FDA Concept Paper: Drug Products That Present Demonstrable Difficulties for Compounding Because of Reasons of Safety or Effectiveness

I. Background

On November 21, 1997, President Clinton signed into law the Food and Drug Administration Modernization Act of 1997 (Public Law 105-115). Section 127 of the Modernization Act amended the Federal Food, Drug, and Cosmetic Act (the act) by adding section 503A (21 U.S.C. 353a), which governs the application of Federal law to pharmacy compounding. Under section 503A(a) of the act, a compounded drug product is a drug product made in response to, or in anticipation of, receipt of a valid prescription order or a notation on a valid prescription order from a licensed practitioner that states the compounded product is necessary for the identified patient. Compounding does not include mixing, reconstituting, or similar acts that are performed in accordance with the directions contained in approved labeling provided by the product's manufacturer and other manufacturer directions consistent with that labeling (section 503A(f) of the act).

Under section 503A of the act, compounded drug products are exempt, under certain circumstances, from three key provisions of the act: (1) The adulteration provision of section 501(a)(2)(B) (21 U.S.C. 351(a)(2)(B)) (concerning current good manufacturing practice (CGMP) requirements); (2) the misbranding provision of section 502(f)(1) (21 U.S.C. 352(f)(1)) (concerning the labeling of drugs with adequate directions for use); and (3) the new drug provision of section 505 (21 U.S.C. 355) (concerning the use of drugs under investigational new drug applications (INDs) and the approval of drugs under new drug applications (NDAs) or abbreviated new drug applications (ANDAs)).

To qualify for these statutory exemptions, a compounded drug product must satisfy several requirements. One requirement is that the drug product may only be compounded if we have not identified it, by regulation, as a drug product that "presents demonstrable difficulties for compounding that reasonably demonstrate an adverse effect on the safety or effectiveness of that drug product" (i.e., is demonstrably difficult to compound) (section 503A(b)(3) of the act). This concept paper presents our preliminary thoughts on developing a list of products that are demonstrably difficult to compound.

II. Our Evaluation Method

A. Early Findings

In our evaluation of drug products for inclusion on the list of products that are demonstrably difficult to compound, we found that some products with similar characteristics (e.g., products using the same sophisticated drug delivery system) raise similar concerns for pharmacy compounding. For example, our preliminary evaluation of metered dose inhaler (MDI) products demonstrated that all MDI products, if compounded, would present the same difficulties in maintaining the safety and efficacy of the drug. We reached the same tentative conclusion regarding the compounding of all dry powder inhaler (DPI) products, transdermal delivery systems (TDSs), and sterile products that are compounded under procedures other than those described in Chapter 1206 ["Sterile Drug Products for Home Use"] of the United States Pharmacopeia (USP). Therefore, we are thinking of including both specific drug products and categories of products that are grouped by relevant factors (e.g., specific drug delivery system) in the list of drug products that are demonstrably difficult to compound. We invite comment on this approach to developing the list.

B. Factors We May Consider

Section 503A of the act requires us to identify drug products that present demonstrable difficulties for compounding that reasonably demonstrate an adverse effect on the safety or effectiveness of the drug product. The potency, purity, and quality of a drug product may affect its safety and effectiveness. These qualities may also be affected by how the drug product is compounded.

To assess the potential effect of compounding on the potency, purity, and quality of a drug product, which affects the safety and effectiveness of the drug product, we are considering evaluating drug product or drug category candidates for inclusion on the list using the following factors.

1. Drug delivery system

· Is a sophisticated drug delivery system required to ensure dosing accuracy and/or reproducibility?

· Is the safety or efficacy of the product a concern if there is product-to-product variability?

2. Drug formulation and consistency

· Is a sophisticated formulation of the drug product required to ensure dosing accuracy and/or reproducibility?

· Because of the sophisticated formulation, is product-to-product uniformity of the drug product often difficult to achieve?

· Is the safety or efficacy of the product a concern if there is product-to-product variability?

3. Bioavailability

· Is it difficult to achieve and maintain a uniformly bioavailable dosage form?

· Is the safety or effectiveness of the product a concern if the bioavailability varies?

4. Complexity of compounding

· Is the compounding of the drug product complex?

· Are there multiple, complicated or interrelated steps?

· Is there a significant potential for error in one or more of the steps that could affect drug safety or effectiveness?

5. Facilities and equipment

· Are sophisticated facilities and/or equipment required to ensure proper compounding of the drug product?

· Is there a significant potential for error in the use of the facilities or equipment that could affect drug safety or effectiveness?

6. Training

· Is specialized, highly technical training essential to ensure proper compounding of the drug product?

7. Testing and Quality Assurance

· Is sophisticated, difficult to perform testing of the compounded drug product required to ensure potency, purity, performance characteristics, or other important characteristics prior to dispensing?

· Is there a significant potential for harm if the product is compounded without proper quality assurance procedures and end-product testing?

In developing the list of products that are demonstrably difficult to compound, we would evaluate products and categories of products in light of each factor described above. We would balance the factors, on a case-by-case basis, in deciding whether a product or category of productsis appropriate for inclusion on the list. No single one of these factors would be considered to be dispositive.

In developing this list and applying these factors, we indicate special equipment, facilities, testing, and formulations that must be used to ensure a safe drug product. It is important to keep in mind that compounded drug products are exempt from the statutory requirements noted above and undergo neither the premarket IND, NDA, or ANDA review processes nor the post-approval GMP inspection process by FDA that would help ensure that these factors are adequately addressed.

C. Comments

We request comment about the use of these factors and about any additional factors that we should consider in evaluating drug products for inclusion on the list of drug products that are demonstrably difficult to compound. We also seek comment on whether we should consider the difficulty or importance of achieving stability for a drug product in our evaluation of whether a drug product is demonstrably difficult to compound.Continue reading here