The regulator issued recommendations to help applicants submit analytical procedures and methods validation data to “support the documentation of the identity, strength, quality, purity and potency of drug substances and drug products” and assemble and present data to support their analytical methodologies.
The recommendations contained in the guidance document concern drug products covered in NDAs, ANDAs, BLAs and supplements to those applications, and complement the ICH guidance “Q2(R1) Validation of Analytical Procedures: Text and Methodology.”
Per the guidance, NDAs and ANDAs are required to contain the analytical procedures needed to ensure the identity, strength, quality, purity and potency of a drug substance and drug product. For BLAs, a full description of the manufacturing process must be included, including analytical procedures demonstrating that the manufactured product is up to prescribed standards of identity, quality, safety, purity and potency.
When an analytical procedure gets approved or licensed as part of the NDA, ANDA or BLA, it becomes the FDA-approved procedure for that particular product. A procedure can come from recognized sources, such as a compendial procedure from the USP/NF, or from a validated procedure submitted by a sponsor that the FDA found was acceptable. The document notes that to apply an analytical method to a different drug product, sponsors should consider appropriate validation or verification studies for compendial procedures with the new product’s specifications.
In its guidance, the FDA goes over analytical methods development, saying an analytical procedure is developed to test a characteristic of a drug against an “established acceptance criteria” for that particular characteristic. When it comes to the content of analytical procedures, the FDA recommends that these be described in “sufficient detail” to enable an analyst to reproduce the necessary conditions and get results within the proposed acceptance criteria. The document lists 10 pieces of “essential information” that should be included for an analytical procedure, including principle/scope, apparatus/equipment, operating parameters, reagents/standards, calculations and procedure, among others.
Also covered in the guidance are reference standards and materials, which are defined in a number of ICH guidances. The FDA calls for applicants to include information supporting all reference standards and materials that will be used in an application. While reference standards can be obtained from USP and other organizations listed in the guidance, the FDA notes that a new batch of reference standard materials needs to be qualified/calibrated against the current standards.
In going over analytical method validation, which is defined as the process to show the suitability of an analytical procedure for its intended purpose, the FDA also covered noncompendial and compendial analytical procedures.
Under the noncompendial section, the document notes validation data needs to be generated under a sponsor-approved protocol, and applications should contain details of the validation studies and results, with specificity, linearity, range, accuracy and detection limit among some of the typical characteristics. The FDA points to ICH Q2(R1) as the main reference for recommendations and definition of validation characteristics.
When it comes to compendial analytical procedures, whether an analytical procedure is suitable should be verified under actual conditions of use. Data to show that USP/NF procedures are appropriate for the drug product or substance should be contained in the submission and generated under a verification protocol. The FDA says the protocol should have components including compendial methodology verified with predetermined acceptance criteria and details of the methodology.
The guidance also covers statistical analysis and models, stating statistical analysis of validation data can be used to assess validation characteristics against predetermined acceptance criteria, while other methods might use chemometric or multivariate models.
Also described are life cycle management of analytical procedures, with the FDA stating that over the life cycle of a product, there may be new data and risk assessments warranting a new or alternative analytical method. According to the guidance, if a risk-based evaluation leads to modifications in the analytical procedure or substitution with a new method, applicants should consider revalidation, a new validation exercise, an analytical method comparability study or a combination of those exercises.