Volker Sigwarth Tel.: Skan +41 (0)61 485 4444

Skan AG Tel.: direct +41 (0)61 485 4470

Binningerstrasse 116 Fax.: +41 (0)61 485 4445

CH- 4123 Allschwil E-Mail: Volker.Sigwarth@skan.ch

Switzerland

**Comments on**

**FDA Draft Guidance:**

**" Sterile Drug Products Produced by Aseptic Processing -\
Current Good Manufacturing Practice"**

**APPENDIX 1: ASEPTIC PROCESSING ISOLATORS**

**Docket No. 2003D-0382**

**Global Comment:**

The final version of this guidance will represent a leading voice in the
application and use of isolator technology for aseptic processing.
Therefore the finalization of this guidance should be proceeded with
high priority by the FDA, to establish a valuable and useful foundation
for the industry to design, implement and use isolator technology in
aseptic processing.

**Specific Comments:**

***Line 1544 to 1552***

Useful paragraph, the following points could add significant value
concerning the integrity of isolator systems:

-   A rational of the isolator integrity (e.g. quantified as leakage
    rate) should be established based on the isolator design and its
    capability of maintaining the requisite environmental conditions
    within the isolator.

-   A mechanical / physical integrity test of the isolator system should
    also be performed routinely.

-   A significant breach of an isolator could then be defined as
    "exceeding the defined leakage rate"

-   Transfer system should also be considered regarding integrity and
    should also be part of the maintenance program of an isolator
    system.

***Line 1556 to 1562***

Useful and practical paragraph, the following point could add value
concerning the glove integrity:

-   A rational of the glove integrity (e.g. quantified as leakage rate)
    should be established.

-   Only based on a defined, quantifiable value the result of a
    mechanical / physical glove integrity test can be useful evaluated
    and justified.

***Line 1573 to 1575***

The following point could add value concerning isolator openings:

-   The capability of these openings to maintain the requisite
    environmental conditions within the isolator should be carefully
    considered.

-   The parameters which ensures the proper functionality of such
    opening should be continuously monitored.

***Line 1568***

Concerning the design of isolators the following point could add value:

-   The zone where aseptic processing takes place and in which the
    requisite environmental conditions should be maintained and
    monitored should be clearly defined (by the design of an isolator).

***Line 1577 to 1578***

Even by using isolator technology it should not be recommended to place
an aseptic processing line in a strictly turbulent isolator system. Any
aseptic processing will lead at least to the generation of particles.
The impact of these particles to the aseptic process is more or less
uncontrolled in a turbulent isolator system. This problem can be solved
by using unidirectional air flow.

The following change of this lines could add value:

-   Turbulent flow is normally acceptable within closed isolators, which
    are generally compact in size and do not house processing lines,
    e.g. sterility test- and transfer- isolators.

***Line 1581 to 1582***

In practice and for economical reasons, with isolator using
unidirectional air flow, parts of the air are recirculated from the
bottom of the critical zone via a return air system through the terminal
filter again into the top of the critical zone. Additionally fresh air
is supplied by an intake air unit with dedicated filter system and
exhaust air is handled by an additional exhaust air unit with dedicated
filter system.

The following point could reduce potential, confusing discussions:

-   In most sound designs, air showers over the critical zone once and
    then is systematically exhausted out of the critical zone.

***Line 1582***

The following point could add value concerning the chosen air velocity
with in the critical zone:

-   The air velocity of the unidirectional air flow within the critical
    zone of an isolator should be based on its capability to protected
    the individual aseptic process from potential contamination.

-   The capability of the chosen air velocity to protected the
    individual aseptic process from potential contamination should be
    supported by qualification studies.

***Line 1587 to 1589***

The following point could add value concerning the selection of
construction materials:

-   The suitability of any construction material, which is incorporated
    into to decontamination process of the critical zone of the isolator
    system, to the intended decontamination method (process) should be
    carefully considered.

***Line 1615 to 1616***

Here it would be helpful to point out, if this also includes isolators
for sterility testing.

Such isolator could be placed in a room which is unclassified but
controlled an of restricted access.

***Line 1620 to 1633***

To this paragraph the following points could add value:

-   The design of transfer systems and any transferring process should
    not compromise the requisite environmental conditions within the
    critical zone of the isolator.

-   Weak points of transfer systems should be carefully considered and a
    clear procedure should be established to minimize a potential risk
    during routing handling of transfer systems.

***Line 1642***

The following points could add value concerning the decontamination of
isolators:

-   The decontamination agent should enter the critical zone of the
    isolator through the terminal intake air filter.

This would ensure, that the terminal intake air filter is decontaminated
on both sides at each decontamination cycle.

-   The chosen residual concentration of the decontamination agent
    should not have any impact on the product quality and on any
    environmental monitoring result.

Often an underestimated issue in using isolator technology.

***Line 1657 to 1659***

*" The characteristics of these agents generally preclude the reliable
use of statistical methods (e. g. fractional negative) to determine the
process lethality (Ref. 14)."*

This sentences is not clear enough and could be misleading. Here it
should be more clear separated between cycle development and final cycle
validation.

During cycle development stage the proper use of fractional negative
methods can add significant value to evaluate reliable cycle parameters,
to justify the suitability of the used biological indicator and finally
determine the worst case positions regarding decontamination effect
within an isolator system.

The proper use of fractional negative studies during cycle development
could help to reach the *"...thorough determination of cycle
capability.",* required in line 1656 to 1657.

During final cycle validation the use of fractional negative methods
should clearly be precluded, (for any inactivation process) because it
would never be possible to justify if the fractional results comes from
a low killing position, a weak decontamination cycle or an unsuitable
biological indicator.

But to develop a decontamination cycle for bottom up and to quantify its
inactivation effect over each single process step, including the
determination of worst case positions regarding the decontamination
effect, the use of fractional negative methods, if proper applied and
understood, is a powerful an scientific based tool for process
development.

***Line 1662 to 1663***

*" Normally, a four- to six- log reduction can be justified depending on
the application"*

Here two point should be considered carefully:

-   To define the required process lethality the commonly used term
    *"six- log reduction"* should be replaced by *"total kill of a six
    log population"* (...*of an appropriate test organism using a
    suitable biological indicator*). This term is first from a
    scientific point of view a clear quantification of a process
    lethality and second it defines clearly what is expected by using
    the term *"six- log reduction".\
    *Also this definition goes in line with precluding fractional
    negative methods for final cycle validation. A "*six- log
    reduction"* could be clearly demonstrated using fractional negative
    methods, the *"total kill of a six log population"* could never be
    demonstrated by fractional negative methods.

Remark:

The reliable total kill of a defined initial population requires an
inactivation effect of four log steps more than the initial population,
e.g. to achieve a reliable total kill of a **six** log population
requires at least an inactivation effect of **ten** log steps

-   For the most aseptic processing applications using isolator
    technology, especially if processing lines are isolated the required
    target process lethality on the inner surfaces of the critical zone
    should be defined as: *"total kill of a **six** log population of an
    appropriate test organism using a suitable biological indicator"*\
    In mostly all aseptic processing application / lines some parts has
    at least secondary contact with the product (e.g. stopper hoppers,
    stopper lines, conveying systems etc.) and the gloves are used for
    manipulations or intervention during aseptic processing. Therefore a
    four log reduction seems to be inadequate for the inner surfaces of
    the critical zone. This definition goes also in line with *line 1692
    to 1694* of the draft guidance.\
    Furthermore to proof a total kill of a six log population is even
    from an economical point of view possible in state of the art
    isolator technology.

***Line 1664 to 1666***

The following point could add value to define the process lethality of a
decontamination process used to transferred material into an aseptic
isolator.

-   The capability of a decontamination process used to transfer
    material into the critical zone of an aseptic isolator should be
    able to achieve the same target lethality on the surface of the
    transferred material than the defined target lethality of the inner
    surfaces of the isolator, based on the bioload (bioburden) of the
    transferred material.

-   The bioload (bioburden) of those materials has to be carefully
    considered and monitored routinely.

-   Even if the bioload (bioburden) of the transferred material is
    significant low, the minimum process lethality of the
    decontamination (transfer) process should be defined as *"total kill
    of a **four** log population of an appropriate test organism using a
    suitable biological indicator".*

Example:

As described above, a proven total kill of a four log population
requires a process lethality of at least eight log steps (four log steps
more than the initial population to be inactivated).

Based on an estimated material bioload of e.g. one log per square inch,
such a process lethality would lead to a "surface quality" on the
transferred material which goes in line with the inner surface of the
isolator.

***Line 1694***

In correspondence to line 1662 to 1663 the following definition of the
target lethality could add value:

-   *"total kill of a six log population of an appropriate test organism
    using a suitable biological indicator"* instead of *"six-log
    reduction".*

***Line 1681***

The following point could add value concerning an isolator breach.

-   A breach of isolator integrity, which may leads to a contamination
    of the critical zone of the isolator, should lead to a
    decontamination cycle.

Best regards,

Volker Sigwarth, Skan AG