Understanding Acceptable – Analytical Method – Submissions

Preparing a submission for US FDA approval (or approval from any other regulator for that matter) is a laborious business – but your chances of success are greatly increased if it is immediately clear to the reviewer that the documentation meets all of their specific requirements. For analytical methods, it is crucial to describe what you did and how you did it, share your results, and provide proof that the product meets all the criteria – using validated tests. To encourage the preparation of acceptable submissions, the FDA issued a new guidance document in July 2015 titled, ‘Analytical Procedures and Methods Validations for Drugs and Biologics’. The guidance lays out seven key points that need to be included in a submission to support the identity, strength, quality, purity and potency of drug substances and products. It applies whether the submission is a New Drug Application, an Abbreviated New Drug Application, a Biologics Licence Application, a supplement to one of these, or even a Drug Master File.

While this guidance does not contain any information that is new, this is the first time that it has all been assembled in one place so it forms a one-stop shopping guide that provides very clear guidance on exactly what the FDA is looking for.

The seven key areas are as follows:

1. Analytical Methods Development
The analytical procedures submitted can be from recognized sources, such as the US Pharmacopeia (USP)/National Formulary, but this does not have to be the case – it could also be a validated procedure developed in-house specifically for that product. These methods are used to test defined characteristics of the drug substance or product against established specifications. The instrument used must also be evaluated to show that it can provide the required data. Any changes made while developing a method, to enhance its robustness and suitability, must be done systematically, starting with a risk assessment followed by multivariate experiments. The development data for a new method must also be included.

2. Analytical Procedures
The method imust be described in sufficient detail to allow a competent analyst to reproduce the necessary conditions – and obtain results within the proposed acceptance criteria, including in any specific instructions that may affect the test’s outcome. The guidance contains a long list of what the FDA considers to be essential information for each analytical procedure, ranging from apparatus to operating parameters, reagents and standards, sample preparation, procedure, system suitability, calculations and reporting.

3. Reference Standards and Materials
The FDA gives pointers towards what makes a standard suitable. The submission will have to show that storage and usage conditions are strictly followed. Qualification test reports and certificates of analysis should be included. Reference standards must either be obtained from USP or another approved source – or characterized via procedures described in ICH Q6B. Each new batch should be calibrated against the previous batch.

4. Analytical Method Validation
If you choose to use a non-compendial method, it must be validated. You will have to show a clearly defined methodology and objective derived from scientifically based method development and optimization studies. Detailed information about the validation protocols and results should be included. Reviewers will be looking for information about specificity, linearity, accuracy, precision, range, and both quantitation and detection limits. Stability tests that detect changes in quality during storage must also be validated, via forced degradation studies, spiking the test sample or either accelerated or real-time storage. If a compendial method is used, data showing its verification under actual conditions must be submitted.

5. Statistical Analysis and Models
Statistical analysis can be used to evaluate validation characteristics against predetermined acceptance criteria, but all procedures and parameters must be based on sound principles. Validated software or independent verification of correctness is required. Chemometric or multivariate models may be appropriate, but there must be a sufficient number of samples in the model to ensure statistical power and range. Model parameters should also be deliberately varied to test the model’s robustness.

6. Life Cycle Management of Analytical Procedures
Validation is an ongoing process and methods should be evaluated at defined intervals to determine their continued suitability throughout the product’s lifecycle. Changes to the drug substance, product make-up or impurity profile will require re-evaluation of the method and possible re-validation – as could advances in instrument technology. If the method is altered, then the FDA requires comparability studies and advises that samples should be retained in case they are required as comparators in the future. Comparative studies are also suggested if the testing laboratory is changed or moved. Post-marketing changes such as this must always be reported to FDA.

7. FDA Methods Verification
The agency may want to include an FDA laboratory assessment of your analytical procedure. If so, they will request the samples, reagents or standards they need, and will submit their results to the submission’s product quality reviewer.

Of course, there are many more details on all of these points in the full guidance, which I encourage you to delve into. In my view, careful adherence to all the guidance provided will significantly increase your chances of your submission being accepted first time, without the need to provide further clarification. Be especially careful to cover all ten points that the FDA requires to be covered in the content of the Analytical Procedures area. This is one of the most clearly written guidances that the FDA has issued – and at only 12 pages long it is very clear and searchable.

Adherence to this guidance will provide the FDA with all the information needed to make an informed decision about your submission concerning analytical methods and save both the manufacturer and the FDA a lot of time and money.