Top Early Stage Method Validation Mistakes and How to Avoid Them

Mistakes to avoid before method validation begins

Inadequate method validation persists as a significant problem in pharmaceutical development and manufacturing. When not performed properly, method validation can be costly for a number of reasons. It can result in delays in product approval, require re-do of API development, and/or result in regulatory problems during commercialization. Knowing the causes of common mistakes, and how to avoid them, will help ensure analytical methods are successfully validated during Phase II clinical trials and beyond.

This article will focus on why method validation is critically important and the top mistakes that should be avoided even before method validation begins. Building a solid foundation keeps API development projects on track and on time.

What regulators want

Generally speaking, the FDA and EMA require methods validation data that support and document the identity, strength, quality, purity, and potency of drug substances and drug products. As well, the methods submitted must be reproducible time and again.

The FDA provides clear guidance on method validation requirements: https://www.fda.gov/downloads/drugs/guidances/ucm386366.pdf

The FDA’s guidance complements the International Conference on Harmonisation (ICH) guidance 29: Q2(R1) Validation of Analytical Procedures: Text and Methodology (Q2(R1)) for developing, and 30: validating analytical methods, http://www.ich.org/products/guidelines.html

Top mistakes found in audits

Although these guidelines are comprehensive, following them can be challenging, especially when drug developers attempt to use a cookie cutter approach that is often found to be inadequate upon review. In fact, the majority of negative audit findings fall into three main categories:

1. The use of a non-validated methodfor critical decision making.
2. Inadequate method validationthat does not provide the necessary information.
3. Method validationthat lacks appropriate controls to maintain the integrity of the validation.

Consequences of inadequate method validation

In addition to potential delays in starting clinical trials or shipping the product, incomplete method validation has four main consequences.

1. The product may not meet specifications due to inaccurate results.
2. Product stability studies may not meet specifications.
3. Efficacy impact: a failing batch may become a passing batch, which could impact product efficacy and stability studies.
4. Most important, safety may be compromised if the level of impurity in the API was inadequately determined.

The root of method validation problems

Method validation problems can begin even before validation studies begin, and the root cause is a lack of thorough understanding of the physiochemical properties of the molecule, each of which must 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
• Heat sensitivity
• Corrosivity
• Polymorphism
• Dissociation
• Other physical or chemical properties unique to the molecule of interest.

Mistake 1: Improper design of validation study

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.

As a CDMO, we are often given methods by our sponsors. We have learned from decades of experience to test these methods again before proceeding to method validation. Our clients appreciate the diligence, as there have been instances where the suggested methods actually degraded the product. The bit of additional testing of physiochemical characteristics in early stages of engagement yielded better information, which in turn allowed us to develop more appropriate methods, saving our clients time and money.

Mistake 2: Not asking these 10 questions ahead of developing a reliable method for a product’s intended use

The appropriate method validation studies are also dependent on understanding the product’s intended use. Ahead of preparing a methods validation plan, questions we ask include:

1. Is this method for release of raw material?
2. Is this method for in-process control?
3. Is this method for final product release testing?
4. What is the route of administration for this product?
5. What is the maximum daily dose for this product?
6. How long does the drug product’s administration take?
7. What are the crucial components that need to be monitored for each sample?
8. What are the specifications?
9. Does the compound have any genotoxic impurity?
10. What is the impurities profile?

Mistake 3: Not preparing diligently enough for further 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.  In past articles we’ve discussed this in relation to risk management and why a sharp focus on analytic methods pays off.

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.

Mistake 4: 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 we previously described in “Early and Late Phase Drug Development,” 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.

Summary

At PCI Synthesis we take great care to assure that the analytical method optimization and validation are continuous and avoid costly mistakes including improperly designed validation studies and failure to understand a product’s intended use. No method should be considered routine given how critically important time, cost and efficiency are to our sponsors. All methods should have adequate data to support their suitability for precise, accurate and robust analysis of the specified compound, which will be used to support manufacturing, release and stability programs. 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.