Revised Q&A on Stability Issued – Clarity Provided on Some Issues But Questions Still Remain

The Revised Q&A Guidance on stability for ANDA drug products and drug substances was posted on the CDER web page today (here). While the Agency did a good job in terms of some of the clarifications requested by questions submitted in response to the initial document, there are still some unanswered questions that may require clarification to the clarifications! 

While it looks like the Generic industry might have gotten relief on the number of time points required on accelerated stability (the original Q&A document noted 0.3, 6 months and one other time point) the newly issued Guidance suggests the following:

E. Q1: What will be the expected testing time points on accelerated conditions?

A1: The applicant should test at 0 (initial release), 3, and 6 months; for additional time points on accelerated conditions, please follow ICH Q1A(R2) recommendations for all ANDAs.

Looking at Q1A(R2) the recommendation does have an caveat relative to the three times point requirement:

At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended. Where an expectation (based on development experience) exists that results from accelerated testing are likely to approach significant change criteria, increased testing should be conducted either byadding samples at the final time point or by including a fourth time point in the study design.

The question then remains-how does one know there is an expectation for significant change on accelerated stability unless there are developmental batches that show a potential change?  How can you be certain that the 3 time points will be sufficient?

One other clarification is that generic applicants should place product on intermediate conditions at the time the primary stability lots are placed on stability; otherwise if the intermediate conditions is necessary for review, it will be impossible to have that data for submission.

We also think there may be a typo in the Guidance document under C. Q4 A4

Q4: What is the Agency’s position on using different lots of APIs and/or packaging materials? How many API lots should be used in the manufacture of finished product lots used to support the ANDA?

A4: It is not necessary to use different lots of APIs or packaging material, except in cases where the packaging material could affect drug product performance and/or delivery. A minimum of two lots of the drug substance should be used to prepare the three primary batches of drug product.

This excerpt seems to say (in the first sentence) that it is not necessary to use different lots of API for the answer, but in the last sentence it says that a minimum of two lots of drug substance should be used.  We are confused and this clearly needs additional clarification.

In many of its clarifications, the FDA refers to other Guidance documents where the issues are addressed, rather than providing actual narrative that addresses the question.  Easier for the FDA but more difficult for the industry to be sure it gets it right.  Seems simple, but we all know that we all read things differently.  For instance I am still a little fuzzy on the need for when secondary packaging must be used in the stability program!

I can also read the requirements for packaging of the three primary stability batches for solid oral dosage forms in more than one way where the Guidance says:

Oral dosage forms

(a) Tablets/Capsules (e.g., immediate release, extended release, chewable, orally disintegrating and delayed release tablets or capsules): Two of the three batches should be of at least 10 percent of the proposed production batch or 100,000 finished dosage units, whichever is greater (i.e., pilot scale batches). The third batch can be smaller than the 10 percent of the proposed production batch, but should not be less than 25 percent of the pilot scale batch. We recommend stability data be generated for the three ANDA submission batches in the proposed marketing container. A minimum of 100,000 units in all proposed presentations is recommended. Representative samples from all three batches must be packaged in a sufficient number of proposed marketing presentations to comply with 21 CFR 211.166(a)(1-5) and 211.166(b) .

…but does this mean at least 100,000 dosage units total from the three batches or 100,000 from one of the batches and then a sufficient quantity of the other two primary stability batches to meet the requirements for stability and reserve samples?  All in all the debate and discussion relative to stability has been a hot topic even before Hatch-Waxman passed and will likely continue to be a bone of contention for some time to come.  Unfortunately, with the June 20, 2014 deadline around the corner, if you made a mistake in interpretation on these issues for applications that will be submitted on or after the implementation date, it may already be too late for you!

Read it now and keep asking questions if something is not clear.  Remember understanding is in the eye of the beholder!