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This is the final part of our series looking at the FDA's approach for the 503B Outsourcing Facilities regarding "Essentially Copies." The Guidance, released in January 2018, is arranged as follows:
- INTRODUCTION AND SCOPE
- BACKGROUND
- Section 503B of the FD&C Act
- Compounding, Generally
- Compounded Drugs that are Essentially Copies of Approved Drug Products
- Compounded Drugs that are Essentially Copies of Unapproved Non-Prescription Drug Products
- POLICY
- Definition of Essentially a Copy of an Approved Drug
- Recordkeeping
APPENDICES A & B
This week, we will look at the highlighted section in the POLICY above as an aid in understanding the position of the FDA.
A. Definition of Essentially a Copy of an Approved Drug
This Guidance applies to a compounded drug that is "identical or nearly identical" to an approved drug or an unapproved non-prescription drug. The FDA does not intend to take action against an outsourcing facility for failing to compound in accordance with section 503B(a)(5) if it fills orders for a compounded drug that is essentially a copy of an approved drug that has been discontinued and is no longer marketed.
1. Compounded Drug is Compared to an Approved Drug
- A compounded drug is essentially a copy of an approved drug if the compounded drug is identical or nearly identical to an approved drug, unless the approved drug appears on the drug shortage list in effect under section 506E at the time of compounding, distribution, and dispensing.
- The FDA intends to consider a compounded drug product to be identical or nearly identical to an approved drug if the compounded drug product and the FDA-approved drug have the same:
- active ingredient(s),
- route of administration,
- dosage form,
- dosage strength, and
- excipients.
Shortage
A compounded drug product that has all of these characteristics in common with an FDA-approved drug product is essentially a copy of an approved drug, unless the approved drug appears on the FDA's drug shortage list at the time of compounding, distribution, and dispensing.
It is important to patients and prescribers that compounded drugs prepared to address a shortage closely resemble the drug in shortage, and, for that reason, the statute seeks to allow compounders to compound drugs that are as close as possible to the drug in shortage.
The FDA recognizes that there may be circumstances in which a drug product is in shortage when the outsourcing facility compounds the drug, but the shortage is resolved before the outsourcing facility distributes it. The FDA does not intend to take action against an outsourcing facility for filling orders for an approved drug that was on the FDA's drug shortage list at the time that the outsourcing facility received the order, provided the drug also appeared on the FDA drug shortage list within 60 days of the outsourcing facility distributing or dispensing the drug.
Bulk Drug Substance
Compounded drugs containing a bulk drug substance that is a component of an approved drug is essentially a copy of an approved drug, unless there is a change that produces, for an individual patient, a clinical difference, as determined by the prescribing practitioner, between the compounded drug and the comparable approved drug.
Prescriber Determination of Clinical Difference
If an outsourcing facility intends to rely on such a determination to establish that a compounded drug is not essentially a copy of an approved drug, the outsourcing facility should ensure that the determination is noted on the prescription or order (which may be a patient-specific prescription or a non-patient specific order) for the compounded drug.
Office Stock
The FDA is aware that a healthcare practitioner who orders a compounded drug from an outsourcing facility for office stock will not know the identity of the individual patients who will receive the compounded drug at the time of the order. In that case, the outsourcing facility should obtain a statement from the practitioner that specifies the change between the compounded drug and the comparable approved drug and indicates that the compounded drug will be administered or dispensed only to a patient for whom the change produces a clinical difference, as determined by the prescribing practitioner for that patient. Such assurances should be provided by the healthcare practitioner or a person able to make the representation for the healthcare practitioner.
Format
A specific format is not needed. For example, the following would be sufficient for office stock:
- "Liquid form, compounded drug will be prescribed to patients who can't swallow a tablet" (if the comparable drug is a tablet)
- "Dilution for infusion solution to be administered to patients who need this formulation during surgery" (if the comparable drug is not available at that concentration, pre-mixed with the particular diluent in an infusion bag)
- "1 mg, pediatric patients need lower dose" (if the comparable drug is only available in a 25-mg dose)
For those outsourcing facilities that also compound drug products based on prescriptions for identified individual patients in the following examples:
- "No Dye X, patient allergy" (if the comparable drug contains the dye)
- "Liquid form, patient can't swallow a tablet" (if the comparable drug is a tablet)
- "150 mg drug X in 120 mL Cherry-flavored Syrup USP, patient needs alcohol-free preparation (if the comparable drug is only available in formulations that contain alcohol)
Nonsterile Compounding Only
An entity that only compounds nonsterile drugs does not meet the statutory definition of an outsourcing facility. The definition states, in part, that an outsourcing facility "is engaged in the compounding of sterile drugs."
Price
Factors such as a lower price are not sufficient to establish that the compounded product is not essentially a copy of the approved drug.
Clinical Difference Enforcement
At this time, the FDA generally does not intend to question the determinations of clinical difference that are documented in a prescription or order as described above. However, they do intend to consider whether a prescription or order relied upon by an outsourcing facility to establish that a drug is not essentially a copy documents that the determination was made.
Combination of Two Different Commercial Products
The FDA intends to consider a compounded drug product that has bulk drug substances that are components of one or more approved drugs to be essentially a copy of an approved drug product, unless the prescribing practitioner determines that there is a change that produces a clinical difference for an individual patient between the compounded drug product and the comparable approved drug.
- For example, if there are two approved drug products that are tablets, one containing 5 mg of active ingredient A and the other containing 10 mg of active ingredient B and the outsourcing facility compounded a tablet that offered both active ingredients in the same dosage strengths, the compounded drug would be essentially a copy absent a prescriber determination of clinical difference.
Over-the-counter Drug Products
a. Compounded drugs that are identical or nearly identical to a covered OTC [over-the-counter] drug product.
Note: This section may not apply to the majority of 503B Outsourcing Facilities, so it is recommended that any facility involved in OTC drug products read, very carefully, this section in the Guidance.
To All: Please read the Guidance in its entirety. Granted, it is very confusing and takes some time to understand. A complete copy of the Guidance can be obtained at:
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatory
information/guidances/ucm510153.pdf
Just a reminder, this is for 503B Outsourcing Facilities, NOT traditional 503A pharmacies.
Loyd V. Allen, Jr., PhD, RPh
Editor-in-Chief
International Journal of Pharmaceutical Compounding
Remington: The Science and Practice of Pharmacy Twenty-second edition
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