- Jul 23
- 5 min read

Analytical Development for Pharmaceutical Products: A Comprehensive Guide

Updated: Jul 24

In the pharmaceutical industry, ensuring the safety, efficacy, and quality of drug products is paramount. Analytical method development plays a crucial role in achieving these objectives by providing reliable and accurate measurement of critical quality attributes (CQAs).

Analytical Development

Analytical development encompasses a wide range of activities that are essential for the consistent production of high-quality pharmaceutical products. These activities begin early in the product lifecycle and continue through commercialization and post-market surveillance.

Determining Critical Quality Attributes (CQAs)

The foundation of analytical development is the identification of CQAs. CQAs are defined as the physical, chemical or microbiological properties or characteristics that must be maintained within specified limits to ensure product quality. Identifying these attributes involves a comprehensive understanding of the drug product and its intended use.

Drafting Specifications Based on ICH Requirements

Following the identification of CQAs, the next step is drafting and justifying specifications. Specifications are typically set for the release of the product and a different set of specifications that are used for shelf-life determination. Specifications are detailed lists of tests, references to analytical procedures, and acceptance criteria that ensure each CQA is consistently met. The specifications are set based on ICH Q6A, Specifications: Test Procedure and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances. Other acceptance criteria are based on knowledge of the product, its intended use and anticipated shelf life. These specifications are crucial for maintaining the desired quality standards of the drug product throughout its lifecycle. Each component of the specification should be justified with reference to a relevant guidance or based on drug product data.

Identifying Potential Process Impurities and Degradants

The control of organic impurities from the active pharmaceutical ingredient is dictated by ICH Q3B(R2), Impurities in New Drug Products. A thorough understanding of the manufacturing process of the active pharmaceutical ingredient is necessary to identify potential process impurities. Degradants of the API can be identified by conducting forced degradation and accelerated stability studies. Process impurities are controlled with the API specification and are not included in the specification for the drug product.

Evaluating Residual Solvents and Elemental Impurities

Residual solvents are used or produced in the manufacture of the raw materials of the drug product and in the manufacture of the drug product itself. These impurities are controlled by ICH Q3C, Guideline for Residual Solvents. The guidance requires that the residual solvents in the drug product do not exceed safe levels for pharmaceutical products. The limits in ICH Q3C are the limits for the drug product. These limits are often applied to the raw materials and the raw materials are tested individually to ensure that they meet the ICH limits. In the case where the solvent is used in the manufacturing process, the drug product should be tested for that solvent.

Elemental impurities are controlled in a similar fashion as the residual solvents. The elemental impurity limits are dictated by ICH Q3D, Guideline for Elemental Impurities, and the evaluation includes a risk assessment of the potential for the elemental impurity to be present. The elements to be considered are based on the route of administration (i.e. oral, parenteral, inhalation). A risk assessment should be conducted to ensure that the manufacturing process and packaging do not introduce any additional elemental impurities throughout the drug product’s shelf life.

Performing Packaging Studies

Packaging studies are integral to assessing the potential for contaminants to be extracted or leached from packaging materials into the drug product. An ICH Guidance (Q3E) is in works to provide guidance on how packaging studies should be conducted. These studies help ensure that the packaging does not compromise the product's quality or safety. Understanding the interactions between packaging and product is crucial for maintaining the integrity of the drug throughout its shelf life.

Determining Shelf Life

Shelf-life determination involves conducting stability studies to assess how the quality of a drug product varies over time under various environmental conditions, such as temperature, humidity, and light. ICH Q1A, Stability Testing of New Drug Substances and Products provides a guideline for the design of stability studies that are required for the submission of a drug product. The study design depends on the region where the drug product will be sold and the capability of the drug product to meet the established specifications. These studies are essential for establishing the product's shelf life and determining appropriate storage conditions. Stability testing ensures that the drug product remains safe and effective throughout its intended use period.

Support of Formulation and Process Development

Analytical development supports both formulation and process development with the analysis of prototype formulations and in-process/scale-up product. These studies are used to support the pharmaceutical development required by ICH Q8, Pharmaceutical Development, and help to define the product’s design space.

Method Development and Validation

Method development and validation are critical components of analytical development, ensuring that the analytical methods used are robust, reliable, and capable of producing accurate and reproducible results.

Analytical Method Development

Method development involves creating procedures for accurately measuring a drug product’s CQAs. A new ICH guideline, ICH Q14, Analytical Procedure Development, was published in November 2023. This guideline provides instruction for science and risk-based approaches for the development of analytical procedures. Methods should be designed to deliver consistent and accurate results that can measure CQAs under various conditions.

Method Validation

Method validation is the process of demonstrating that an analytical method is suitable for its intended purpose. According to ICH Q2 guidelines, validation parameters include accuracy, precision, specificity, detection limit, quantitation limit, linearity, range, and robustness. Each parameter is rigorously tested to ensure the method performs reliably and consistently.

Accuracy: The closeness of the test results obtained by the method to the true value.

Precision: The degree of agreement among individual test results when the method is applied repeatedly to multiple samplings.

Specificity: The ability to assess the analyte unequivocally in the presence of components that may be expected to be present. This often includes an assessment of the degradants formed during forced degradation studies.

Detection Limit: The lowest amount of analyte that can be detected, but not necessarily quantified, under the stated conditions.

Quantitation Limit: The lowest amount of analyte that can be quantitatively determined with suitable precision and accuracy.

Linearity: The method's ability to obtain test results that are directly proportional to the concentration of analyte in the sample.

Range: The interval between the upper and lower levels of analyte that have been demonstrated to be determined with precision, accuracy, and linearity.

Robustness: The method's capacity to remain unaffected by small, deliberate variations in method parameters.

Conclusion

Analytical development of pharmaceutical products is a critical process that ensures the quality, safety, and efficacy of drug products. By adhering to ICH and FDA guidelines, pharmaceutical companies can develop robust analytical methods that reliably measure critical quality attributes, identify impurities, evaluate residual solvents and elemental impurities, and determine shelf life. Method development and validation further ensure that these methods are accurate, precise, and fit for their intended purpose, ultimately safeguarding patient health and well-being.