove barriers to entry, which will no doubt lead to a more saturated 503B market.
Restricting Compounding of Drugs that are Essentially copies of FDA-Approved Drugs
FDA finalizes Guidance for Industry – Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503B of the Federal Food, Drug, and Cosmetic Act. Click here to read the full guidance document.
- The FDA’s goal with the final guidance is to maintain the integrity of the drug pre-market approval process. Thereby, incentivizing pharmaceutical manufacturers to continue to develop new and generic drug products. Additionally, the goal will extend to ensure that patients do not receive a compounded product unnecessarily when an FDA-approved drug is appropriate and available.
- The guidance defines under what parameters the FDA will decide that a compounded product is essentially a copy of a commercial drug product as it applies to 503B operations.
- The agency does not consider the compounded drug a copy if it appears on the shortage list at the time of compounding, distribution, and dispensing.
- FDA considers a compound identical or nearly identical if it has the same:
- Active ingredient(s)
- Route of administration
- Dosage form
- Dosage strength; and
- Excipients.
If compounds are produced that differ with one or more of the above characteristics, it is generally not considered identical, or nearly identical.
- For compounds produced from Bulk drug substances, that are a component of an approved drug product, a statement of clinical difference by a prescriber is required. Otherwise, the compound will be considered essentially a copy. The prescriber clinical difference statement will need to be documented on a patient-specific or non-patient specific prescription order.
- Provides guidance on non-sterile compounds produced by a 503B outsourcing facility.
- Defines when the agency would consider a compounded combination drug a copy of approved drug products, when two or more approved drugs could be used.
503B facilities should pay very close attention to this finalized guidance document, as it has potentially serious implications, particularly when compounding from bulk drug substances. Simply changing an excipient, such as producing a preservative free version of an approved drug product, will no longer be acceptable practice unless a statement of clinical difference is made by a clinician. We plan to provide a more in depth commentary on the requirement of this finalized guidance document in the near future.
Regulating Compounding from Bulk Drug Substances
The 2018 priorities plan states that 503B facilities may compound drugs in accordance with the FD&C Act using bulk drug substances, if the FDA has determined there is a clinical need with the substance and places it on the 503B bulks list, or if the drug appears on the drug shortage list.
- The Agency reiterated that they issued a draft interim guidance regarding compounding from bulk drug substances and encourages 503B facilities to refer to this document for guidance during the interim period.
- The Agency also states that they intend to issue draft guidance in March, 2018 that proposes the criteria for making clinical need determinations for the purposes of establishing the 503B bulks list. The Agency cautions, that enforcement discretion used during the interim time period, for any certain nominated drug substance, does not warrant a determination by the agency that the substance belongs on the 503B bulks list.
The are no significant changes announced with regard to this topic, however, the finalized guidance on compounds that are essentially copies of commercial products addresses 503B compounding from bulk. 503B facilities should continue following the interim guidance for compounding from bulk, while also considering the finalized guidance addressing bulk compounding using ingredients available in commercial products.
Finalization of Biological Products Guidance
The Agency issued the revised guidance document, titled: Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application. (Click here for a link to the revised draft guidance)
- The guidance document includes, but is not limited to the following:
- Biological products are not eligible for exemptions under sections 503A or 503B of the FD&C Act.
- The conditions under which a 503A or 503B facility may mix, dilute, or repackage a biological product.
- The requirements for assigning BUDs for state-licensed pharmacies and federal facilities.
- The requirements for assigning BUDs, or extended BUDs, for outsourcing facilities. (Appendix A)
- The requirements for release testing of biologics for outsourcing facilities. (Appendix B)
- Outlines the labeling requirements based on the facility type.
The Agency issued the finalized guidance document, titled: Repackaging of Certain Human Drug Products by State-Licensed Pharmacies and Outsourcing Facilities. (Click here for a link to the final guidance)
- The guidance document includes, but is not limited to the following:
- The conditions under which a 503A or 503B facility may repackage human drug products, other than biologics.
- The requirements for assigning BUDs for state-licensed pharmacies and federal facilities for both sterile and non-sterile drug products.
- The requirements for assigning BUDs for outsourcing facilities. For extending BUDs, the document references the cGMP Interim Guidance for 503B Outsourcing Facilities.
- Outlines the labeling requirements based on the facility type.
For 503B facilities, these documents provide fairly clear and concise guidance regarding general repackaging, as well as, repackaging of biological products. The documents clearly layout the requirements for a 503B to extend the dating of repackaged biologic and non-biologic products. However, the guidance does distinguish between allergenic extracts and provides details on the requirements for repackaging by 503B facilities. Entities which repackage allergenic extracts, should pay close attention to the associated sections and adjust their compounding practices as required.
Clarifying Other Policies on Activities that Compounders Undertake
The Agency also announces the intention to create a guidance document on the “definition of a facility” in section 503B.
- This guidance will aim to address the question of whether a 503B can be co-located within the same facility as a 503A.
A final guidance will be published regarding the compounding and repackaging of radiopharmaceuticals for state licensed nuclear pharmacies, federal facilities, and certain other entities.
A revised draft guidance describing examples of conditions that the FDA considers to be insanitary and in violation of the FD&C Act.
- The revised draft guidance will address concerns raised by some providers who compound small quantities in their office; AND
- Will better define the conditions under which the agency believes drugs are compounded in a manner that creates negligible risk, and subsequently not subject to the same regulatory requirements.
A final rule will be issued regarding additions and changes to the list of drugs that cannot be compounded because they have been withdrawn from the market for lack of safety or efficacy.
The above priorities were not listed under any specific heading in the FDA’s priorities plan, but none the less will have an impact on 503B operations. 503B facilities should pay close attention to the revised guidance regarding insanitary conditions and establish policies & procedures consistent with the guidance. Additionally, 503B facilities sharing a location with a 503A operation should be excited to finally get some guidance from the Agency. It may not be the news they want to hear, but at least there should be some finite guidance on the subject.
Author: Kristopher Le, Pharm. D.
