Best Practices for Setting Analytical Method Specifications

Mastering the Art of Analytical Methods: Best Practices for Setting Specifications in Drug Development

Analytical methods specifications are crucial for ensuring the quality and consistency of drug products in the Chemistry, Manufacturing, and Controls (CMC) drug development process. It involves understanding regulatory requirements, defining critical quality attributes (CQAs), establishing analytical method suitability criteria, determining acceptance criteria, establishing an ongoing verification plan, ensuring adequate method transfer, and documenting the process. When setting analytical methods specifications, it is vital to consider the differences between drug substance and drug product, which include complexity, analytical methods, specifications, validation, and regulatory requirements. By following these best practices and understanding the differences between drug substances and drug products, drug developers can ensure successful development and ultimate approval.

An Essential Component of the Drug Development Process

The specifications ensure that the analytical methods used to test drug products are reliable and consistent throughout the development process. As such, setting analytical methods specifications is a crucial part of the CMC drug development process. Here are some best practices for setting analytical methods specifications in CMC drug development.

•    Understand the Regulatory Requirements

The first step in setting analytical methods specifications is understanding the regulatory requirements. The regulatory agencies, such as the US Food and Drug Administration (FDA), have specific requirements for analytical methods validation and the setting of specifications. It is important to review these requirements and ensure that the analytical methods specifications are following them.

•    Define the Critical Quality Attributes (CQAs)

Critical Quality Attributes (CQAs) are the physical, chemical, biological, or microbiological characteristics that are critical to ensuring the quality of a drug product. Defining the CQAs early in the drug development process is critical to setting the analytical methods specifications. The analytical methods should be able to measure the CQAs accurately and precisely.

•    Establish Analytical Method Suitability Criteria

Analytical method suitability criteria are established to ensure that the analytical method can produce accurate and reliable results. The criteria should include parameters such as linearity, accuracy, precision, specificity, the limit of detection, and the limit of quantitation. These parameters should be established based on the CQAs of the drug product.

•    Determine the Acceptance Criteria

The acceptance criteria are the criteria that are used to determine whether the analytical method is acceptable or not. The acceptance criteria should be based on the analytical method suitability criteria and the CQAs of the drug product. The acceptance criteria should be established with a clear understanding of the risks associated with the product.

•    Establish a Plan for Ongoing Verification

Analytical methods specifications are not static and should be reviewed and updated throughout the drug development process. An ongoing verification plan should be established to ensure that the analytical methods specifications remain appropriate and relevant. This plan should include a review of the method performance, identification of potential sources of variability, and the establishment of appropriate action limits.

•    Ensure Adequate Method Transfer

Analytical methods may need to be transferred to different laboratories or manufacturing sites during drug development. Adequate method transfer should be ensured to ensure the reliability and consistency of the analytical method. The transferred method should be validated and verified at the receiving site to ensure it meets the established analytical methods specifications.

•    Document the Process

The process of setting analytical methods specifications should be well-documented to ensure that the information is available to all relevant parties. The documentation should include the rationale for the analytical methods specifications, the acceptance criteria, the method suitability criteria, and the ongoing verification plan. The documentation should be easily accessible and maintained throughout the drug development process.

Some differences between Drug Substance and Drug Product when Setting Analytical Methods Specifications

It is essential to understand the differences between drug substances and drug products when setting analytical methods specifications. Here are some critical differences between drug substances and drug products when setting analytical methods specifications in CMC drug development.

•    Definition

Drug substance refers to the active pharmaceutical ingredient (API) in the drug product, which is responsible for the therapeutic effect. On the other hand, drug product is the finished dosage form that contains the drug substance and other inactive ingredients. Examples of drug products include tablets, capsules, injections, and inhalers.

•    Complexity

A drug substance is usually a single chemical entity, while drug product can be a complex mixture of the drug substance and other excipients. As a result, the analytical methods used to test drug substances and drug products may differ.

•    Analytical Methods

The analytical methods used to test drug substances and drug product may be different. For drug substances, the analytical methods usually focus on the purity, identity, and potency of the API. These methods may include chromatography, spectroscopy, and elemental analysis. For drug products, the analytical methods may focus on the uniformity, stability, dissolution, and bioavailability of the drug product. These methods may include dissolution testing, content uniformity testing, and bioavailability testing.

•    Specifications

The specifications for substance and product may differ based on the intended use of the product. The drug substance specifications usually include purity, potency, and identity, while drug product specifications may include additional attributes such as appearance, particle size, and stability.

•    Validation

The validation of analytical methods for drug substances and drug products may also differ. The validation of analytical methods for drug substances usually focuses on the analytical performance of the method. In contrast, the validation of analytical methods for drug products may include additional factors such as the effect of formulation and manufacturing processes on the analytical method.

•    Regulatory Requirements

The regulatory requirements for drug substances and drug products may also differ. The regulatory agencies usually require the drug substance and drug product to meet specific analytical method validation and specifications criteria. However, the criteria may differ based on the intended use of the product, and the regulatory requirements for drug substances and drug products may differ.

How a Sponsor might set Analytical Methods Specifications, some examples

Here are some best practices for sponsors to follow when setting analytical methods specifications, along with examples:

•    Define the intended use of the product

Sponsors should define the intended use of the product, such as the patient population, dosage form, and route of administration. This information will help determine the CQAs and analytical methods needed to ensure the safety and efficacy of the product.

Example: If the intended use of the product is for pediatric patients, the analytical methods should be validated for accuracy and precision over the expected range of dosages for that patient population.

•    Use a risk-based approach

Sponsors should use a risk-based approach to identify the CQAs that need to be tested and the appropriate analytical methods to use. This approach involves identifying the potential risks to the product and the patient and prioritizing the analytical methods accordingly.

Example: If the drug product has a low risk of degradation, the sponsor may only need to test for potency and identity using a validated chromatography method.

•    Consider the product lifecycle

Sponsors should consider the product lifecycle when setting analytical methods specifications, as the specifications may need to be adjusted as the product evolves. The specifications should be reviewed and updated regularly as new information becomes available.

Example: If the product is in the early stages of development, the sponsor may set wider specifications for the analytical methods to allow for more flexibility in the manufacturing process. As the product matures, the specifications can be tightened.

•    Establish acceptance criteria

Sponsors should establish acceptance criteria for each analytical method based on the CQAs and the intended use of the product. The acceptance criteria should be based on scientific data and statistical analysis.

Example: If the analytical method is testing for impurities, the sponsor may establish an acceptance criterion of no more than 0.1% for any individual impurity.

•    Validate the analytical methods

Sponsors should validate the analytical methods to ensure they are fit for their intended purpose. The validation should include accuracy, precision, specificity, and robustness testing.

Example: If the analytical method is a high-performance liquid chromatography (HPLC) method, the validation should include testing for linearity, accuracy, precision, specificity, and robustness.

Does the number of data points or batches of material determine how a sponsor sets specification?

The number of data points or batches of material can influence how a sponsor sets specifications, but it should not be the only determining factor. While having more data points and batches can provide more information to establish appropriate specifications, the quality and relevance of the data are equally important.

When setting specifications, sponsors should consider the CQAs of the substance or product, the intended use of the product, and the potential risks to the patient. They should also use a risk-based approach and scientific principles to determine the appropriate specifications.

If the sponsor has limited data points or batches, they can use statistical tools and modeling to establish appropriate specifications. However, it is important to note that the data used to set specifications should be representative of the entire population and should not be biased or skewed. If the sponsor has concerns about the data quality or quantity, they may need to conduct additional testing or manufacturing to generate more data.

Conclusion

Overall, in CMC drug development, setting analytical methods specifications is critical to ensuring the quality, safety, and efficacy of drug products. To set analytical methods specifications, some best practices include understanding regulatory requirements, defining critical quality attributes (CQAs), establishing analytical method suitability criteria and acceptance criteria, establishing a plan for ongoing verification, ensuring adequate method transfer, and documenting the process. When it comes to differences between drug substances and drug products in setting analytical methods specifications, they include definition, complexity, analytical methods, specifications, validation, and regulatory requirements. It is important to consider these differences when setting analytical methods specifications to ensure that the methods used to test drug substances and drug products are reliable, accurate, and consistent.