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 regulations that will certainly impact the operations of both 503A and 503B compounding facilities. Below, I have provided a brief synopsis of the key elements, stratified by how it may impact 503A facilities. (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issue proposed regulations on the cGMP requirements 503B Outsourcing Facilities meet, through a revision to the current draft guidance.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 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- The revised draft guidance will also outline circumstances, in which the FDA does not intend to take action against a 503B facility, and provides exemptions from certain cGMP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.
It seems, under the updated draft guidance, the FDA may provide exemptions from certain cGMP practices based mostly on the perceived risk to public health. Risk may be determined by type of compounds produced, the scale of batches, processing techniques, or all of the above. The priorities plan is not clear on how risk will be determined, and they do not make a statement with regard to when the updated draft guidance will be open for comment.
Based on this priority, 503A facilities who have previously considered, but have been weary of their ability to maintain a cGMP operation, might have an opportunity to enter this market with reduced regulatory risk.
Restricting Compounding of Drugs that are Essentially copies of FDA-Approved Drugs
The FDA finalizes Guidance for Industry – Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A 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 503A operations.
- The guidance requires a statement of significant difference, by the prescriber, on the original prescription for every specific patient, when the compounded product is similar to a commercially available product.
- The FDA plans an outreach program for prescribers to educate them in the determination whether there is a change between a compounded drug and commercially available drug, or comparable approved drug, that produces a clinical difference for a specific patient.
- The plan announces a priority review of situations in which a compounded drug is produced from bulk drug substance to a product that can be made by diluting an FDA-approved drug according to its labeled instructions.
The new finalized guidance documentation contains a lot of specific information and definitions regarding how the FDA will determine if a compounded product is essentially a copy of an FDA-approved drug. Compounding practices that have generally been accepted, such as making minor changes to excipients or doses of active ingredients, will need to be reasonably justified. We will be releasing a more in depth commentary to further guide 503A facilities through the changes associated with this guidance document.
Regulating Compounding from Bulk Drug Substances
The 2018 priorities plan states that 503A facilities may compound drugs in accordance with the FD&C Act using bulk drug substances that comply with existing USP or NF monograph standards; are components of FDA-approved drugs; or appear on a list developed by the FDA through regulation, after consultation with USP and the Pharmacy Compounding Advisory Committee (the 503A bulks list).
- The Agency reiterated that they issued a draft interim guidance regarding compounding from bulk drug substances and encourages 503A facilities to refer to this document for guidance during the interim period.
- The Agency also states that they intend to issue final regulation regarding the 503A bulks list as part of their 2018 compounding priorities. In addition, the agency will continue the process for evaluating additional substances that have been nominated for the 503A 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 503A bulks list.
This section of the priorities plan, simply reiterates the agency’s position on compounding from bulk drug substances. They do state a finalized guidance is one of their priorities, so expect that guidance sooner rather than later. They do mention the plan to finalize the bulk guidance for 503B facilities in March or 2018, so perhaps both documents will be finalized then. One thing is certain, 503A facilities should not accept ignorance from an inspector as tacit compliance of a particular drug being considered acceptable. Facilities should be referencing the interim guidance and tailoring their business models around the current draft bulks list until everything is finalized.
Solidifying FDA’s Partnership with State Regulatory Authorities
The Agency announces their intent to work closely with state boards of pharmacy regarding compounding activities.
- Objective – to allow the FDA to focus on 503B facilities and 503A facilities deemed to present the greatest risk.
- The agency intends to clarify circumstances in which they will look to state BOPs to enforce compounding standards for patient specific compounds shipped within the associated state.
- The agency announces that the draft Memorandum of Understanding (MOU) will be significantly revised within the upcoming months.
- The revision will be in response to the numerous comments and congressional interest obtained during the comment period, to include:
- Redefinition of an “inordinate amount” of compounded product interstate, from greater than 30% to greater than 50% of the total prescriptions per month.
- The Agency states that, the inordinate amount definition will not be a hard limit for state action, but instead serve as a trigger for certain reporting requirements. In addition, the states will be given more flexibility when determining what constitutes an inordinate amount.
- The MOU will allow more time for states to report, making it easier for state regulatory agencies to commit to the requirements.
The changes outlined in this section of the priorities plan are positive for 503A facilities, relative to the previous draft MOU. Allowing the states more flexibility about which facilities pose the greatest risk, and subsequently, which facilities should be reported to the FDA further removes the Agency from 503A specific enforcement activities. However, any limitation to the number of compounded products a 503A facility can ship via interstate commerce, may have a negative effect on pharmacies whose primary model is compounding, particularly those in the I.V. home infusion markets. The Agency is not clear whether the revised draft MOU will be open for comment, so 503A facilities should be checking regularly as the finalized version could significantly impact their operations.
Finalization of Biological Products Guidance and Clarifying Other Policies on Activities that Compounders Undertake
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.
Regarding 503A operations, these documents provide fairly clear guidance regarding the acceptable practices associated with repackaging biologic and non-biologic human drug products. However, while the document provides a process for the extending of BUDs for 503B outsourcing facilities, it does not provide a clear path for the extending of BUDs for a 503A facility. It makes sense that a 503A would be able to extend the BUD for a product if they were to fully comply with the regulatory requirements set forth for 503Bs, but the Agency does not address it specifically within these documents.
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.
- Address concerns raised by some providers who compound small quantities in their office.
- 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 503A operations. 503A facilities should pay close attention to the revised guidance regarding insanitary conditions and establish policies & procedures consistent with the guidance. Additionally, 503A facilities sharing a location with a 503B 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.
