December 2009


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"Mazzeo (R&D), Tony" <[log in to unmask]>
Reply To:
Pharmaceutical Stability Discussion Group <[log in to unmask]>
Mon, 21 Dec 2009 12:46:48 -0500
text/plain (101 lines)
Last October I sent out a questionnaire  on CCIT for stability.  Below are the responses received from six companies: one manufacturing unit, four R&D units, and one unit involved in both R&D and manufacturing.  Feel free to continue to send responses.
Best regards and Happy Holidays

Tony Mazzeo, PhD
Analytical Research and Development/Stability
Bristol-Myers Squibb Company
PO Box 191
New Brunswick, NJ  08903

1. What method do you use now for CCIT (dye immersion, pressure, vacuum decay, etc.)?

Company A (manufacturing): We were asked by the FDA to perform CCIT at the end of our stability studies for our drug substance, which is a solution stored in bag manifolds.  We assure CCI by means of sterility testing.

Company B (R&D): Dye immersion
Company C (R&D): Bacterial Immersion with vacuum and pressure cycle
Company D (R&D and manufacturing): Dye immersion using pressure.

Company E  (R&D): Dye immersion

Company F (R&D):  Mostly dye immersion, with pressure and vacuum.

2. Do you have plans to change to a new method in the future (e.g. from dye method to vacuum decay?

Company A (manufacturing): Yes.  Because our drug substance is not purported to be sterile, it seems a bit risky, to confirm CCI by means of sterility testing.  (If results come back as sterile, fine, but if they came back as nonsterile it would be unknown whether the microbes were there to begin with or whether they were introduced due to a breach of CCI.  We plan on switching to probably a methylene blue dye immersion method.
Company B (R&D): No
Company C (R&D): no
Company D (R&D and manufacturing): Not that I know of
Company E (R&D): No
Company F (R&D): Yes

3. How did you determine your sample size for CCIT (e.g. mil spec, USP sterility sampling, etc.)?

Company A (manufacturing): USP sterility sampling
Company B (R&D: USP sterility
Company C (R&D: mil spec
Company D (R&D and manufacturing): Always 10 samples, not sure what the rationale was
Company E (R&D: USP sterility sampling
Company F (R&D): Statistical sampling derived from mil spec.

4. Do you monitor CCIT in a stability program of some kind (e.g. part of product development or registrational stability studies)?
Company A(manufacturing): See answer to #1
Company  (R&D)B: Yes in lieu of sterility testing

Company C (R&D): no, we do ours as part of our media simulation anytime we have a new container closure

Company D (R&D and manufacturing): Yes, it is on our stability protocols.

Company E (R&D): Yes
Company F (R&D): Not part of stability for clinical manufacturing.  CCIT performed as part of product/process development, then eventually reported in NDA.

5. If you answered yes to #4, do you report that data to the FDA and/or other health authorities?
Company A (manufacturing): Yes. FDA and BfArM.
Company B  (R&D): Yes
Company C  (R&D): No response
Company D(R&D and manufacturing): Yes, FDA.
Company E  (R&D): Yes
Company F  (R&D): No response

6. In the case that one unit fails the CCIT test, what is your likely next course of action (e.g. test more samples, discard the batch, etc.)?
Company A (manufacturing): Luckily, we've never encountered a failure.  But since this testing is only performed on our drug substance and not our finished product, as long as the rest of the stability attributes were in spec, we would not discard the batch. Company B (R&D): Investigate
Company C (R&D): have not had a failure yet, knock on wood :-)
Company D (R&D and manufacturing): It is handled as a deviation and likely more testing (confirmation of original), but determined as appropriate during investigation of original.
Company E (R&D): Follow OOS procedure.
Company F (R&D): Would investigate

7. Does your company plan to perform CCIT in lieu of sterility testing for stability studies, and if so, do you also plan to defend that approach to countries outside the US?
Company A (manufacturing): No.  For the finished product we perform sterility testing upon release and on a yearly basis in stability studies.
Company B (R&D): Yes
Company C (R&D): no
Company D (R&D and manufacturing): This has come up recently and we would likely look to stop performing sterility on stability and use CCIT.
Company E (R&D): No
Company F(R&D) : No.  Need sterility data for filings outside USA.

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