September 21, 1999

Dockets Management Branch (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852

RE: **Docket No.** 99D-1738

> Draft Guidance for Industry on Bioavailability and Bioequivalence
> Studies for Nasal Aerosols and Nasal Sprays for Local Action

Dear Administrator:

Kos Pharmaceuticals, Inc. (Kos), and Aeropharm Technology, Inc. (ATI), a
wholly owned subsidiary of Kos, is submitting comments to FDA in
response to the request published in the June 24, 1999 Federal Register
regarding the *Draft Guidance for Industry, on Bioavailability and
Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local
Action*, Docket No. 99D-1738. Our General comments to the guidance
document are attached.

Kos/ATI is a member of the IPACT-1 Consortium and also supports this
group's position concerning the development of Nasal Aerosols and Nasal
Sprays guidances. Kos/ATI believes that the comments to be submitted by
this group should play a central role in the continued development of
this guidance for industry.

Kos/ATI greatly appreciates and supports FDA's efforts to develop a
guidance for Industry for Nasal Aerosols and Nasal Sprays products. If
you have any questions concerning our comments, please call me at (305)
512-7039. Thank you for the opportunity to provide FDA with our comments
and suggestions.

Sincerely,

JoAnn H. Smith

Regulatory Affairs, Associate

**SECTION V - Bioavailability and Bioequivalence: In Vitro Studies**

Section V (B) -- Test and Metrics

The guidance recommends the use of automated actuation stations for all
comparative BE *in-vitro* tests to decrease variability in drug delivery
due to operator factors. From this point on, the guidance reads as
though this is a requirement, not a recommendation. Also, the guidance
does not provide any information for use of a non-automated testing
mechanism. Consideration should be given and specified within the
guidance document for use of non-automated testing systems.

Section V (B) (2)(b) -- Instrumental Methods

Laser Diffraction

Laser diffraction may not be a viable method for measuring particle size
distribution in all cases. Kos suggests that particle size distribution
data from the plume be included as a requirement and that appropriate
test methods be specified within the guidance.

> Multistage Cascade Impaction (CI) or Multistage Liquid Impinger (MSLI)

The guidance states that the deposition of the drug should be reported
for all Group I accessories and the upper stage, i.e., valve stem,
actuator, inlet port. Does this mean drug mass only? Is particle size
required?

Section V (B) (3) -- Instrumental Methods

Spray Pattern

In this section the guidance specifies that spray pattern measurements
should be taken at three appropriate distances from the actuator.
However, the CMC guidance for Nasal Spray and Inhalation Solution,
Suspension, and Spray Drug Products states only that measurements should
be taken "at different distances (e.g., two)." Consistency between both
guidance documents is needed.

Section V (B) (4) -- Instrumental Methods

Plume Geometry

The guidance requires two views for plume geometry. Kos suggests that
one view is sufficient to collect the data specified within this section
of the guidance.

**CONCLUSION**

Kos strongly supports the development of a guidance document for
Industry on Nasal Aerosols and Nasal Spray Drug Products and appreciates
the Agency's efforts in developing the current draft guidance. Given the
variety and complexity of formulations and devices in this drug delivery
technology area, Kos recognizes the difficulties and challenges present
in the development of a single guidance document that adequately covers
this range of diverse products. Kos also recognizes the value to
industry of a guidance of this type, and believes it is important that
this guidance be written in a way that recognizes and incorporates the
diversity of products represented by this class of pharmaceuticals.

Kos believes this will clarify for industry what aspects of
pharmaceutical performance and quality the Agency considers important to
control. In addition, a general guidance document will help industry
understand the reasoning behind the Agency's views and the Agency's
expectations for new products. Further, when product attributes and
technical issues dictate alternate approaches, developers can easily
focus their interactions with the Agency on those specific issues.

We hope our comments will be of value to the Agency and we look forward
to the ultimate publication of a final guidance that will effectively
serve the current and future needs of the Nasal Aerosol and Nasal Spray
products industries.