# Presentation: 160402

## Demonstrably Difficult to Compound Drug Products

- Kathleen Anderson, Pharm. D.
- Division of Prescription Drug Compliance and Surveillance
- Office of Compliance
- Center for Drug Evaluation and Research

**Notes:**
Good Morning, my name is Kathy Anderson and I am a Consumer Safety Officer in the Division of Prescription Drug Compliance and Surveillance, Office of Compliance, Center for Drug Evaluation and Research. 

I’ll be providing an overview of the approach FDA is proposing to use in developing this list.  This afternoon our CDER experts will present the scientific rationales, based on our preliminary findings, for including certain products on the difficult to compound list.  They will also be available to answer any technical questions.

## Section 503A(b)(3)(A)

- States that “a drug product may be compounded under subsection (a) only if such drug product is not identified by the Secretary 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.”

**Notes:**
Section of 503A(b)(3)(A) of the Federal Food, Drug, and Cosmetic Act states that a drug product may be compounded under subsection (a) only if such drug product is not identified by the Secretary 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.  

To do this, we convened an internal agency work group and worked with experts from CDER. 
It was decided that the best way to develop this list was to identify criteria or factors that could be used to evaluate products for inclusion on the list.  

## Factors

- 1.  Drug Delivery System
- 2.  Drug Formulation and Consistency
- 3.  Bioavailability
- 4.  Complexity of Compounding
- 5.  Facilities and Equipment
- 6.  Training
- 7.  Testing and Quality Assurance

**Notes:**
In identifying these factors we considered attributes that could affect a product’s safety and efficacy, namely a product’s potency, purity, and quality.  
We then identified factors that we could use to help us evaluate the effect of compounding on a product’s potency, purity, and quality.

## 1.  Drug Delivery System

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

**Notes:**
The factors we identified are:

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

## 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?

**Notes:**
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 efficacy of the product a concern if the bioavailability varies?

**Notes:**
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?

**Notes:**
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?

**Notes:**
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?

**Notes:**
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?

**Notes:**
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?

## Factors

- 1.  Drug Delivery System
- 2.  Drug Formulation and Consistency
- 3.  Bioavailability
- 4.  Complexity of Compounding
- 5.  Facilities and Equipment
- 6.  Training
- 7.  Testing and Quality Assurance

**Notes:**
We propose to evaluate products in light of each of these factors, in developing the list of difficult to compound drugs.  Each factor would be balanced, on a case‐by‐case basis, in deciding whether a product would be an appropriate candidate for inclusion on the list.  
We seek input from this committee on any additional factors that should be used in evaluating products for inclusion on the list.  We specifically request input on whether to consider as a factor the difficulty or importance of achieving stability for a drug product in our evaluation of products for the list.
We would like the advice of the committee on the use of these factors, are they appropriate?

## Approach

- Began a preliminary evaluation of products for inclusion on the list
- Focusing on products with ** **
- evidence in the literature and
- potential to affect the public health

**Notes:**
After we developed the factors, we then began a preliminary evaluation of products for inclusion on the list focusing on products with evidence in the literature and with the potential to affect the public health. 

## Approach

- Some products with similar characteristics raise similar concerns for pharmacy compounding
- tentatively proposing to include both specific drug products and categories of drug products that are grouped by relevant factors

**Notes:**
In this preliminary evaluation, we found that some products with similar characteristics raise similar concerns for pharmacy compounding.  For example, all drug products contained in certain dosage forms, such as metered dose inhalers, if compounded, would present the same difficulties in assuring the safety and efficacy of the drug product.  We have also tentatively determined that the compounding of all dry powder inhalers and transdermal delivery systems are demonstrably difficult to compound. Therefore, we are tentatively proposing to include both specific drug products as well as, categories of products that are grouped by relevant factors (for example, a specific drug delivery system, such as metered dose inhalers) in the list of drug products that are demonstrably difficult to compound. 

## Approach

- Some products could raise concern for pharmacy compounding if minimum standards are not met
- tentatively proposing to include drug products that are demonstrably difficult to compound unless certain minimum standards are met

**Notes:**
We also found in this preliminary evaluation, that some products could raise concern for pharmacy compounding if minimum standards are not met.  For example, we recognize that the compounding of sterile products is a complicated issue.  As described in our concept paper, the preparation of sterile products is unavoidably complex.  We believe that the concerns associated with the compounding of sterile products may be alleviated by the use of minimum standards.  We evaluated a variety of existing guidelines for pharmacy prepared sterile products and have tentatively determined that USP Chapter 1206 describes comprehensive controls, that if followed would ensure the quality of sterile products.  Therefore, we are proposing to include drug products that are demonstrably difficult to compound unless certain minimum standards or controls are met on the list.  We are tentatively proposing that sterile products compounded under procedures other than described in USP Chapter 1206 would be considered demonstrably difficult to compound.   

## Preliminary Findings

- Our concept paper describes in detail our preliminary findings for tentatively including the following products on the demonstrably difficult to compound list:
- Metered Dose Inhalers
- Dry Powder Inhalers

**Notes:**
Our concept paper describes in detail our preliminary findings.  We seek input from this committee on our proposed approach and whether it is appropriate to include the following products on the difficult to compound list:
Metered Dose Inhalers
Dry Powder Inhalers

## Preliminary Findings

- Transdermal Delivery Systems
- Sterile Products Compounded Under Procedures Other Than Those Described in Chapter 1206 of the United States Pharmacopoeia (USP)

**Notes:**
Transdermal Delivery Systems
Sterile Products Compounded Under Procedures Other Than Those Described in Chapter 1206 of the USP

## Preliminary Findings

- Scientific Rationales

**Notes:**
This afternoon, our CDER experts will be presenting the scientific rationales for tentatively including each of these drug products on the difficult to compound list.
Dr. Brian Rogers from the Office of New Drug Chemistry will discuss Metered Dose Inhalers and Dry Powder Inhalers;
Dr. Vinod Shah and Dr. Amit Mitra from the Office of Pharmaceutical Sciences will discuss transdermal delivery systems;   AND
Dr. Peter Cooney also from the Office of New Drug Chemistry, will discuss sterile drug products.

## Additional Products

- We intend to identify and evaluate additional products and categories of drug products for the list

**Notes:**
We view this process as an on-going project and intend to continually identify and evaluate additional products as well as categories of drug products for inclusion on the list.  

We seek input from this committee for additional products and product categories for evaluation as candidates for the list.

Thank you.

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