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FDA Releases Flurry of Compounding-Related Documents

Health Law Alert Susan B. Trujillo

Busy, busy, busy! That is the only way to describe the FDA over the past few weeks, issuing multiple draft guidance documents affecting both 503A and 503B compounding. Here is a summary and analysis, along with links to the source documents for you to review in your free time. The topics cover compounding with bulk drug substances, compounding products that are essentially copies of commercially available products, and a welcome change in the FDA's procedure for inspection of 503A facilities.

Compounding Using Bulk Drug Substances—Interim Guidance

In June 2016, the FDA released its interim policies on compounding using bulk substances for 503A and 503B facilities. The documents provide the FDA's current thinking and enforcement strategy regarding pharmacies, physicians, and outsourcing facilities that compound using bulk drug substances, explaining that it is doing so to "avoid unnecessary disruption to patient treatment while FDA evaluates the bulk drug substances nominated for use" and clarifies how the FDA is evaluating those substances.

The interim guidance was prompted by the July 2014 FDA guidance, Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug and Cosmetic Act, which stated that until a bulk drug substances list is published as a final rule, compounders can only use bulk substances that are components of approved drugs or subject to USP or NF monographs. The FDA received comments back noting that this may cause disruptions in patient care in the 503A sphere, as there were already patients receiving drugs compounded with bulk products not meeting those requirements, but that may end up on the list. The commenters stated that care shouldn't be disrupted for those patients. For 503B facilities, the argument was similar. The FDA was required under Section 503B to prepare a bulk drug list, which it is currently evaluating, but since it will need to go through the federal rulemaking process, there needed to be an interim approach to these products.

In response to those comments, the FDA issued its draft guidance to describe its current process for evaluating nominated products, identify three categories for those products, and identify the policy position regarding the use of these products currently:

  • Category 1: Bulk Drug Substances Under Evaluation may be eligible for inclusion, nominated with sufficient information, and do not appear on any other list
    • 503A: Substances on list may be used for compounding if original and subsequent bulk substance manufacturers are registered under 510; substance accompanied by valid COA; and compounded in compliance with all other conditions of 503A.
    • 503B: Substances on list may be used for compounding if original and subsequent bulk substance manufacturers are registered under 510; substance accompanied by valid COA, if the subject of a USP or NF monograph and complies with monograph, and compounded in compliance with all other conditions of 503B
  • Category 2: Bulk Drug Substances That Raise Significant Safety Risks were nominated with sufficient information, but the FDA has identified significant safety risks.
    • 503A: May NOT be used for compounding—the current list is Domperidone, Germanium Sesquioxide, and Quinacrine Hydrochloride for intrauterine administration.
    • 503B: May NOT be used for compounding—Germainum Sesquioxide (Quinacrine not nominated, and Domperidone in Category 3 assumedly because nominating party did not provide sufficient information).
  • Category 3: Bulk Drug Substances Nominated Without Adequate Support may be eligible for inclusion on bulks list, but were nominated with insufficient support. The FDA will allow Category 3 substances to be renominated with additional supporting information, and allows for new nominations for substances that were not previously nominated. However, the draft guidance states that the FDA does not intend to evaluate these submissions until it completes its review of Category 1 substances.
    • 503A & 503B: May NOT be used for compounding

As noted above, the FDA will need to follow the formal rulemaking process to create these lists, but until what is likely to be a multiyear process is complete, it has provided this interim guidance for how they will approach enforcement regarding bulk substances.

Compounded Products that are Essentially Copies of Commercially Available Drugs—Draft Guidance

As any compounder knows, one of the conditions that must be met to qualify for exemptions under 503A and 503B is that the compounder "does not compound regulatory or in inordinate amounts (as defined by the Secretary) any drug products that are essentially copies of a commercially available product." See Section 503A(b)(1)(D) and 503B(d)(2)(B). That concept does not include a product where there is a change for an individual patient which produces a significant difference as determined by the prescribing practitioner. See Section 503A(b)(2). The FDA has now released draft guidance that describes how the FDA intends to approach all of these concepts. The public comment period on these documents closes on October 5, 2016.

First, the FDA will not consider a drug commercially available if it has been discontinued or is no longer marked or appears on a drug shortage list. Second, the FDA will consider a compounded product to be essentially a copy if:

  • The product has the same active pharmaceutical ingredient (API) as the commercially available product;
  • The APIs have the same, or similar, or an easily substitutable dosage strength; and

The commercially available product can be used by the same route of administration as prescribed for the compounded product, UNLESS the prescriber determines there is a change made for an identified individual patient which produces a significant difference from the commercially available product.

The FDA then further expounds on each element, noting that it intends to consider two drugs to have similar dosage strength if the compounded product is within 10 percent of the dosage strength of the commercially available product. In other words, very small changes in the dosage strength may not be enough to avoid the FDA's scrutiny. Also, if the compounded product has the same API and route of administration (regardless of the label), the FDA may consider it to be essentially a copy. As an example, the guidance states that a commercially available drug labeled for intramuscular use may not be compounded with the same API and strength for subcutaneous administration unless the prescriber indicates that the compounded product has a significant difference for the patient.

Finally, the FDA delves into the prescriber's determination of significant difference. The FDA states that a compounder may not rely simply on the fact that the prescriber wrote the prescription to indicate that the prescriber feels there will be a significant benefit to the patient, and that lower price is also not sufficient reason. The FDA does not provide a particular format, instead stating that as long as the face of the prescription indicates the relevant change AND the significant difference. This indication can be written either by the prescriber or by the compounder after consultation with the prescriber. The FDA provides the following as examples of sufficient information:

  • No Dye X, patient allergy (if the compounded product is necessary to exclude the dye)
  • Liquid form, patient can't swallow tablet (if the commercial product is a tablet)
  • 6 mg, patient needs higher dose (if commercial drug is only available in 5 mg dose).

Finally, the FDA offers guidance on what it considers to be compounding of copies done "regularly or in inordinate amounts." The FDA will look at the number of prescriptions for the compounded product the prescriber writes, whether the compounder regularly substitutes compounded products for commercially available products, whether the compounder uses pre-printed prescription pads where no determination of significant difference is provided, and whether the product is compounded on a routine basis. The guidance further notes that it does not intend to take action if the compounder fills four or fewer commercially available compounded prescriptions (including refills) without the significant difference indication in a calendar month.

For 503B outsourcing facilities, the guidance is essentially the same in that compounded drugs either need to be on a shortage list or, if they are not and might be considered a copy, there must be a change that produces a clinical difference for a patient. Because outsourcing facilities are permitted to compound for office use where the individual patient may not be identified prior to sending the product, the guidance permits the outsourcing facility to obtain a statement from the practitioner or health care facility indicating that the product will only be administered to a patient for whom the change produces a clinical difference.

Notice Regarding FDA Inspections of 503A Compounders

Last but not least, the FDA sent out a notice recently advising of a change to the inspection procedures for entities compounding under 503A. Beginning August 1, 2016, when inspecting a 503A facility (i.e., a pharmacy), FDA investigators will make a preliminary assessment of whether compounding entities are in compliance with section 503A before closing an inspection. If the entity is operating in full compliance with 503A, the investigator will not include any 483 observations that relate to compliance with current good manufacturing practice (CGMPs). However, if any of the pharmacy's compounding is not in full compliance with 503A, the investigator will include CGMP violations and FDA will apply CGMP standards when taking any enforcement action against the pharmacy. One big caveat is the catch-all 483 observation of "insanitary conditions." The FDA states that the prohibition against preparing, packaging, and holding drugs in insanitary conditions applies to all entities that prepare, package, or hold drugs. In the past, when the FDA has issued a warning letter, it has only cited compounders that were not registered as an outsourcing facility for violations of CGMP requirements where there was evidence that some of its drugs were not compounded in accordance with section 503A. According to the FDA Notice, a substantial majority of facilities were compounding at least some of their drugs not in accordance with section 503A, subjecting their drugs to CGMP requirements.

For questions, contact Susan Trujillo at 229-5318 or your Quarles & Brady attorney.