Drugs repackaged in outsourcing facilities have to meet certain additional requirements related to labeling, reporting of adverse events, enclosure of prescribing information from the original package and the inclusion of the drug product on required biannual drug product reports to the FDA.

The first few months of 2015 have proven very active for the U.S. Food and Drug Administration (FDA) and its regulation of pharmaceutical compounding. On February 13, 2015, FDA announced the release of five new documents related to drug compounding and repackaging.[1] The documents provide further instruction on FDA's thinking as to the 2013 Drug Quality and Security Act (DQSA), which was discussed in an earlier Duane Morris Alert. These documents are as follows:

• Draft Guidance on whether an entity should register as an outsourcing facility under section 503B of the Federal Food, Drug, and Cosmetic Act (FDCA)
• Draft Guidance on repackaging of drugs by pharmacies and outsourcing facilities
• Draft Guidance on mixing, diluting or repackaging biological products without an approved Biologics License Application (BLA)
• Draft Guidance on adverse event reporting by outsourcing facilities
• Draft Memorandum of Understanding (MOU) between states and FDA relating to the distribution of compounded drugs

In addition, on March 9, 2015, FDA announced the creation of a new public docket[2] to collect general comments and recommendations related to human drug compounding. This new docket is intended to be a repository for comments on compounding-related issues not covered by already-open, subject-specific dockets such as those created for the recent draft guidance documents and MOU. In fact, FDA has stated that comments should not be submitted to more than one docket.

Draft Guidance on Whether to Register as an Outsourcing Facility

As of January 1, 2015, entities that wish to be registered as outsourcing facilities under section 503B of the FDCA must pay a nonrefundable registration fee and comply with various other requirements, as further explored in an earlier Duane Morris Alert. This Draft Guidance recommends that facilities not register as outsourcing facilities if the entity:

• Does not intend to compound all drugs in compliance with current Good Manufacturing Practices (cGMPs) and section 503B of the FDCA;
• Engages only in non-sterile or animal drug compounding;
• Only repackages drugs;
• Only works with biological products subject to licensure under section 351 of the Public Health Service Act (PHS Act); or
• Wishes to remain eligible for exemptions set forth under section 503A of the FDCA.

FDA is accepting comments on the Draft Guidance through May 20, 2015. Comments may be submitted electronically at http://www.regulations.gov or in writing to the FDA Division of Dockets Management. Further details on the procedure for submitting comments to the Draft Guidance are available on the FDA's notice in the Federal Register.

Draft Guidance on Repackaging of Human Drug Products

In general, repackaged drugs are subject to the FDCA's requirements for premarket approval, misbranding and adulteration. This Draft Guidance confirms FDA's intent not to enforce these rules for the repackaging of human prescription drugs[3] by state-licensed pharmacies, federal facilities and registered outsourcing facilities if the following conditions are met:

• The drug is a prescription drug product approved under section 505 of the FDCA (unless it meets certain requirements for unapproved drugs on FDA's drug shortage list under section 506E of the FDCA);
• The drug has not been withdrawn from the market for being unsafe or ineffective;
• The drug is repackaged pursuant to a patient-specific prescription or written order, or based on a history of orders for such prescriptions over a previous 14-day period;
• The repackaging occurs under the direct supervision of a licensed pharmacist;
• The repackaging complies with the drug's approved product labeling;
• The package is assigned a beyond-use date in accordance with standards set forth in the Draft Guidance;
• The drug is repackaged in accordance with applicable USP standards for sterile or non-sterile drugs, or if in an outsourcing facility, in compliance with cGMP;
• The facility distributes the repackaged drug only in states where it meets all state requirements; and
• The drug product is not sold or transferred by an entity other than the entity that repackaged the product.

Drugs repackaged in outsourcing facilities have to meet certain additional requirements related to labeling, reporting of adverse events, enclosure of prescribing information from the original package and the inclusion of the drug product on required biannual drug product reports to the FDA. Finally, the Draft Guidance indicates that FDA will not take enforcement action against pharmacies repackaging drugs on the FDA drug shortage list provided that the repackaging meets the above requirements.

FDA is accepting comments on the Draft Guidance through May 20, 2015. Comments may be submitted electronically at http://www.regulations.gov or in writing to the FDA Division of Dockets Management. Further details on the procedure for submitting comments to the Draft Guidance are available on the FDA's notice in the Federal Register.

Draft Guidance on Mixing, Diluting or Repackaging Biological Products[4] Outside the Scope of an Approved Biologics License Application

In this Draft Guidance, FDA describes its policy with respect to conditions under which FDA intends to allow state-licensed pharmacies, federal facilities or outsourcing facilities to dilute, mix or repackage certain biological products without obtaining an approved BLA. It is important to note that the Draft Guidance clarifies that it does not apply to any of the following:

• Biological products not subject to licensure under section 351 of the PHS Act (i.e., biological products for which a New Drug Application (NDA) could properly be submitted under Section 505 of the FDCA);
• Products intended for use in animals;
• Mixing, diluting or repackaging biological products by entities other than state-licensed pharmacies, federal facilities or outsourcing facilities;
• Removing a biological product from the original container at the point of care for immediate administration to a single patient after receipt of a patient-specific prescription or order;
• Upon receipt of a patient-specific prescription, a licensed pharmacy removing from one container the quantity of solid oral dosage form biological products necessary to fill the prescription and placing it in a smaller container to dispense directly to the customer;
• Mixing, diluting or repackaging a licensed biological product in accordance with the FDA-approved labeling for the product; and
• Mixing, diluting or repackaging of blood and blood components for transfusion.

This Draft Guidance is thus limited to certain biological products subject to licensure under section 351 of the PHS Act. Section 351 provides a pathway for regulatory approval of a biologics application through either a BLA or an Abbreviated Biologic License Application (aBLA). This is different from the regulatory pathway for drug approvals through an NDA or Abbreviated New Drug Application (ANDA) under section 505 of the FDCA. Products for which an NDA can be or has been submitted are outside the scope of the guidance.

The Draft Guidance explains that biological products subject to licensure under section 351 of the PHS Act are not eligible for the exemptions offered to compounded drugs under section 503A and 503B of the FDCA. Sections 503A and 503B provide certain exemptions for compounded medications from section 505 of the FDCA, but do not provide exemptions from section 351 of the PHS Act.

With respect to biological products subject to licensure under section 351, the Draft Guidance advises that FDA will not engage in enforcement actions against state-licensed pharmacies, federal facilities or outsourcing facilities for violations of adequate directions-for-use labeling requirements or against the first two types of entities for violations of cGMP requirements related to the mixing, diluting or repackaging of biological products as long as the following conditions are met:

• The product is an FDA-licensed biological product, not a biological product licensed for further manufacturing, and not a bulk drug substance;
• The biological product is mixed, diluted or repackaged in a state-licensed pharmacy, federal facility or outsourcing facility;
• If the mixing, diluting or repackaging occurs in a state-licensed pharmacy or federal facility, it is done pursuant to a valid patient-specific prescription or written order, or in expectation of demand based on a history of such prescriptions and orders;
• The mixing, diluting or repackaging occurs under the direct supervision of a licensed pharmacist;
• The mixing, diluting or repackaging does not conflict with the drug's approved labeling;
• The package is assigned a beyond-use date in accordance with standards set forth in the Draft Guidance;
• If the mixing, diluting or repackaging occurs in a state-licensed pharmacy or federal facility, such activity complies with USP Chapter 797; if occurring in an outsourcing facility, such activity complies with cGMP requirements;
• The biological product is not sold or transferred by an entity other than the entity that mixed, diluted or repackaged the product;
• The facility mixing, diluting or repackaging the drug distributes it only in states where it meets all state requirements; and
• Outsourcing facilities meet the specific labeling and reporting requirements of the Draft Guidance.

To determine the regulations and policy applicable to a particular product, it may be worthwhile to determine whether the product is a drug for which an application could be or has been submitted under section 505 of the FDCA, in which case this Draft Guidance does not apply. For biological products not eligible for approval under section 505, but subject to licensure under section 351 of the PHS Act, this Draft Guidance provides the scope of permissible activities for mixing, diluting or repackaging such products.

FDA is accepting comments on the Draft Guidance through May 20, 2015. Comments may be submitted electronically at http://www.regulations.gov or in writing to the FDA Division of Dockets Management. Further details on the procedure for submitting comments to the Draft Guidance are available on the FDA's notice in the Federal Register.

Draft Guidance on Adverse Event Reporting by Outsourcing Facilities

Section 503B mandates adverse event reporting for registered outsourcing facilities. The Draft Guidance document provides further details as to FDA's expectations related to adverse event reporting.

In the Draft Guidance, FDA recommends reporting all "serious adverse drug experiences" associated with compounded drug products, rather than reporting only the required "serious, unexpected adverse drug experiences." Whenever an outsourcing facility receives notification of a possible adverse event, FDA recommends that the facility further investigate four types of information: (1) an identifiable patient[5]; (2) an identifiable reporter (i.e., the original source of information about the possible adverse event); (3) a suspect drug; and (4) a serious adverse event.[6] The facility is required to report the adverse event to FDA as soon as possible, and no more than 15 days after it first received information about the event (15-day Alert Report). If the facility was not able to obtain information related to all four data points, it should continue its investigation after the submission of the 15-day Alert Report and provide any additional information discovered to FDA.

The Draft Guidance specifies the means by which adverse events may currently be reported; at present, such reports must be submitted in hard copy. During an inspection, FDA may investigate adverse event information received by an outsourcing facility, as well as the facility's procedures for handling such information. Outsourcing facilities have to maintain records of all adverse events for 10 years, and should also keep records of its efforts to obtain information related to the four adverse event data points discussed above.

FDA is accepting comments on the Draft Guidance through May 20, 2015. Comments may be submitted electronically at http://www.regulations.gov or in writing to the FDA Division of Dockets Management. Further details on the procedure for submitting comments to the Draft Guidance are available on the FDA's notice in the Federal Register.

Draft Memorandum of Understanding Between States and FDA

Section 503A directs FDA to enter into a Memorandum of Understanding (MOU) with the states that addresses the distribution of inordinate amounts of compounded drugs interstate and provides for appropriate investigation by the state of complaints about compounded drugs distributed out of state. This draft MOU replaces FDA's never-implemented January 1999 proposal and marks FDA's first attempt at this type of agreement with the states since the passage of the DQSA.

The draft MOU attempts to address, among other things, the distribution of inordinate amounts of compounded drugs interstate by proposing to limit out-of-state distribution and dispensing of compounded drugs to less than 30 percent of the total prescriptions that a pharmacy dispenses and distributes. The draft MOU defines "inordinate amount" as an amount equal to or greater than 30 percent of the number of units of compounded and non-compounded human drug product distributed or dispensed both intrastate or interstate by a pharmacy each month. The draft MOU further defines "distribution" to include dispensing. The draft MOU requires the states to report to FDA any pharmacy that reaches or exceeds this 30-percent limitation. Either FDA or the state will take action because, under the rationale set forth in the draft MOU, the facility that meets or exceeds this 30-percent monthly limit will be deemed to have lost the exemptions to the FDCA set forth in Section 503A, which means that the pharmacy can be deemed by FDA and/or the Board of Pharmacy to be operating as an illegal drug manufacturer.

FDA is accepting comments on the draft MOU through June 19, 2015. Comments may be submitted electronically at http://www.regulations.gov or in writing to the FDA Division of Dockets Management. Further details on the procedure for submitting comments to the Draft Guidance are available on the FDA's notice in the Federal Register.

Conclusion

FDA's latest documents address some of the issues raised by the implementation of the DQSA, provide additional insight into FDA's current thinking and present FDA's proposed MOU. As the DQSA presents many issues not addressed by current FDA guidance documents, in addition to the opportunities to comment to the new documents released, FDA created a new public docket to collect general comments and recommendations related to human drug compounding. Industry members may want to take advantage of the multiple opportunities to comment on how FDA is interpreting the DQSA and regulating compounding.

For Further Information

If you have any questions about this Alert or would like more information, please contact Rachael G. Pontikes; Patrick C. Gallagher, Ph.D.; Alison T. Rosenblum; any of the attorneys in our Pharmaceutical, Medical Device, Pharmacy and Food industry group; or the attorney in the firm with whom you are regularly in contact.

Notes

1. Official notices for each of the guidance documents were published in the Federal Register on February 19, 2015.
2. Docket No. FDA–2015–N–0030.
3. FDA considers repackaging of a prescription drug product to be the transfer of a finished product from the package in which it was distributed by its manufacturer to a new package.
4. Biological products are defined by section 351(i)(1) of the PHS Act as "a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings."
5. There has to be sufficient information in order to demonstrate that a specific patient experienced an adverse event. If the information received by the outsourcing facility indicates that multiple people were affected, the facility has to submit separate reports for each individual patient affected.
6. An outsourcing facility is required to report adverse events resulting in death, a life-threatening experience, inpatient hospitalization or prolonging of existing hospitalization, persistent or significant disability or incapacity, or a congenital anomaly or birth defect.

Disclaimer: This Alert has been prepared and published for informational purposes only and is not offered, nor should be construed, as legal advice. For more information, please see the firm's full disclaimer.