FDA deficiency letter

Table of contents

• Introduction and Background
• Deficiency letters
• Sections on which Deficiency letters are given
• How to deal with DL
• DL related to identification test for Chiral molecules
• Deficiency letters related to identification test for Achiral molecules
• Conclusion

Introduction and Background; What is an FDA deficiency letter?

Managing FDA deficiency letters is a challenging task for pharmaceutical professionals that requires both knowledge and skills. While some deficiency letters require redoing experiments, others are unforeseeable and put pharma professionals in difficult situations. So, how can deficiency letters be minimized or avoided? In this article, I will share a skill-based approach to avoid deficiency letters from various regulatory agencies such as FDA, KFDA, TGA, MHRA, PMDA, ANVISA, EMEA, and more. By reading this post, you will learn:

• What is the deficiency letter?
• Why deficiency letters are given?
• What are the different sections in which deficiency letters are given?
• How are deficiency letters answered?
• What should be a proactive approach to avoid deficiency letters?

Deficiency letters

If the FDA authority finds any discrepancy during the scientific review, write a letter to the applicant for additional information. That letter is called a deficiency letter/DL. It is intended to inform deficiencies identified during the review and is not intended to list concerns about the product. Deficiency letters are delivered via email.

Sections on which Deficiency letters are given

It is very difficult to predict the section of probable deficiency letters. The following are the common sections in which Deficiency letters’ are given:

• Nomenclature of the molecule
• Structure of the molecule
• General properties
• Description of the manufacturing process and process control
• Manufacturing process and development
• Control of materials
• Starting materials (SM) and key starting materials (KSM)
• Control of Genotoxic impurities
• Control of Chirality (in case of chiral molecule)
• Control of critical stages and intermediates
• Process validation
• Elucidation of structure and other characteristics
• Impurities
• Specifications
• Analytical procedures
• Validation of Analytical methods
• Identification test, assay test, related substances test, Chiral purity, OVI etc.
• Batch analysis
• Justification of specification
• Drug substance Reference standards
• Impurities Reference standards
• Packaging specifications
• Labelling
• Stability summary and conclusion

How to deal with DL

Answering deficiency letters needs both knowledge and skills and the answer should be given surgically. Some typical Responses of Deficiency letters related to chiral and achiral molecules are being explained in this article for better understanding.

DL related to Identification test for Chiral molecules

The general approach to keep identification tests for Chiral molecules:

The retention time of the main peak in the sample solution should match with Retention time of the standard peak in the standard solution as given in the Assay/Related substances test.

But regulatory agencies does not accept the above approach.

The above identification applies only to the Achiral molecule and not to the Chiral molecule. For Chiral molecules there must be chiral/optical identification test and identification must be specific (e.g. by chromatographic method). That is why regulatory agencies does not accept achiral identification approach in for chiral molecules.

The following are the some typical DL on identification test for Chiral molecules. because

Case study: DL on identification of Chiral molecules

Typical DL: Please use the Chiral-HPLC method for identification in lieu of the current achiral HPLC method

Hence, chiral identification test must be given for chiral molecules to avoid such deficiency letters.

Deficiency letters related to identification test for Achiral molecules

Generally for Achiral molecules, only one identification test based on retention time by HPLC/GC is kept. But authorities don’t accept it and insist on at least two identification tests by different techniques.

In almost all cases Deficiency letters are received on identification tests.

Case study: DL on identification of Achiral molecules

Typical DL: You are requested to include and specify identification tests such as IR or UV 

To avoid the above identification letter, at least two identification tests must be kept in all cases for achiral molecules. One identification by chromatographic technique and the second preferably by spectroscopic techniques (IR/UV).

Acceptance criteria

• HPLC: The retention time of the major peak in the chromatogram of the sample corresponds to that of the major peak in the chromatogram of the standard in the assay.
• FTIR: The infrared absorption spectrum of the preparation of the test specimen exhibits maxima at the same wavelengths as that of the standard.

Related topic: Impurities Control Strategies In Pharmaceuticals

Conclusion

Responding to a deficiency letter is a challenging task that requires both analytical knowledge and expertise. This post aims to clarify any doubts you may have regarding deficiency letters. You will now be able to manage deficiency letters related to the identification test of Achiral and Chiral molecules. That’s all for this post. Please feel free to leave any questions or opinions related to this post in the comment section.

Abbreviations:

• DL: Deficiency letters
• IR: Infrared spectroscopy
• UV: Ultraviolet spectroscopy
• HPLC: High pressure liquid chromatography
• GC:Gas chromatography
• FDA: Food and drug administration

References:

• https://www.fda.gov/regulatory-information/search-fda-guidance-documents/developing-and-responding-deficiencies-accordance-least-burdensome-provisions
• https://www.sec.gov/Archives/edgar/data/934936/000119312511065268/dex992.htm
• https://njlabs.com/fda-deficiency-letters/