Jack Lysfjord's Comments to "Sterile Drug Products Produced by Aseptic
Processing---Current Good Manufacturing Practice" Draft. Docket \#
2003D-0382.

An overall general comment that communications are improving between the
Agency and industry. A great deal of listening took place between the
September 2002 version and the September 2003 version. My compliments to
the team for all their work and to PQRI and other organizations and
industry experts for the positive changes in this document.

#1 Line 143,157.,.,.,.,......

If we are looking to the future and not the past, why are we using the
obsolete "Class 100" designator instead of ISO 5? If class 100 is
referenced IT should be in parentheses not the ISO value. ISO has
superceded the old system.

#2 Line 196, 199

Why does the document dance between "Laminar Flow" and "Unidirectional
Flow"?

My understanding is that terminology is now "Unidirectional Flow".

#3 Lines 1534-1540

Thank you for the very positive statement on the favorable use of
isolators for aseptic processing. This paragraph only refers to positive
pressure isolators.

As new pharmaceutical and biopharmaceutical products are developed,
there is a trend toward a great increase in the number of potent
products requiring containment. The 2002 Survey conducted by
Lysfjord/Porter found 32 out of 108 respondents reported using isolators
for containment reasons or 29%. This number will be increasing based on
the products in development and clinical trials. Depending on the
product operator exposure levels and therefore the design requirements
of the isolator system, a negative pressure system may be the best
compromise along with a change in surrounding room classification. A
brief paragraph at the end of appendix 1 that would allow the
possibility for this type of design based on good science would keep
this document viable for a longer time period and not create the
impression that ONLY positive pressure isolators are acceptable.

#4 Lines 1570-1583 Airflow

I don't understand why turbulent flow is allowable in a closed isolator
and not an open isolator. As and isolator gets narrower and narrower,
turbulence has a greater probability compared to an open cleanroom. The
goal is unidirectional flow as much as possible, KEEPING PEOPLE OUT of
the critical area and maintaining the requisite environmental conditions
within the isolator.

#5 Lines 1591- 1607 Pressure Differential

This is an example of "more is not necessarily better". Increasing
pressure can cause the following:

-   Blowing over of small lightweight containers at transition points
    (Mouseholes)

-   Powder filling lines where product "float" is an issue can be
    detrimental. This is especially true when the product is potent and
    requires containment.

-   Higher particle counts in a specific location due to vortexes
    picking up particles on either side of a depyrogenation tunnel belt.

-   Pressure balance issues for depyrogenation tunnels connected to
    isolators

The controlling issue again is maintaining the requisite environmental
conditions within the isolator and not the pressure by definition. The
design and qualification of the system should protect the product by
maintaining the interior environmental conditions.

Respectfully submitted 11-04-2003

Jack Lysfjord, Vice President Consulting

Valicare Division, Bosch Packaging Technology

763 493 6771

Fax: 763 493 6783

<jack.lysfjord@boschpackaging.com>