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October 10, 2003

Division of Dockets Management (HFA 305)

Food and Drug Administration

5600 Fishers Lane

Rockville, MD 20857

Re: Docket No. 2003D-0382

Dear Sir or Madam:

The purpose of this letter is to comment on the Food and Drug
Administration document entitled *Draft Guidance for Industry on
''Sterile Drug Products Produced by Aseptic Processing."* As a general
comment, I would like to commend the agency for the amount of work that
unquestionably went into the revision of the 1987 Guidelines on the same
topic. The proposed draft clearly reflects a substantial effort to
provide well-intended guidance to the industry in many areas that were
vague or left out of the 1987 Guideline. Despite the fact that the
review team went out of their way to justify the proposed changes in
light of the basic cGMP regulations, the agency will most likely receive
formalized responses from trade and professional associations that focus
on the impact and the associated hardship the proposed draft will have
on the "convenience" of their membership more so than safety issues the
agency is, by rights, more sensitive to. Even without the justification
and direct references to the cGMP regulations, various areas addressed
in the draft, such as media fills, equipment qualification and
environmental control programs tend to guide the industry to a better
understanding of the processes performed. In my opinion, this "gain
control" spirit is missing in the section regarding sterile filtration.
This aspect of the proposed guideline needs to be addressed, since even
if better controlled, aseptic processing steps subsequent to sterile
filtration cannot improve the sterility assurance of the product
solution once sterile filtered. In anticipation that the agency will
most likely receive very little input on this topic from other sources
and considering that sterile filtration is my area of expertise, I
concentrated my comments on this topic.

Much like the rest of the document, the section that covers sterile
filtration presents a number of valuable concepts that may be better
understood by the industry if rearranged in a more consequential manner,
as I suggest in the attached redlined rewrite. In addition, my main
concern continues to be that as presented by the agency, sterile
filtration will again be taken for granted, since some aspects needed to
bring this crucial processing step under the control of filter users
continue to be treated as lightly, if not worse, than they were in 1987.
If not modified, the message of the proposed draft will very likely
continue to be read by the industry as it has been for several decades,
namely, "Don't worry, let the filter manufacturer tell you how good
their filters are..."

HGS 10/10/03 Comments on Docket No. 2003D-0382 -- page 2/9

Without a push by the agency for a better understanding of any process,
the industry has always taken the easier way out. Case in point: moist
heat sterilization. Prior to the advent of Validation in the 1970's,
most pharmaceutical companies settled for following the generic cycle
instructions provided by autoclave manufacturers. The then "new"
requirement for autoclave users to become involved in the validation of
autoclave cycles created increased awareness of moist heat sterilization
and later many other processes. Unquestionably, this had an immediate
positive impact on the sterility assurance of terminally processed
parenterals, and, ultimately, overall product quality. In sharp contrast
to the progress made in moist heat sterilization, filter users have yet
to become aware of potential limitations of sterile filtration, and
failure by users to "gain control" over this crucial process step has no
doubt been the cause of loss of product from unexplained sterility
problems and likely even allowed non-sterile injectable products to
inadvertently slip into the distribution channels. If the relaxed
attitude towards sterile filtration is perpetuated, filter users will
not gain control of the process nor will they perform meaningful
validations. Why should they, if for practical purposes the validation
of sterile filtration continues to be optional? And revalidation of
sterile filtration is not even mentioned, no matter how sensible the
task seems to the agency and the industry alike for most other
operations and far more permanent installations such as autoclaves.

A sound set of regulations should assist the industry in producing
pharmaceutical products of better quality, but this may not be the case
if filter users strictly follow the proposed guidelines for sterile
filtration. The regulations in other countries are no that much better
in this area, but sadly enough, other countries look at the regulations
of our great nation for guidance. Thus, in order to make the guideline
more meaningful, I offer a few additional suggestions in the attached
redlined text. A rationale for some of those suggestions follows below.

Specific comments:

1\. Section IV D (starting on line 262) talks about the importance of
purity and microbial quality of compressed gases. Additional guidance is
warranted.

Rationale: The draft recognizes the importance of "sterile" compressed
gases for such purposes and suggests the use of membrane filters, but it
provides no guidance on how the expected filter performance can be
validated. It would be very difficult to end up with a sterile product
if the compressed nitrogen to pressurize or dry, let us say, a
1000-liter sterile holding tank is allowed to have the microbial
allowance made for critical areas.

2\. Line 969 states: \"...rated porosity of 0.2 micron or smaller.\"
This should be changed to "...a numerical retention rating of 0.2
micrometers or smaller."

Rationale: Technically, porosity cannot be measured in micrometers. If
the expression were changed to "...rated pore size..." the statement
would be in conflict with the (correct) observation that the numerical
rating assigned by the filter manufacturers is "...a figment of their
imagination..." as stated by Ed Fry in \"FDA Update on Aseptic
Processing Guideline\", J. Parenteral Sci, Technol. 41 (2) 56 (1987). It
is not the "rating" but the actual "integrity" (a combination of true
pore size and absence of defects) of the filter that assures the desired
retention characteristics. The numerical rating was discouraged in 1987
and should have no place in 2003 regulations either. A better approach
would be to define retention performance by using a model organism,
e.g., B diminuta, as discussed

HGS 10/10/03 Comments on Docket No. 2003D-0382 -- page 3/9

on lines 974+. However, it must be recognized that the suitability of B.
diminuta is challenged in several articles, "commercially driven," as
they may be:

-   S. Sundaram, J. Eisenhuth, G. Howard Jr., and H. Brandwein,
    "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 (2001).

-   S. Sundaram, S. Mallick, J. Eisenhuth, G. Howard Jr., and H.
    Brandwein, "Retention of Water-Borne Bacteria by Membrane Filters
    Part II, SEM and FAME Characterization of Bacterial Species
    Recovered Downstream of 0.2 / 0.22 Micron Rated Filters", PDA J.
    Pharm. Sci. Technol. **55** (2): 87 (2001).

-   S. Sundaram, J. Eisenhuth, G. Howard Jr., and H. Brandwein,
    "Retention of Water-Borne Bacteria by Membrane Filters Part III,
    Bacterial Challenge Tests on 0.1Micron Rated Filters", PDA J. Pharm.
    Sci. Technol. **55** (2): 114 (2001).

Perhaps time has come for the agency to investigate the choice of a
microbial model independently, much like over 30 years ago the switch
from S. marcescens to B. diminuta as a marker organism for sterile
filtration was prompted by FDA research.

3\. Line 984: \"A challenge concentration of at least 10\^7 organisms
per cm\^2...\" is specified, but emphasis should also be made on the
expected \"zero" passage.

Rationale: Self evident.

4\. Lines 985 to 987: \"A commercial lot\'s actual influent bioburden
should not include microorganisms of a size or concentration that would
present a challenge beyond that considered by the validation study.\"
This statement should be changed to read "A commercial lot\'s actual
influent bioburden should not include microorganisms of a size smaller
than and/or a total concentration that would present a challenge beyond
a factor of 10^-x^ (where "x" is a safety margin that should be
suggested by the agency) of the level covered by the retention
validation study."

Rationale: As proposed in the draft, this statement presents a serious
and unacceptable health risk to the general public since it makes no
allowance for a safety margin. "Luckily," the statement is in conflict
with common sense and other (safer) statements made within the document,
e.g., Section X C on Pre-filtration Bioburden, which "...should be
minimal...." (line 1316). Albeit the lack of a numerical specification,
this is far more suitable guidance. Much like the safety margin in
terminal sterilization, the ratio between the validated retention
capability of the filter and the actual bioburden of a batch of product
can be interpreted as a safety margin for the sterile filtration
process. As stated in the draft, the Agency endorses the outcome of
sterile filtration to be, in essence, a 50-50 toss-up. The autoclave
equivalent on line 1100 would be "...A sterility assurance level of
10^0^ is adequate..." instead of suggesting the traditional 10\^6 safety
margin. The level of 10\^7 per cm\^2 can cautiously be compared to the
10\^12 overkill, also good for a safety margin of 10\^6 only if there
are no more than 10\^6 microbes of a D-value of 1 minute in the original
bioburden. Such equivalents between regular sterilization and sterile
filtration need to be understood by the agency and filter users before
regulations like this one can be considered sound and reasonable.

5\. Lines 1001+: The draft lists the various parameters that affect the
retention capability of sterile filters. A more consequential
rearrangement of these very important concepts is suggested in the
attached (redlined) revision. It is also important to point out that if
validated as (appropriately) requested, i.e., "over-kill" bioburden
level, product as a carrier vehicle and simulation of the process
parameters, practically all of the variables

HGS 10/10/03 Comments on Docket No. 2003D-0382 -- page 4/9

become fixed parameters, leaving only the "integrity" of the filter as
the key parameter against which the retention performance can be
correlated. Hence, the importance of filter integrity, but this aspect
does not receive the attention necessary to provide sound guidance to
the filter user. Vague requirements such as the statements in lines 1017
to 1025 regarding the validity of the scale-up from challenge test level
to the production setting should be more specific. Also please refer to
comment 7 below.

6\. Lines 1010+ state: \"When the more complex filter validation studies
go beyond the capabilities of the filter user...\" Please see redlined
text, but this sentence should, by rights, be completed with "...the
firm shall not be granted a license to produce sterile products by
aseptic processing.\"

Rationale: The use of independent third party laboratories might be
justifiable, but allowing filter manufacturers to be "judge and jury" of
their own products goes against all rules of common sense and the
general spirit of "validation" as set forth throughout GMP regulations
and FDA Guidelines. Even PDA TR No. 26 suggests the filter user take
responsibility for in-product retention validation. Ideally, much like
25 years ago the industry learned how to work around previously
"non-existing" cold-spots in autoclaves, the industry should learn how
to cope with the filtration equivalent thereof. Filter users need to be
encouraged to become more involved in the validation and gain control of
this important process step, not offered an easy way out. This 1987
mistake should not be perpetuated even in light of the request that
"...it is the responsibility of the filter user to review..."
(line1012), since the fact is that most filter users end up basing their
review on potentially biased information provided to them by filter
manufacturers. How can the FDA have confidence in a process that by the
filter user's own admission needed to be explained to the agency by the
filter supplier? (See Millipore advertisement campaign "testimonials" on
back covers of Pharmaceutical Technology, a sad but evidently real
reflection of the industries "control" over this important tool).

7\. Line 1024 states: \"A production filter\'s integrity test
specification should be consistent with data generated during filtration
efficacy studies.\" This is appropriate, but the currently accepted
practice of "diffusion" integrity testing production filters at 80% of
the minimum bubble-point value established in the challenge studies, as
promoted by the filter manufacturers, is technically unacceptable. A
detailed discussion of this error can be found in H. G. Schroeder,
"Rationalization and Valid Scale-Up of Integrity Test Parameters for
Sterilizing Grade Filters," PDA J. Pharm. Sci. Technol. **55** (2): 134
(2001). A "certificate of compliance" often issued by "judge and jury"
of their own filter product line is also a poor substitute for a sound
integrity test.

8\. Line 1027 endorses the use of sterilizing grade filters in series.
While this has indeed become common practice, it also creates a false
sense of security. In an oral presentation at the December 2001 PDA
meeting, Dr. Sundaram presented compelling evidence that redundant
filtration is not a fool-proof safeguard against passage of organisms
able to penetrate filters recognized as sterilizing grade by a B.
diminuta challenge test. Improperly validated filters in series are as
unsafe as two consecutive un-validated autoclave cycles. (This concept
was moved into the "validation" portion of the section with a caveat to
test both filters for integrity if two are required to assure
sterility.)

Last, but not least, the definition on line 2038: \"Sterilizing grade
filter- A filter that, when appropriately validated, will remove all
microorganisms from a fluid stream, producing a sterile effluent.\" No
room for error? Such a statement gives filter users a false sense of

HGS 10/10/03 Comments on Docket No. 2003D-0382 -- page 5/9

security that is sure to lead them into trouble. Even the reliability of
autoclave cycles is validated to within a finite probability of
survival, and an equivalent probabilistic limitation must be recognized
for sterile filtration as well. The statement is particularly surprising
in view of the fact that the FDA is (pain)fully aware of sterility
failures that have occurred in the field as a consequence of filter
failures, such as described in the above cited article by Ed Fry while
he was working for the agency. At best, the concept of absoluteness is
"commercial" rather than scientifically sound. Even articles written by
the very filter manufacturers in support of their own product line shows
clearly that under currently accepted filter integrity test practices it
is mathematically impossible to count on "total" retention when a filter
is challenged to the prescribed 10^7^ cfu/cm^2^ (e.g., Pall, D.B., and
E. Kirnbauer, "Bacteria Removal Prediction in Membrane Filters", 52^nd^
Colloid and Surface Science Symposium, University of Tennessee,
Knoxville, TN, 12 June 1978, reprints available from the Pall
Corporation as STR PUF 13, Pall Corporation 1990).

Please note that these comments are limited to the area of sterile
filtration, and only address issues covered in the proposed draft. In
addition to the pivotal importance of bacteria retention capability,
other aspects (e.g., compatibility, extractables, etc.) of sterile
filters need to be considered, but such are not addressed in the
document at all. Evidently, such aspects are not considered pertinent by
the agency from a regulatory point of view. The reader is correctly
referred to PDA Technical Report No. 26 for additional information and
guidance on such issues, but it needs to be pointed out that the roster
of the Sterile Filtration Task Force was practically dominated by filter
suppliers. The resulting "consensus" is not necessarily in the best
interest of the advancement of general knowledge in the field of
filtration, since filter manufacturers prefer for users (and the agency,
for that matter) not to know "too much" about sterile filtration.

One final comment: Some members of our community who are actively
involved in the field of sterile filtration may take exception to the
choice of references cited. A broader and more appropriate reference
base can be found in PDA Technical Report No. 26.

Independently and respectfully submitted,

![](media/image1.png){width="2.3229166666666665in"
height="0.6145833333333334in"}

Hans G. Schroeder, Ph.D.,

Senior Consultant

cc: Mr. Richard Friedman, CDER (HFD--320)

HGS 10/10/03 Comments on Docket No. 2003D-0382 -- page 6/9

Suggestions for the section on "Filtration Efficiency"

Draft --- Not for Implementation

***Contains Nonbinding Recommendations***

*\\\\CDS029\\REGAFF\\!guidanc\\1874dft.doc*

*08/22/03*

**B. Filtration Efficacy**

Filtration is a common method of sterilizing drug product solutions.
Ideally, an appropriate sterilizing grade filter is one that
reproducibly removes all microorganisms from the process stream,
producing a sterile effluent. Such filters usually have a numerical
retention rating of 0.2 micrometers or smaller. Whatever filter or
combination of filters is used, validation should include
microbiological challenges to simulate worst-case production conditions
regarding the size of microorganisms in the material to be filtered and
integrity test results of the filters used for the study. The
microorganisms should be small enough to both challenge the filter and
simulate the smallest microorganism that may occur in production. The
microorganism *Brevundimonas diminuta* (ATCC 19146) when properly grown,
harvested and used, can be satisfactory in this regard because it is one
of the smallest bacteria . Bioburden of unsterilized bulk solutions
should be determined on a "x" basis (the agency should have a suggestion
as to batch per batch, weekly, monthly...) to trend the characteristics
of potentially contaminating organisms. In certain cases, when justified
as equivalent as or better than use of *Brevundimonas diminuta*, it may
be appropriate to conduct bacterial retention studies with a bioburden
isolate. The number of microorganisms in the challenge is important
because a filter can contain a number of pores larger than the nominal
rating, which have the potential to allow passage of microorganisms. The
probability of such passage is considered to increase as the number of
organisms (bioburden) in the material to be filtered increases (?Refs.
10, 11, 12). A challenge concentration of at least 10\^7 organisms per
cm\^2 of effective filtration area of *B. diminuta* should generally be
used, and no passage should be observed for the filter to be considered
sterilizing. A commercial lot\'s actual influent bioburden should not
include microorganisms of a size smaller and/or a total concentration
that would present a challenge beyond a factor of 10^-x^ (where "x" is a
safety margin that should be suggested by the agency) of the level
covered by the retention validation study. While the retention
capability should be assessed against physical integrity test results of
a single filter, the use of two sterilizing-grade filters in series is
recommended in order to enhance the margin of safety of the filtration
step; this is a common practice. If redundant filtration is found to be
necessary to achieve sterility, both filter units should meet validated
integrity criteria.

The filter related factors that affect the retention performance
obviously include the filter itself, the compatibility of the filter
materials and components with the product to be filtered and most
importantly the state of integrity of the filter as documented by a
suitable physical integrity test. *Forward flow and bubble point* tests,
when appropriately employed, are two integrity tests that can be used. A
production filter's integrity test specification should be consistent
with data generated during filtration efficacy studies.

(Note: Concepts not deleted, just reorganized...) Product related
factors that can affect filter performance include the viscosity

HGS 10/10/03 Comments on Docket No. 2003D-0382 -- page 7/9

of the material to be filtered, the pH, the osmolarity and other
physicochemical properties of the product filtered. Therefore, direct
inoculation of the challenge organism into the formulation provides the
most appropriate assessment of the effect of the product on the
retention performance of the filter and as well as the impact of the
formulation on the challenge organism. However, directly inoculating *B.
diminuta* into products with inherent bactericidal activity or into
oil-based formulations can lead to erroneous conclusions.

Processing related factors that can affect the filter performance
include the applied pressure differential, flow rates, use time,
temperature, and the effects of hydraulic shock. When designing the
validation protocol, it is important to address the effect of the
extremes of processing factors on the filter capability to produce
sterile effluent. Filter validation should be conducted using the
worst-case conditions, such as maximum filter use time and pressure
(Ref. 12). When sufficiently justified, the effects of the product
formulation on the membrane\'s integrity can be assessed using an
appropriate alternate method. For example, the drug product could be
filtered in a manner in which the worst-case combination of process
specifications and conditions are simulated. This step could be followed
by filtration of the challenge organism for a significant period of
time, under the same conditions, using an appropriately modified product
(e.g., lacking an antimicrobial preservative or other antimicrobial
component) as the vehicle. Any divergence from a simulation using the
actual product and processing conditions should be justified.

Filter validation experiments, including microbial challenges, need not
be conducted in the actual manufacturing areas. However, it is essential
that laboratory experiments simulate actual production conditions. The
specific type of filter used in commercial production should be
evaluated in filter validation studies. When the more complex filter
validation tests go beyond the capabilities of the filter user, tests
may be conducted by independent third party laboratories . However, it
is the responsibility of the filter user to review the validation data
on the efficacy of the filter in producing a sterile effluent. The data
should be applicable to the user\'s products and conditions of use
because filter performance may differ significantly for various
conditions and products.

After a filtration process is properly validated for a given product,
process, and filter, it is important to ensure that identical filter
replacements (membrane or cartridge) used in production runs will
perform in the same manner. Normally, integrity testing of the filter is
performed prior to processing, after the filter apparatus has been
assembled and sterilized. It is important that integrity testing be
conducted after filtration to detect any filter leaks or perforations
that might have occurred during the filtration. Sterilizing filters
should be routinely discarded after processing of a single batch.

HGS 10/10/03 Comments on Docket No. 2003D-0382 -- page 8/9

Suggestions for the section on "Filtration Efficiency" (redlines
"accepted")

Draft --- Not for Implementation

***Contains Nonbinding Recommendations***

*\\\\CDS029\\REGAFF\\!guidanc\\1874dft.doc*

*08/22/03*

**B. Filtration Efficacy**

Filtration is a common method of sterilizing drug product solutions.
Ideally, an appropriate sterilizing grade filter is one that
reproducibly removes all microorganisms from the process stream,
producing a sterile effluent. Such filters usually have a numerical
retention rating of 0.2 micrometers or smaller. Whatever filter or
combination of filters is used, validation should include
microbiological challenges to simulate worst-case production conditions
regarding the size of microorganisms in the material to be filtered and
integrity test results of the filters used for the study. The
microorganisms should be small enough to both challenge the filter and
simulate the smallest microorganism that may occur in production. The
microorganism *Brevundimonas diminuta* (ATCC 19146) when properly grown,
harvested and used, can be satisfactory in this regard because it is one
of the smallest bacteria. Bioburden of unsterilized bulk solutions
should be determined on a "x" basis (the agency should have a suggestion
as to batch per batch, weekly, monthly...) to trend the characteristics
of potentially contaminating organisms. In certain cases, when justified
as equivalent as or better than use of *Brevundimonas diminuta*, it may
be appropriate to conduct bacterial retention studies with a bioburden
isolate. The number of microorganisms in the challenge is important
because a filter can contain a number of pores larger than the nominal
rating, which have the potential to allow passage of microorganisms. The
probability of such passage is considered to increase as the number of
organisms (bioburden) in the material to be filtered increases (?Refs.
10, 11, 12). A challenge concentration of at least 10\^7 organisms per
cm\^2 of effective filtration area of *B. diminuta* should generally be
used, and no passage should be observed for the filter to be considered
sterilizing. A commercial lot\'s actual influent bioburden should not
include microorganisms of a size smaller and/or a total concentration
that would present a challenge beyond a factor of 10^-x^ (where "x" is a
safety margin that should be suggested by the agency) of the level
covered by the retention validation study. While the retention
capability should be assessed against physical integrity test results of
a single filter, the use of two sterilizing-grade filters in series is
recommended in order to enhance the margin of safety of the filtration
step; this is a common practice. If redundant filtration is found to be
necessary to achieve sterility, both filter units should meet validated
integrity criteria.

The filter related factors that affect the retention performance
obviously include the filter itself, the compatibility of the filter
materials and components with the product to be filtered and most
importantly the state of integrity of the filter as documented by a
suitable physical integrity test. *Forward flow and bubble point* tests,
when appropriately employed, are two integrity tests that can be used. A
production filter's integrity test specification should be consistent
with data generated during filtration efficacy studies.

HGS 10/10/03 Comments on Docket No. 2003D-0382 -- page 9/9

(Note: Concepts not deleted, just reorganized...) Product related
factors that can affect filter performance include the viscosity of the
material to be filtered, the pH, the osmolarity and other
physicochemical properties of the product filtered. Therefore, direct
inoculation of the challenge organism into the formulation provides the
most appropriate assessment of the effect of the product on the
retention performance of the filter and as well as the impact of the
formulation on the challenge organism. However, directly inoculating *B.
diminuta* into products with inherent bactericidal activity or into
oil-based formulations can lead to erroneous conclusions.

Processing related factors that can affect the filter performance
include the applied pressure differential, flow rates, use time,
temperature, and the effects of hydraulic shock. When designing the
validation protocol, it is important to address the effect of the
extremes of processing factors on the filter capability to produce
sterile effluent. Filter validation should be conducted using the
worst-case conditions, such as maximum filter use time and pressure
(Ref. 12). When sufficiently justified, the effects of the product
formulation on the membrane\'s integrity can be assessed using an
appropriate alternate method. For example, the drug product could be
filtered in a manner in which the worst-case combination of process
specifications and conditions are simulated. This step could be followed
by filtration of the challenge organism for a significant period of
time, under the same conditions, using an appropriately modified product
(e.g., lacking an antimicrobial preservative or other antimicrobial
component) as the vehicle. Any divergence from a simulation using the
actual product and processing conditions should be justified.

Filter validation experiments, including microbial challenges, need not
be conducted in the actual manufacturing areas. However, it is essential
that laboratory experiments simulate actual production conditions. The
specific type of filter used in commercial production should be
evaluated in filter validation studies. When the more complex filter
validation tests go beyond the capabilities of the filter user, tests
may be conducted by independent third party laboratories. However, it is
the responsibility of the filter user to review the validation data on
the efficacy of the filter in producing a sterile effluent. The data
should be applicable to the user\'s products and conditions of use
because filter performance may differ significantly for various
conditions and products.

After a filtration process is properly validated for a given product,
process, and filter, it is important to ensure that identical filter
replacements (membrane or cartridge) used in production runs will
perform in the same manner. Normally, integrity testing of the filter is
performed prior to processing, after the filter apparatus has been
assembled and sterilized. It is important that integrity testing be
conducted after filtration to detect any filter leaks or perforations
that might have occurred during the filtration. Sterilizing filters
should be routinely discarded after processing of a single batch.