Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers lane, Rm 1061

Rockville, MD 20852

**Comments on Draft Guidance for Industry: Validation of Growth-Based
Rapid Microbiological Methods for Sterility Testing of Cellular and Gene
Therapy Products**

1)  The Draft Guidance, under [C. What Elements Should Be Considered to
    Validate an RMM?]{.underline} pg. 5, states "We recommend that
    validation include comparison studies between the RMM and the method
    described in 21 CFR 610.12 to demonstrate equivalence as required
    under 21 CFR 610.9. For this purpose, equivalence may be
    demonstrated by evidence that the performance of the RMM assay
    provides assurances equal to or greater than assurances provided by
    the method in 21 CFR 610.12. Because validation studies of
    microbiological methods encompass a large degree of variability, the
    concept of the RMM being "equal to" or "greater than" the
    traditional method is demonstrated in parallel comparisons to the
    traditional method using as many identical parameters as possible to
    claim equivalence."

# Comment & Justification

> The development of cellular and gene therapy based products often
> involves the use of materials that are in limited supply. In the
> development of a new **product**, appropriate test methods for
> assuring sterility are developed. A RMM used during the development
> process and validated for use throughout the **product** development
> cycle, following the growth promotion and bacteriostasis and
> fungistasis guidelines in 21 CFR 610.12 or USP \<71\> sterility test
> methods, should be considered to provide assurances of sterility equal
> to 21 CFR 610.12. For the development of a new **product,** requiring
> a parallel validation with 21 CFR 610.12 to establish assurances of
> sterility that are equal to or greater may create a burden on
> resources.

2)  The Draft Guidance, under [D. How Do I Select a Panel of Appropriate
    Challenge Microorganisms for Validating an RMM?]{.underline} pg 7,
    states "We recommend that such studies include the initial challenge
    test panel of organisms indicated in Table 2, cultured with the
    indicated media, or a recognized equivalent media, at the prescribed
    temperatures."

# Comments & Justification

The adjective 'recognized' used to describe 'equivalent media' is
confusing. It implies acceptance by a regulatory entity. Further
description of 'recognized' is needed for clarification or removal of
the word should be considered.

> This section clearly states the [recommendations]{.underline} for the
> conditions under which validation should be performed. However, for
> clarification, specifically pertaining to 'prescribed temperatures',
> although it is accepted that incubations at 20-25 ^o^C and 30-35 ^o^C
> will promote growth of the widest variety of microorganisms,
> incubation at a single temperature within the range of 20-35 ^o^C,
> should be allowed when validated as suitable for recovery of
> challenge, bioburden and environmental isolates representing
> contaminants associated with the product being tested.
>
> In Table 2, in the row associated with [Organisms that grow well under
> aerobic conditions]{.underline}, *[Propionibacterium
> acnes]{.underline}* is listed under [Microorganism]{.underline}. Since
> this is an anaerobic, non-sporeforming species, it should be moved and
> listed under [Organisms that grow well under anaerobic
> conditions]{.underline}.
>
> On page 7 under the recommendations of categories of microorganisms to
> include in the challenge panel, it states "[fastidious microorganisms
> for the RMM]{.underline}". We propose this statement is expanded to
> state "[fastidious microorganisms for the RMM that are relevant to the
> product and process]{.underline}". Rarely is a RMM sold specifically
> for a clearly defined application. Manufacturers of RMMs list general
> limitations associated with certain microorganisms in order to inform
> customers for whom the limitation may have significance. Although this
> guidance contains general recommendations, often users interpret them
> as required. Expanding this statement will clarify the recommendation
> thereby avoiding any confusion in establishing the appropriateness of
> the RMM for specific applications.

3)  [Comment & Justification]{.underline}

> Routinely, the FDA [Guideline on General Principles of Process
> Validation]{.underline} is referenced by companies and professional
> organizations when describing approaches to process validation (IQ,
> OQ, PQ). This document is not listed in the Draft Guidance references.
> Although it is not listed, does it have relevance to the validation of
> a RMM?

Sincerely,

Elizabeth J. Landon

Staff Regulatory Affairs Specialist

919-620-2329

elizabeth.landon@na.biomerieux.com