# To

Dockets Management Branch (HFA -- 305)

Food and Drug Administration,

5630 Fisher Lane, Rm. 1061

# Rockville, MD 20852

# 

# 

# 

# Dear Sirs,

I have reviewed the new proposal for the Guidance for Industry on
Aseptic Processing (issued August 2003) and I submit comments for review
by the agency.

I want to emphasize that this document is a vast improvement over the
previous released comment document from September 2002. It is obvious,
that a great deal of listening to the comments provided from all corners
helped greatly, especially the PQRI input.

**Some general [technical]{.underline} comments:**

Unidirectional airflow is now the commonly used expression to
characterise air flow derived from installations applied in
pharmaceutical manufacturing. Therefore there should be consistency in
the phrases, and not a swing between laminar flow and sometimes
unidirectional air flow (e.g line 196, \...)

Remove all phrases referring to obsolete FS 209 E (e.g. line 226) and
state only the valid ISO classes (e.g. 14644-1) in the main text.

In Appendix 1 Aseptic Processing Isolators the term decontamination
should be replaced by biodecontamination where this refers to removal of
unwanted viable particles.

**There is a lack of definitions on:**

Routine (used e.g. in line 147or 693, etc\....)

Continuously (used in line 243)

Mechanical (line 1560)

**Specific comments line by line**

1.  **Line 303 - 304:**

Text: \...Capable of retaining at least 99.97 percent \...

Comment: The specification of a minimum leak rate of 0.03 % does not
correlate with international standards for HEPA filters. These
guidelines have a [leakage criteria]{.underline} that steps down in
0.25, 0.025, etc and the leakage criteria is directly linked to the
specified retention grade.\
There is always confusion on what is the requirement of the agency. As
we read the text, FDA is talking on the retention grade of a HEPA filter
being installed and measured in situ. Therefore a retention grade should
be mentioned that complies with international guidelines (0.025 for a
HEPA with a certified retention grade of 99.95 %). I even think it is
better to make reference to an international -- also adopted standard by
US -- standard specifying a certified HEPA filter retention grade and
not mentioning an insitu retention grade at all.

Proposal: All HEPA filters should be certified and leak tested according
to a written procedure. Acceptance criteria for passing filter integrity
testing should be calculated according international standards, such as
EN 1822

2.  **Line 312 - 314:**

Text: \...depending on the accuracy of the photometer.. with an
appropriate photometer probe ..air flow rating.

Comment: Since there are other challenge aerosols on the market and
widely used (Emery 3004), DOP, which is under suspect to cause cancer,
should not be mentioned as the only one. On the other hand, it is
superfluous to mention the upstream concentration since later one the
requirement for leakage calculation is required, which makes it
necessary anyway to have an upstream concentration sufficient for
reaching acceptance criteria.

Proposal: The leak test should be done with a challenge aerosol (e.g.
Emery 3004, DEHS, or DOP) with an upstream concentration sufficient to
allow leak rate calculation in the specified range.

3.  **Line 312 & 315:**

Text: \... with an appropriate photometer probe, \...

Comment: New ISO 14644-3 allows use of photometers AND particle
counters, therefore not a single device type should be mentioned.
Instead please use approach of ISO 14644-3 and leave it open, which
devices and procedure are used.

Proposal: \... with an appropriate photometer or particle counter

4.  **Lines 935 - 944:**

Text: When filling \...following investigation

Comment: These recommended criteria go away from all the other standards
being applied throughout the world (e.g. ISO 13408 Aseptic processing of
health care products, EC-GMP guideline, PIC/S guideline). They are not
only more stringent than the ones mentioned above, they also do not have
any statistical considerations in it. In consequence it will lead the
industry to fill only the minimum number specified (5000, up to 10.000
and 10.000 only, since there is no rational given, what are the expected
results for a 30.000 unit media fill.\
Therefore I propose to stick to the already existing acceptance criteria
and take these acceptance criteria from ISO standards into the guideline
text .

Proposal: Acceptance criteria for media fills should be derived from ISO
13408.

5.  **Line 1560:**

Text: Mechanical integrity tests \...

Comment: It is probably not meant, that the gloves are subjected to
mechanical stress prior to batch. If it is meant, that gloves should be
test by physical means and not only by visual inspection, then this
should be clearly stated.

Proposal: Automated integrity tests should be performed routinely along
with visual inspection.

6.  **Line 1588:**

Text: \... well as ease of cleaning and sterilization.

Comment: This refers to the construction materials of the isolation
systems and components, and not to the components of a filling unit with
a aseptic fluid path. Therefore the expression should be exchanged to
the word sanitization, because this is what is required. The whole
paragraph does only talk on decontamination and not on sterilisation.

Proposal: \... well as ease of cleaning and bio-decontamination

7.  **Line 1597:**

Text: \... approximately 0.07" to 0.2" water gauge.

Comment: Most of the other text is stating limits in metric values,
therefore this should be applied here as well. SI units should be used.
0.2 is not widely used in aseptic filling operations in isolation
technology. Therefore the upper limit mentioned should be decreased to a
more widely used value.

Proposal: \... approximately 12.5 -- 30 Pa in most cases. Special cases
exist for designated processes.

8.  **Line 1615 - 1616:**

Text: An aseptic processing isolator should not be located in an
unclassified room.

Comment: Since the whole guide is on aseptic processing, it is not
necessary to mention "aseptic" isolator (scope of this guide). If it is
the agency's opinion, that isolators for aseptic processing should be
located in class 8 (ISO) (as a minimum), then this should be clearly
stated in the sentence above.

Proposal: Delete whole sentence

9.  **Line 1654:**

Text: A decontamination method should be developed, that renders the
inner surface of the isolator free of viable microorganisms.

Comment: This wording tends to say, that the agency is asking for a
sterilisation cycle for the inner surfaces of the isolator. This is in
conflict with the surface requirement for viable particles stated in
line 143. There a limit of one is mentioned for air borne particles, and
none for surfaces. European and PIC/S guidelines require a limit of 1
for viable surface contaminants as well. Therefore rephrase in such a
way, that there is the overall goal of developing and applying a
bio-decontamination cycle is to achieve a inner surface contamination of
less than 1 cfu/sample (e.g. obtained by applying rodac contact plate
multi sampling).

Proposal: Bio-decontamination cycle development should prove that a
quantified challenge of BIs can be reduced to the specified limit.
Normally a 4 log reduction for inner surfaces is seen as sufficient.

10. **Line 1681:**

Text: A breach of isolators integrity should lead to a decontamination
cycle.

Comment: This requirement is not justified. Not every loss in integrity
(e.g. pin hole in a glove that is far away from the critical area is per
definition a loss of integrity. We think, it is the intent of the agency
to require subsequent bio-decontamination when there was a "major"
event. Since major is not easy to specify, we propose to request a hold
in production, failure investigation (what happened) and risk
assessment. Based on assessment of risk a stop of production and new
bio-decontamination might be necessary.

Proposal: A breach of isolators integrity should lead to a hold in
production, failure investigation (what happened) and risk assessment.
Based on this risk assessment a stop of production and new
bio-decontamination might be necessary. A decision tree for potential
faults should be developed with rationale.

11. **Line 2001 - 2002:**

Text: High efficiency particulate air filter with a minimum 0.3 micron
particle retaining efficiency of 99.97 percent

Comment: This definition does not comply with national and international
adopted standards (ISO guidelines). Therefore a rephrasing should be
done.

Proposal: HEPA (High efficiency particulate air) filter in the sense of
this guideline means a filter of a certified retention grade of 99.95 as
a minimum.

12. **Line 2008 - 2010:**

Text: Isolator: A decontaminated unit, \...

Comment: An isolator can be in a status either "bio-decontaminated" or
"not bio-decontaminated" (depending on the state of operation or modus);
it is not necessary said, that someone can call this installation an
isolator only after biodecontamination has been executed. Therefore
rephrase in such a way that an isolator in the sense of this guideline
is a device being capable of being bio-decontaminated automatically
(this would also comply to ISO 13408-6 and ISO 14644-7).

Proposal: A device complying to ISO class 5 or higher in operation,
being capable of being bio-decontaminated, that provides uncompromised,
continuous isolation \...

best regards

Dr. Berthold Düthorn

Director Validation Services

ROBERT BOSCH GmbH

Packaging Technology Division

P.O. Box 1454

D-74554 Crailsheim

Telefon: +49 (0) 7951 402 - 414

Fax: +49 (0) 7951 402 - 405

E-Mail: berthold.duethorn@boschpackaging.com