Method validation is essential in proving the quality, reliability and consistency of a chemical being developed. Proper validation of a method provides documented evidence of method performance and prescribes ongoing measures to ensure quality monitoring for the life of the method. It is essentially the blueprint for future manufacturing of the chemical. Yet, inadequate method validation persists as a significant problem in pharmaceutical development and manufacturing. When not performed properly, it can result in delays in product approval, require a complete doover of API development, or cause regulatory delays in commercialization. But, being aware of common mistakes, and how to avoid them, will help ensure analytical methods are successfully validated, leading to successful commercialization.
What the FDA Wants
Generally speaking, the FDA requires method validation data that supports and documents the identity, strength, quality, purity, and potency of drug substances and drug products, which must be reproducible time and again.
The FDA provides clear guidance on method validation requirements, which is closely aligned to the International Conference on Harmonisation (ICH) guidance. According to the guidance, early in the development of new analytical procedures, the choice of analytical instrumentation and methodology should be selected based on the intended purpose and scope of the analytical method. Parameters that may be evaluated during method development are specificity, linearity, limits of detection (LOD) and limits of quantitation (LOQ), range, accuracy, and precision.
During early stages of method development, the robustness of methods should be evaluated to help Contract Manufacturing Organizations (CMOs) and other scientists, decide which method will be submitted for approval. Analytical procedures in the early stages of development are initially developed based on a combination of a mechanistic understanding of the basic methodology and prior experience.
Top Mistakes Found in Review
Although these guidelines are comprehensive, following them can be challenging, especially when drug developers attempt to use a cookie cutter approach that often is found to be inadequate since it doesn’t take into consideration the uniqueness of each New Chemical Entity (NCE) or Active Pharmaceutical Ingredient (API) being developed. In fact, the majority of negative audit findings fall into three main categories:
- The use of non-validated methods for critical decision making
- Inadequate method validation that does not provide the necessary information
- Method validation that lacks appropriate controls to maintain the integrity of the validation
The consequences of negative audit findings are numerous for both a sponsor and a CMO in terms of cost and commercialization potential. In addition to potential delays in starting clinical trials or shipping the product, incomplete method validation can impact stability studies that don’t meet specification. In addition the proven efficacy of the drug or even its safety profile can be compromised.
Typical Culprits in Method Validation Problems
Method validation problems can be found even before validation studies begin, and the root cause is a lack of thorough understanding of the physiochemical properties of the molecule, which should be determined at the start of the project. These include ascertaining the molecule’s solubility, pH, pKA, reactivity, melting point, boiling point, moisture sensitivity, light sensitivity and other characteristics.
Only when the physiochemical nature of the compound is firmly established can the appropriate validation studies be designed. For example, if it is known that a material is light sensitive or moisture sensitive, then it is clearly understood that during validation studies it should not be exposed to light, heat or air. That type of information must be captured for an appropriate method validation plan.
But aside from improper assessment of the physiochemical properties, there are three common mistakes that occur in method development:
Ignoring the 10 questions. Ahead of developing a reliable method for a product’s intended use, many scientists fail to prepare a methods validation plan which asks the following key questions:
- Is this method for the release of raw material?
- Is this method for in-process control?
- Is this method for final product release testing?
- What is the route of administration for this product?
- What is the maximum daily dose for this product?
- How long does the drug product’s administration take?
- What are the crucial components that need to be monitored for each sample of the product?
- What are the specifications?
- Does the compound have any genotoxic impurities?
- What is the impurity profile?
Not thinking ahead to future methods testing. It’s critical from the start to prepare for further review of all analytical methods developed. Ultimately methods will undergo validation via peer review, then QA review, then regulatory review. The most effective analytical method development assures that lab resources are optimized and that the methods developed can be validated at each progressive step in the process. If changes to a method are required, it’s best to do so, and document the changes, before moving on to the next validation step.
Insufficient method optimization. Once initial studies look promising for the product’s intended use, method optimization should be incorporated. Typical method optimization involves, for example, improving method specificity, sensitivity, and studying solution stability. A system suitability determination can also be made. As drug development progresses the analytical methods that will form the backbone of the regulatory submission should be constantly optimized for increased yield and efficiency.
CDMOs that undertake complex API or NCE development projects understand that no method should be considered routine given how critically important time, cost and efficiency are to sponsors, yet it’s surprising how often these common mistakes occur. Analytical methods that are scientifically sound, well understood and properly validated with the regulatory pathway in mind are the basis for successful manufacturing and regulatory approval, as well as safe and effective drugs.