The Importance of Method Validation for the Testing of Compounded Medications

Compounding Evolution

Over the past decade, the compounding industry has been in a state of continuous evolution, in a large part due to the tragic consequences of the 2012 N.E.C.C. fungal meningitis contamination. As a result, the FDA has been applying pressure to the State Boards of Pharmacy to develop meaningful regulations for compounders. There is little doubt that, over time, these regulations will begin to mirror those currently enforced by FDA on drug manufacturers and 503b outsourcing facilities. One of the key components of pharmaceutical manufacturing is the testing of finished product prior to release. It's expected that all batches have validated stability claims, that all batches are tested prior to release, and the results of testing are found to be within a predetermined specification before being sent to the market.

We want to make one thing clear before proceeding - drug manufacturing and drug compounding are very different and have different regulatory requirements. Even though the requirement for a 503A compounding pharmacy to test every batch is unlikely, there will be requirements to have a testing program in place to verify that safe product is being produced. Unlike manufacturers, most compounding pharmacies do not have their own in-house microbiology and analytical labs. This means they'll need to partner with a reputable third party contract lab to perform this testing. From a regulatory standpoint, the contract lab is considered an extension of the compounding facility, and as such, the compounder is responsible for ensuring that the lab is complying with the regulations. This article will clarify some of the critical questions to ask of a contract lab before engaging their services.

Before any reputable contract lab can begin confidently testing your compound, they will need to first validate their testing method. However, depending on the method, the validation exercise can be significantly different. For example, USP compendial methods are considered valid, so the lab only needs to verify that they can effectively execute the method, and that the method works in the presence of the product being tested. Examples of these types of methods are:

• USP <71> Sterility Test
• USP <85> Bacterial Endotoxin Test
• Assay methods specified within USP Monographs.

If during a compendial verification process, a method does not work for a specific product, the lab may need to make slight modifications to the method, or develop and validate a new method for that product.¹

What is Method Verification?

Prior to testing a product using an existing validated method, the lab will first need to "verify" that the product does not interfere with the accuracy of the test method result.

• For sterility testing, verification is often referred to as "Method Suitability." This test proves that the product does not interfere with the ability of the method to detect microbial contamination.
• For bacterial endotoxin testing, verification is referred to as the "Test for Interfering Factors." This test determines if there are factors present in the product that inhibit or enhance the endotoxin result.
• For potency testing (Assay), verification is referred to as "Specificity." This is a portfolio of tests that determine if there are factors from the product such as excipients, impurities, degradation products, matrix effects and/or leachate from the container closure that interfere with the ability of the method to accurately measure the active ingredient.

If, during the verification process, it's determined that the product interferes with the test method, then the lab may make small adjustments to the existing method, and then repeat the verification process. If the interference is significant, such that small adjustments do not eliminate the interference, an entirely new method will need to be developed and validated. The requirement to develop and validate a new method is much more prevalent with potency test methods associated with complex and/or multi-active compounds.

What is Method Validation?

There are specific requirements in the USP² and ICH³ standards for what constitutes a valid method. For the sake of discussion, we will focus on the validation requirements for methods used to "Assay" the active ingredients within a compound. To meet the USP and ICH standards, a validated method must meet predetermined specifications for:

• Accuracy: The closeness of the test result to the true value.
• Precision: The repeatability of the test result.
• Specificity: The ability to assess unequivocally, the active ingredient in the presence of other components, such as impurities, degradation products, and matrix components.
• Linearity: The ability of the test method to elicit results that are directly proportional to the concentration of the active within a specific range.
• Range: The upper and lower limits of the active, where the method demonstrates a suitable level of accuracy, precision, and linearity of measurement.

The robustness, or the sensitivity to slight, but deliberate changes in the method are also be determined. More robust methods allow for greater variance within the established parameters, and a greater potential breadth of use. However, each method has its limits, beyond which the accuracy of the test result will be questionable. When these limits are surpassed, development of a new method will need to be considered.

Costs of Method Development

Developing a new test method can be very costly. A significant amount of R&D resources needed, and depending on the situation, may cost from thousands to hundreds of thousands of dollars. Most labs, who specialize in the testing of compounded product, already have methods developed for the testing of commonly compounded preparations. In this case, the lab will have absorbed the cost of the initial method development, and may need only to extend the current validated test method to the specific formulation through a method verification. The precedent for this approach resides with the USP compendial methods which allow for extension of the compendial method to a compounded medication through verification testing.

For formulations that are more complex, the likelihood of using the compendial method, or of the laboratory having a method that will work decreases. In situations such as these, the laboratory will need to develop a new method resulting in potentially significantly higher costs. A reputable lab will start with an existing method and modify from there, which often mitigates some of the costs. These development projects will run in the thousands to tens of thousands of dollars, depending on the complexity of the formulation and the familiarity of the lab with the compounded medication.

When the active ingredient isn’t currently tested by the lab, or is not available in the USP or other compendia, then the lab must develop the new method from scratch. This is typically the most expensive type of method development project, and can run from the tens of thousands to hundreds of thousands of dollars to complete. These types of situations are few and far between in the compounding space. If a pharmacy wishes to go down this path, the market opportunity will need to be significant to justify the cost.

"My lab tests this same product for multiple customers. Why do I have to pay for method verification or validation?"

Analytical labs use very sensitive equipment. Even the smallest changes in a products configuration or compounding process can have a large impact on the output for a given test. As a result, it is incumbent upon the compounder and the lab to ensure the product is compatible with the method. Some of the things that can change in a compound which can impact the ability of a method to deliver accurate results are:

• Change in the supplier of raw materials (APIs and Excipients)
• Change in the container closure (different leachables and extractables)
• Changes in the compounding process
• Changes in the compound formulation

For products labeled as USP with a supporting USP monograph, there is often a compendial USP method for analytical testing. That method can be assumed to be a valid method "IF" the product is formulated as the USP product. However, the lab would still be required to perform a method verification to ensure that the product formulation does not interfere with the test. Every aspect of the compounding process must be considered to have a potential impact on the analytical test method, which is why it's so important to have compounding procedures defined and standardized. It's also why the FDA requires all manufacturing processes to be fully validated, but I will leave that discussion for another day.

The Cost of Non-Compliance

At the beginning of this article we emphasized the partnership aspect of working with a contract lab. Labs who test pharmaceuticals are required by the FDA to use validated, stability indicating assays to test and determine the quality and stability of pharmaceutical products. As such, compounders are responsible for assuring public safety, by ensuring that their lab is meeting the necessary requirements. Working with the lab closely, as a partner, will facilitate accomplishing this task.

Knowing what to look for, and what questions to ask when engaging a contract lab will go a long way when making the right partnership decisions. It may also result in significant savings in the long run, and much smoother regulatory inspections. During a regulatory inspection, the compounder and potentially the regulatory body, may need to communicate directly with the contract lab. As such, the compounder will need to be in a position where they can work together with a lab to explain and rationalize to the regulatory inspector, what approach they used and why they took that approach. Having to justify and rationalize why a method verification/validation was not performed, can put both the lab and compounder in an uncomfortable position. When a method is fully validated, the lab can confidently answer to the regulatory agency and quickly provide the necessary supporting information.

Regulatory bodies, such as the FDA, expect that test methods are validated. The initial cost of method development, while it can be expensive, is far less expensive than the FDA urging a voluntary recall of all compounded product. In situations where there is an adverse event, or a suspected diversion, validated test methods establish confidence in the release and investigation results. Imagine the situation were the pharmacy receives a customer complaint for decreased or lack of efficacy of a compounded medication. If the potency method used to test the finished product or to conduct the investigation was not validated to work with the product in question, how can one know, with absolute confidence, that the data generated, accurately reflects the quality of the product in question. A pharmacy would have a difficult time defending their decision to not perform product verification testing or validation to a regulatory inspector whose primary goal is to protect public safety.

We will wrap this topic up with discussion of risk. There is risk in everything that we do, and it is impossible to eliminate all risk from any situation. It is however, incumbent upon us, as medical professionals, to minimize that risk when, and where ever we can. So, at a minimum, every pharmacy should have a testing program in place that uses methods validated and verified to work with the products that are being tested. This responsibility is borne by both the pharmacy and the contract lab, because at the end of the day, risk that is left in the system, is born by the patient. Said differently, a pharmacy without an effective testing program, is essentially transferred the test point, and associated risk, to the patient, and no medical professional would want to discover a product failure in the form of an adverse event.

References and Sources

¹USP Chapter 1225 - Validation of Compendial Procedures ¹USP Chapter 1226 - Verification of Compendial Procedures ²United States Pharmacopeia ³The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use

Co-Authored By: Russel D. Odegard, MBA, B.S. linkedin.com/in/russell-odegard-a50882