COMMENTS TO DOCKET \# 99D-1738

CDER requires Particle Size Analysis at different delay times of the
spray (Formation, Intermediate, Dissipate). As a result of measuring
Particle Size Distribution of nasal sprays at several of customer sites,
the following issues were raised. I have also created a recommended
method for accomplishing the 3 delayed measurements.

\*\"Formation, Intermediate, and Dissipate\" (F/I/D) can be defined in a
myriad of ways.

Is it based on real time (Formation = xx milliseconds after actuation of

spray bottle? Intermediate = xx milliseconds after Formation stage?).

Is it based on Optical Concentration / Obscuration (blockage of the
laser

beam by a large number of droplets)?

If based on Optical Concentration, at what Obscuration level does the

spray event start? At what level does it end?

What is the period of time for each stage? 1 millisecond?

10 milliseconds? 10% of the total spray duration time?

\*Obscuration defines blockage of the laser beam, but is not the most
sensitive method to start the spray measurement. As the first few
droplets pass the laser beam, they diffract light onto certain channels
of the detector. This diffraction can be detected much earlier than 1-2%
obscuration, as 1-2% obscuration requires thousands of particles. and is
therefore a more reliable way of detecting the start of the spray.

\*How long should each F/I/D measurement last? With laser diffraction
instruments, it is possible to make 2000+ measurements per second,
creating a series of 0.5ms long \"snapshots\" of the spray event! The
higher the speed, the less representative each slice becomes. Our
observations are that most nasal sprays events last a total of 100ms.

\*The manufacturer\'s recommended obscuration values are not really
relative, as the spray device\'s properties and actuation force
determines the obscuration. As the instrument manufacturer, we have no
control over the obscuration (as we would with dry powder or suspension
measurements), so we have to live with what the spray device is
delivering, be it high or low!

\*It is of utmost importance that a reliable method of actuating the
spray device is used, as the PSD is totally dependent on the spray
device actuation force and location of the spray device relative to the
laser. A means to guarantee consistent and reproducible alignment of the
spray with the laser is required. Ideally the spray device actuation
values should be documented in the software along with the results, and
be included any reports.

OUR RECOMMENDATION:

The measurement of the spray event should start when the signal on the
most sensitive detector channel for the particular spray reaches 1%.
This is a much more sensitive way to start the measurement, as it is
based on detecting the passage of the first few droplets, compared to
Obscuration or Optical Concentration where a mass of droplets are
required. As the overall plume can best be characterized by obscuration,
the formation measurement would begin when obscuration reaches 40% of
the maximum obscuration value, and last 10ms. The intermediate
measurement would begin when the obscuration reaches 98% of the maximum
value, and last 10ms, and the dissipation measurement would begin when
the obscuration decreases to 20% of the maximum value, and last 10ms.
Time resolution should be 1ms or faster, with at least 100ms of data
obtained per spray. A plot showing the entire spray event vs. time, with
d10/d50/d90 and Optical Concentration, should be submitted, as well as
the mean for F/I/D measurements.

Lastly, one measurement should be made which triggers at 1% signal on
most sensitive channel, and continues uninterrupted until the signal
falls below 1%, showing the average PSD for the entire spray dose.

Sincerely,

Joe Wolfgang

Sympatec Inc.

Princeton, NJ

609-734-0404

Sympatec@aol.com