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Subject:
From:
"Hussong, David" <[log in to unmask]>
Reply To:
The Pharmaceutical Microbiology Forum Email List <[log in to unmask]>
Date:
Tue, 16 Dec 2003 17:43:06 -0500
Content-Type:
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Several pertinent regulatory citations follow as correction to Mr. Martin's
posting that stated, "While the 21 CFR GMP regulations suggest sterilizing
filtration processes should not exceed 8 hours...". There are no
regulations in 21 CFR 211 (GMPs) that establish a time limit of 8 hours for
"sterile filtration" of drug products. Within 21 CFR, Sec. 211.111 (Time
limitations on production) requires that a limit be established. The user
is responsible for developing and validating the parameters for filtration
processes (or any other sterilization process). For drug products,
filtration parameters and their validation are submitted in the Technical
Section for Chemistry, Manufacturing and Controls, in the application to
market a new drug (see citations below). The time limit established in the
validation experiment is reviewed as part of the process for approval of the
application to market the new drug or biologics license (see FD&C citation,
below).

There have been instances where prolonged filtration was associated with
microbial contamination downstream from "sterilizing grade" filters. These
events resulted in regulatory scrutiny. However, these are reviewed on a
case by case basis. CDER approves drug products, not manufacturing
processes.

David Hussong


21 CFR Sec. 314.50 Content and format of an application.
(d) Technical sections. The application is required to contain the technical
sections described below. Each technical section is required to contain data
and information in sufficient detail to permit the agency to make a
knowledgeable judgment about whether to approve the application or whether
grounds exist under section 505(d) of the act to refuse to approve the
application. The required technical sections are as follows: (1) Chemistry,
manufacturing, and controls section. A section describing the composition,
manufacture, and specification of the drug substance and the drug product,
including the following:
(i) Drug substance. A full description of the drug substance including its
physical and chemical characteristics and stability; the name and address of
its manufacturer; the method of synthesis (or isolation) and purification of
the drug substance; the process controls used during manufacture and
packaging; and such specifications and analytical methods as are necessary
to assure the identity, strength, quality, and purity of the drug substance
and the bioavailability of the drug products made from the substance,
including, for example, specifications relating to stability, sterility, ...
 (ii)(a) Drug product. A list of all components used in the manufacture of
the drug product (regardless of whether they appear in the drug product);
and a statement of the composition of the drug product; a statement of the
specifications and analytical methods for each component; the name and
address of each manufacturer the drug product; a description of the
manufacturing and packaging procedures and in-process controls for the drug
product; such specifications and analytical methods as are necessary to
assure the identity, strength, quality, purity, and bioavailability of the
drug product, including, for example, specifications relating to sterility,
dissolution rate, containers and closure systems; and stability data with
proposed expiration dating. The application may provide additionally for the
use of alternatives to meet any of these requirements, including alternative
components, manufacturing and packaging procedures, in-process controls,
methods, and specifications. Reference to the current edition of the U.S.
Pharmacopeia and the National Formulary may satisfy relevant requirements in
this paragraph.

FD&C SEC. 505╣. [355] (a) No person shall introduce or deliver for
introduction into interstate commerce any new drug, unless an approval of an
application filed pursuant to subsection (b) or (j) is effective with
respect to such drug.
(b)(1) Any person may file with the Secretary an application with respect to
any drug subject to the provisions of subsection (a). Such person shall
submit to the Secretary as a part of the application (A) full reports of
investigations which have been made to show whether or not such drug is safe
for use and whether such drug is effective in use; (B) a full list of the
articles used as components of such drug; (C) a full statement of the
composition of such drug; (D) a full description of the methods used in, and
the facilities and controls used for, the manufacture, processing, and
packing of such drug;



-----Original Message-----
From: Jerold Martin [mailto:[log in to unmask]
<mailto:[log in to unmask]> ]
Sent: Saturday, December 13, 2003 5:15 PM
To: [log in to unmask]
Subject: Re: [PMFLIST] Filter Usage


Regarding the inquiry from Robert Rosenlof on this topic, I want to
reiterate Bhogi Sheth's comments and add the following...

While the 21 CFR GMP regulations suggest sterilizing filtration processes
should not exceed 8 hours, numerous processes such as form/fill/seal (e.g.
contact lens
solutions) and other applications have been validated to operate up to 7
days or longer.

Even with bacterial retention data under scaled down model conditions,
several Microbiology reviewers remain suspicious of the capability of
filters (i.e. 0.2 Ám rated filters) to consistently yeild sterile effluents
over such long time periods. Per PDA Technical Report #26, "Sterilizing
Filtration of Liquids," the recommended microbial retention validation test
comprises testing only 3 membrane disc samples, with 1 near the "worst case
retention specification" (i.e. minimum bubble point) for the production
membrane. Even passing this test does not provide a high level of
confidence.

Sundaram et al. (see references below) demonstrated that 0.2 Ám sterilizing
grade rated membranes near their minimum bubble point specification are more
likely to show penetration under certain conditions than membranes with
bubble points higher in their specified range. Based on penetration
probabilities, this may not be consistently demonstrated with every minimum
bubble point membrane. For long term filtrations, greater sterilization
assurance is provided by using functionally qualified 0.1 Ám rated filters
(those with supplier-validated high titer reductions for Acholeplasma
laidlawii mycoplasma or model "diminutive" bacteria such as Hydrogenomonas
pseuoflava).

Jerold M. Martin
Sr. V.P., Global Technical Director
Pall Life Sciences
[log in to unmask] email

References:

Sundaram, S., et al. (1999), "Application of Membrane Filtration for Removal
of Diminutive Bioburden Organisms in Pharmaceutical Preparations," PDA J.
Paren. Sci. Technol., 53(4)

Sundaram, S., et al. (2001), "Retention of Water-borne Bacteria by Membrane
Filters: Part I - Bacterial Challenge Tests on 0.2 and 0.22 Micron Rated
Filters," PDA J. Pharm. Sci. Technol., 55(2), 65-86.

Sundaram, S., et al. (2001), "Retention of Water-borne Bacteria by Membrane
Filters: Part III ? Bacterial Challenge Tests on 0.1 Micron Rated Filters,"
PDA J. Pharm. Sci. Technol., 55(2), 114-126.



 

                    Bhogilal Sheth

                    <[log in to unmask] To:
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                    Sent by: The Fax to:

                    Pharmaceutical Subject: Re: [PMFLIST]
Filter Usage
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                    12/12/2003 10:49 AM

                    Please respond to

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The basic issue is not 483s or other regulatory perspectives. The Issue is
process validation.

Hypothetically, you can use a filter for as long as is necessary in your
process. To do this, you would need to validate the process as you wish to
use it. That said, you should avoid what may be considered "abnormal"
extended periods. You would need to take into consideration various
parameters such as the suitability of the filter, bioburden of the product
prior to filtration, environmental status and control of the aseptic area,
personnel training, impact of process interruptions, and many other process
and equipment related issues. You would also need to have a strong
"justification" that an extended process is necessary and provides
significant benefits.

If you ask the question to a regulatory agency representative, the answer
you will most likely get is some variation of "best not to do it". But I
think extended process times are in use in products such as contact lens
solutions. If you propose to validate an "extended time" process, I would
suggest that you review the protocol with appropriate CDER person to clarify
any concerns and doubts.

Bhogi Sheth
[log in to unmask]
----- Original Message -----
From: "Robert Rosenlof" <[log in to unmask]>
To: <[log in to unmask]>
Sent: Friday, December 12, 2003 9:08 AM
Subject: [PMFLIST] Filter Usage


> I am interested in the forums thoughts on filter usage times. When
> using
a
> 0.2um filter for a bulk in-line filtration of solution, are you aware
> of
use
> longer than 24 hours, 48 hours...etc. Have any of you seen issues
> with
483s
> or other regulatory bodies issuing observations for using a filter
> longer than 24 hours? Thanks for any input.
>
> _________________________________________________________________
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http://www.microcheck.com/ <http://www.microcheck.com/> MIDI, Inc. -
http://www.midi-inc.com/ <http://www.midi-inc.com/> Microbial ID, Inc. -
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<http://www.microtestlabs.com/> MIDI Labs, Inc. - http://www.midilabs.com/
<http://www.midilabs.com/> Millipore - http://www.millipore.com/
<http://www.millipore.com/> NovaTek International - http://www.ntint.com
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community.

Please take a second to visit our sponsors' web sites and say thank you for
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<http://www.aaiintl.com/Micro.htm> Accugenix - http://www.accugenix.com/
<http://www.accugenix.com/> Becton Dickinson Microbiology Systems -
http://www.bd.com/industrial <http://www.bd.com/industrial> Microcheck -
http://www.microcheck.com/ <http://www.microcheck.com/> MIDI, Inc. -
http://www.midi-inc.com/ <http://www.midi-inc.com/> Microbial ID, Inc. -
http://www.microbialid.com/ <http://www.microbialid.com/> MicroTest World
Class Services - http://www.microtestlabs.com/
<http://www.microtestlabs.com/> MIDI Labs, Inc. - http://www.midilabs.com/
<http://www.midilabs.com/> Millipore - http://www.millipore.com/
<http://www.millipore.com/> NovaTek International - http://www.ntint.com
<http://www.ntint.com> Raven Biological Labs - http://www.ravenlabs.com
<http://www.ravenlabs.com> Veltek Associates, Inc - http://www.sterile.com
<http://www.sterile.com>

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the scientific community.

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Accugenix - http://www.accugenix.com/
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Microcheck - http://www.microcheck.com/
MIDI, Inc. - http://www.midi-inc.com/
Microbial ID, Inc. - http://www.microbialid.com/
MicroTest World Class Services - http://www.microtestlabs.com/
MIDI Labs, Inc. - http://www.midilabs.com/
Millipore - http://www.millipore.com/
NovaTek International - http://www.ntint.com
Raven Biological Labs - http://www.ravenlabs.com
Veltek Associates, Inc - http://www.sterile.com

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