US FDA Clarifies Guidance on Intermediate Stability Data for Generic Manufacturers

The recently released Q&A​ notes that at the time of an ANDA (abbreviated new drug application) submission, the stability data expectation is six months of accelerated and six months of long-term data. However, the FDA says that “if 6 months accelerated data show significant change or failure of any attribute, 6 months of intermediate data are also recommended at the time of submission​.”

The agency also breaks down a number of more specific questions on whether two lots of finished product at pilot scale batch size can ever be sufficient to support the stability of an ANDA for simple dosage forms (it can’t, says the FDA); and whether a company can file with 3 months stability data with a commitment to supply 6 months data when available if a patent is due to shortly expire and there are no approved ANDAs (also a negative, according to the agency.)

The FDA also extended the implementation date of the guidance from Jan. 1, 2014 to June 20, 2014. 

Michael D. Barron, MBA, director of business development at Quality Chemical Laboratories, told In-Pharmatechnologist.com, "The intermediate stability storage condition Q&A is pretty clear...The meaning is to follow the ICH Q1A (R2).  For companies which have been doing that it is clear the best strategy is to 'set' the stability studies into all storage conditions at the same time and only test the intermediate if or when significant change occurs at accelerated.  ​

"The meaning of providing 6 months data on intermediate at the time of submission (in that case) would mean the only data point on the 30/65 sample would be the 6 month timepoint (besides the initial timepoint which applies to all conditions).  Following ICH Q1A (R2), you then have to commit to two more stability timepoints at 30/65, i.e. the 9 and 12 month timepoints.  Perhaps that is the piece that generic companies not familiar with ICH need to understand,​" he said. 

API Manufacturing​

The FDA also reminds companies that a “minimum of two lots of the drug substance [or API] should be used to prepare the three primary batches of drug product​.”

As far as API sourcing, the agency recommends that if a company proposes to add a second or more than two sources of API for the same drug substance, CMC information should include:

• Comparison and justification of comparability (by the firm) of the physico-chemical properties and impurities of the drug substance from each source;
• Appropriate stability data on three batches of drug product qualifying the first API source used in the bioequivalence (BE) studies as recommended by the stability guidance;
• A single pilot scale batch of the drug product bio-strength(s) manufactured using the second or each of the other proposed API source(s) used to support the ANDA application, along with comparative dissolution data; and
• Appropriate stability data (accelerated and long-term for 6 months at the time of filing) on the strength(s) manufactured for each API source, which may in some cases include intermediate condition stability data.

All manufacturers also should follow the International Conference on Harmonisation (ICH) guidance for industry on Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products and its example tables.