From: Peters, Jenny L [R&D/0200] [jenny.l.peters@pharmacia.com]
Sent: Friday, December 27, 2002 9:43 AM
To: 'fdadockets@oc.fda.gov'
Subject: Input re Docket No. 02D-0389; Draft Guidance for Industry on
Nonc linical Studies for Development of Pharmaceutical Excipients

27 December 2002

Dear Sir/Madam,

Please note the following comments from Pharmacia regarding Docket No.
02D-0389 - Draft Guidance for Industry on Nonclinical Studies for
Development of Pharmaceutical Excipients.

We agree the guidance allows flexibility in the approach to toxicological
qualification of new excipients, particularly regarding the use of existing
human and animal data, the feasibility of omitting acute toxicity studies,
and the option of using a single dose level (MTD or MFD) in carcinogenicity
studies conducted with the active ingredient.  Please note the following
questions and comments.

	1.	General: Sometimes sponsors use very small quantities of
novel excipients.  For instance, a new fragrance can contain a well-known
excipient as the main component (e.g., as the solvent), but can also contain
a number of new excipients at small levels. The guidance should address low
levels of excipients.  We propose that dose-related qualification limits are
established in a way similar to, for example, the ICH guidance Q3B.  

	2.	The guidance concerns the pre-clinical documentation
requirements for novel excipients intended for marketing. The choice of
wordings may in some cases lead one to believe the guidance refers to
documentation requirements during the development phases of a new drug
product. In order to avoid ambiguity we suggest that the title of the
Guidance is changed to "Guidance for Industry - Nonclinical Studies for
Marketing of Pharmaceutical Excipients". This is also consistent with the
main header in the document, Line 116-117: "III. RECOMMENDED DEVELOPMENT
STRATEGIES TO SUPPORT MARKETING OF NEW EXCIPIENTS IN DRUG PRODUCTS"

			a)	We would recommend that "Clinical" in the
sub headers B, C and D of section III (Line 128, 174, 197) be removed to
avoid the implication that this refers to controlled clinical studies.
Consequently, to improve clarity, the word "Dosage" could be placed between
"Maximum" and "Duration."

			b)	Line 47: "Safety data should be submitted to
support...". Change to read: "Safety data should be submitted in the market
application to support..."

			c)	Line 91-93: "This guidance describes what
nonclinical data should be submitted to verify...". Change to read: "This
guidance describes what nonclinical data should be submitted in the market
application to verify..."

			d)	Line 91; Because these recommendations for
the battery of nonclinical safety studies needed for excipient qualification
at the time of registration are much in line with those for new drug
development, will the approach to a recommended battery of studies needed to
support use of new excipients during the phases of clinical trials parallel
that recommended for new drugs? 

	3.	Lines 57 and 110; In cases where toxicology data on
excipients are available in published literature but may represent older
studies conducted before the implementation of GLPs, will the agency accept
these study data as part of the NDA safety evaluation package?  We propose
these be accepted.  Alternatively and, of course, consistent with any
intellectual property rights, will the agency identify if they have human or
animal data not in the public realm that support qualification?  This would
be consistent with FDA's commitments to support reduction of the use of
animals and to help decrease the cost of pharmaceutical research.

	4.	Line 110; Typographical error: "exciptients."

	5.	Line 112-113; The safety of the excipients used in the
formulation is normally well documented in placebo-controlled clinical
studies. The term "adequate" is vague; we suggest it could be replaced with
"comparable." In addition, we suggest "experience" be replaced with
"exposure" as "experience" suggests pharmacokinetic data is available.  We
recommend that the guidance also address the expectations of pre-clinical
data in the case when we have clinical data with the excipient, considering
the challenge to reduce unnecessary use of laboratory animals.

	6.	Line 124-126:  Delete last sentence. This is not necessary
considering the intent of this guidance.  Although true, it is too
prescriptive. 

	7.	Line 133; Please define "infrequently used" and include an
example, if possible.

Please do not hesitate to contact me if questions,  Jenny Peters

Jenny L. Peters
Pharmacia
Director, Global Regulatory Affairs
616.833.8141 phone
616.833.0512 fax
jenny.l.peters@pharmacia.com