When method validation is performed incorrectly, companies pay a price in multiple ways. Inaccurate method validation can lead to substantial financial penalties for organizations. Subpar method validation results in increased costs, process delays, complications with approvals, and problems bringing products to market, among a number of other issues.
What Is Method Validation?
According to the Food and Drug Administration (FDA), analytical method validation serves as a definitive means to demonstrate the suitability of an analytical procedure. Thorough validation ensures that the selected analytical method attains the necessary levels of precision and accuracy.
In the pharmaceutical industry, method validation is indispensable, supplying definitive evidence that a methodology is appropriate for its designated application. The quality, consistency, and dependability of a pharmaceutical substance must be proven, by doing so consumer safety is protected.
The validity of analytical procedures should be consistent for both in-house and outsourced testing. Successful method validation often requires tech transfer, where manufacturing data is shared between different teams, sites, and stages of drug development.
Compliance is paramount. Pharmacopeial standards, International Conference on Harmonization (ICH) guidelines, electronic records, Good Laboratory Practice (GLP), current Good Manufacturing Practice (cGMP), and proper signatures are all vital to the analytical method development process. ICH Q2 (R1) is the main reference for instruction and validation-related definitions. However, the FDA guidance, which complements that of the ICH, also offers specific recommendations for validating chromatographic methods.
The FDA requires data-based proof of the identity, potency, quality, and purity of pharmaceutical substances and products. To avoid negative audit results and penalties, a method must support reproducible results.
Many unfavorable audit findings are due to:
- Methods that have not undergone validation but are used in critical decision-making.
- Method validation that does not yield sufficient data.
- Poorly controlled method validation.
An FDA case study, based on a failed audit, indicated that inadequacies found in the review were due to the incomplete reporting of validation data. The study sponsor only reported results that fell within acceptable limits. In turn, the FDA requested a resubmission that included all the results, and the experiment failed to meet the criteria for acceptance.
Challenges of Method Validation
The execution of a well-defined protocol is simultaneously inclusive, intelligent, and efficient. While accuracy and precision are important, time and cost are also crucial considerations. If a method validation is not quick and cost-conservative, profitability suffers.
To preserve the safety and efficacy of a drug product, LGM Pharma routinely overcomes multiple validation challenges, including sample complexity, equipment issues, and skillset requirements. The challenges must be met with experience and expertise. Moreover, a deep understanding of molecular properties, such as pH, solubility, boiling and melting points, photosensitivity, and water sensitivity, is key.
- Sample Complexity
The nature and number of sample components may give rise to method interference, ultimately lowering the precision and accuracy of the results as well. The factors that could affect method performance, such as the impact of degradation products, existence of impurities, and the variations in sample matrices, should be evaluated during method validation. Since the goal is to measure the targeted analyte, the method must be specific, selective, and accurate, withstanding interference from other sample components.
A variety of samples may need to be tested for the same target analyte. One sample may include all identified interferences; another may include samples stressed by lab or storage conditions. Additional samples may be pulled after the manufacturing process is complete.
- Equipment and Instrumentation
The equipment used during the validation may be unique to the sample undergoing the validation. Commonly, chromatography instrumentation, including gas chromatography (GC) and high-
performance liquid chromatography (HPLC), is used during raw material testing. Another useful tool for identifying and quantifying sample compounds is mass spectrometry (MS). Spectrometry measures the transmission and absorption of light.
Liquid chromatography (LC) and mass spectrometry validation sometimes experience issues with a substance in the matrix. The substance may cause the analyte’s ionization in the mass spectrometer.
- Expertise and Skill
The tools and instrumentation used in validation are frequently complex and require specific skill sets. Additionally, during the early stages of method development and validation, it’s important for the team involved in the process to have prior experience and a clear understanding of the planned methodology.
Considerations for Well-defined Validation Protocols
Proper analytical method development is the result of careful planning and consideration of several factors. As an industry leader, LGM Pharma has identified key steps to building a successful data validation protocol. The steps include:
- Identifying data sources. The determination of data sources should occur at the beginning of the analytical process. Frequently, data is included from multiple sources.
- Defining data quality requirements. To avoid omitting a quality requirement, every requirement for each data source must be identified. The defining process must include the identification of data anomalies and inconsistencies.
- Developing a data validation plan. Even if you already have a set of standard operating procedures (SOPs) for planned development, you will still need a comprehensive plan for data validation. The plan should list the rules that govern the data validation and its criteria. Additionally, the process for validating the data should be well-defined.
We have also established best practices for successful method validation. They include the identification of:
- The data that requires evaluation.
- The evaluation frequency.
- The course of action when data fails to meet validation criteria.
To effectively navigate the validation processes, it is crucial to establish comprehensive SOPs that provide clear guidance to the responsible team. These SOPs should encompass instructions on managing any inconsistencies that may arise.
At LGM Pharma, we recognize that each method is unique, and we firmly believe in avoiding a routine approach. Our experts have deep experience and expertise your organization can rely on to ensure successful method validation in every circumstance. Contact us today for more information.