CVM GFI #92 (VICH GL10(R)) Impurities In New Veterinary Drug Substances

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

92
Guidance for Industry
IMPURITIES IN NEW VETERINARY
DRUG SUBSTANCES (Revision)
VICH GL10(R)
REVISED FINAL GUIDANCE
Comments and suggestions regarding the document should be submitted to Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD
20852. Submit electronic comments to http://www.regulations.gov. All comments should be identified
with the Docket No. 1999D-2215.
For questions regarding this document, contact Dennis Bensley, Center for Veterinary Medicine, (HFV-
143), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 240-276-8268, e-mail:
dennis.bensley@fda.hhs.gov.
Additional copies of this final guidance document may be requested from the Communications Staff
(HFV-12), Center for Veterinary Medicine, Food and Drug Administration, 7519 Standish Place,
Rockville, 	MD 	20855, 	and 	may 	be 	viewed 	on 	the 	Internet 	at
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.ht
m.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Veterinary Medicine
November 26, 2007

VICH GL10 (QUALITY)
September 2007
Revision at Step 9
I MPURITIES IN 	N EW 	V ETERINARY 	D RUG
S UBSTANCES 	(R EVISION )
Revised at Step 9
by the VICH Steering Committee in September 2007
This revised Guidance has been developed by the appropriate VICH Expert Working Group and is subject
to consultation by the parties, in accordance with the VICH Process. At Step 9 of the Process the final
draft will be recommended for adoption to the regulatory bodies of the European Union, Japan and USA.

Contains Non-Binding Recommendations
TABLE OF CONTENTS
1. 	INTRODUCTION 	4
2. 	CLASSIFICATION OF IMPURITIES 	5
3. 	RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES 	5
3.1 	Organic Impurities 	5
3.2 	Inorganic Impurities 	6
3.3 	Solvents 	6
4. 	ANALYTICAL PROCEDURES 	6
5. 	REPORTING IMPURITY CONTENT OF BATCHES 	7
6. 	LISTING OF IMPURITIES IN SPECIFICATIONS 	8
7. 	QUALIFICATION OF IMPURITIES 	9
8. 	GLOSSARY 	11
Attachment 1 - Thresholds 	13
Attachment 2 - Illustration of Reporting Impurity Results for Identification and
Qualification in an Application 	14
Attachment 3 - Decision Tree for Identification and Qualification 	15
3

Contains Non-Binding Recommendations
VICH GL10(R)
Impurities in New Veterinary Drug Substances (Revision)
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on the subject
matter. It does not create or confer any rights for or on any person and does not operate to bind FDA or
the public. 	You can use an alternative approach if the approach satisfies the requirements of the
applicable statute(s) and regulation(s). If you want to discuss an alternative approach, contact the FDA
staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call
the appropriate number listed on the title page of this guidance.
1. 	INTRODUCTION
This document is intended to provide guidance to registration applicants on the content and
qualification of impurities in new veterinary drug substances intended to be used for new
veterinary medicinal products, produced by chemical syntheses and not previously registered in a
country, region, or member state. This guidance does not address new veterinary drug substances
used during the clinical research stage of development. The following types of new veterinary
drug substances are not covered in this guidance: biological/biotechnological, peptide,
oligonucleotide, radiopharmaceutical, fermentation products and semi-synthetic products derived
therefrom, herbal products, and crude products of animal or plant origin.
Impurities in new veterinary drug substances are addressed from two perspectives:
Chemistry Aspects including classification and identification of impurities, report
generation, listing of impurities in specifications, and a brief discussion of analytical
procedures; and
Safety Aspects including specific guidance for qualifying those impurities that were not
present, or were present at substantially lower levels, in batches of a new veterinary drug
substance used in safety and clinical studies.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and
should be viewed only as recommendations, unless specific regulatory or statutory
requirements are cited. The use of the word “should” in Agency guidances means that
something is suggested or recommended, but not required.
4

Contains Non-Binding Recommendations
2. 	CLASSIFICATION OF IMPURITIES
Impurities can be classified into the following categories:
• 	Organic impurities (process- and drug-related)
• 	Inorganic impurities
• 	Residual solvents
Organic impurities can arise during the manufacturing process and/or storage of the new
veterinary drug substance. They can be identified or unidentified, volatile or non-volatile, and
include:
• 	Starting materials
• 	By-products
• 	Intermediates
• 	Degradation products
• 	Reagents, ligands and catalysts
Inorganic impurities can result from the manufacturing process. They are normally known and
identified and include:
• 	Reagents, ligands and catalysts
• 	Heavy metals or other residual metals
• 	Inorganic salts
• 	Other materials (e.g., filter aids, charcoal)
Solvents are inorganic or organic liquids used as vehicles for the preparation of solutions or
suspensions in the synthesis of a new veterinary drug substance. Since these are generally of
known toxicity, the selection of appropriate controls is easily accomplished (see guidance VICH
GL18, Residual Solvents in New Veterinary Medicinal Products, Active Substances and Excipients).
This document does not address: (1) extraneous contaminants that should not occur in new
veterinary drug substances and are more appropriately addressed as Good Manufacturing Practice
(GMP) issues, (2) polymorphic forms, and (3) enantiomeric impurities.
3. 	RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES
3.1 	Organic Impurities
The registration applicant should summarize the actual and potential impurities most likely to
arise during the synthesis, purification, and storage of the new veterinary drug substance. This
summary should be based on sound scientific appraisal of the chemical reactions involved in the
synthesis, impurities associated with raw materials that could contribute to the impurity profile of
the new veterinary drug substance, and possible degradation products. This discussion can be
5

Contains Non-Binding Recommendations
limited to those impurities that might reasonably be expected based on knowledge of the
chemical reactions and conditions involved.
In addition, the registration applicant should summarize the laboratory studies conducted to
detect impurities in the new veterinary drug substance. This summary should include test results
of batches manufactured during the development process and batches from the proposed
commercial process, as well as the results of stress testing (see guidance VICH GL3, Stability
Testing of New Veterinary Drug Substances and Medicinal Products) used to identify potential
impurities arising during storage. The impurity profile of the new veterinary drug substance
batches intended for marketing should be compared with those used in development and any
differences discussed.
The studies conducted to characterize the structure of actual impurities present in the new
veterinary drug substance at a level greater than (>) the identification threshold given in
Attachment 1 (e.g., calculated using the response factor of the new veterinary drug substance)
should be described. Note that any impurity at a level greater than (>) the identification threshold
in any batch manufactured by the proposed commercial process should be identified. In addition,
any degradation product observed in stability studies at recommended storage conditions at a
level greater than (>) the identification threshold should be identified. When identification of an
impurity is not feasible, a summary of the laboratory studies demonstrating the unsuccessful
effort should be included in the application. Where attempts have been made to identify
impurities present at levels of not more than (≤) the identification thresholds, it is useful also to
report the results of these studies.
Identification of impurities present at an apparent level of not more than (≤) the identification
threshold is generally not considered necessary. However, analytical procedures should be
developed for those potential impurities that are expected to be unusually potent, producing toxic
or pharmacological effects at a level not more than (≤) the identification threshold. All impurities
should be qualified as described later in this guidance.
3.2 	Inorganic Impurities
Inorganic impurities are normally detected and quantified using pharmacopoeial or other
appropriate procedures. Carry-over of catalysts to the new veterinary drug substance should be
evaluated during development. The need for inclusion or exclusion of inorganic impurities in the
new veterinary drug substance specification should be discussed. Acceptance criteria should be
based on pharmacopoeial standards or known safety data.
3.3 	Solvents
The control of residues of the solvents used in the manufacturing process for the new veterinary
drug substance should be discussed and presented (see guidance VICH GL18 for Residual
Solvents).
4. 	ANALYTICAL PROCEDURES
The registration application should include documented evidence that the analytical procedures
are validated and suitable for the detection and quantification of impurities (see guidances VICH
GL1 and GL2 for Analytical Validation). Technical factors (e.g., manufacturing capability and
6

Contains Non-Binding Recommendations
control methodology) can be considered as part of the justification for selection of alternative
thresholds based on manufacturing experience with the proposed commercial process. The use of
two decimal places for thresholds does not necessarily reflect the precision of the analytical
procedure used for routine quality control purposes. Thus, the use of lower precision techniques
(e.g., thin-layer chromatography) can be acceptable where justified and appropriately validated.
Differences in the analytical procedures used during development and those proposed for the
commercial product should be discussed in the registration application.
The quantitation limit for the analytical procedure should be not more than (≤) the reporting
threshold (see Attachment 1).
Organic impurity levels can be measured by a variety of techniques, including those that compare
an analytical response for an impurity to that of an appropriate reference standard or to the
response of the new veterinary drug substance itself. Reference standards used in the analytical
procedures for control of impurities should be evaluated and characterized according to their
intended uses. The new veterinary drug substance can be used as a standard to estimate the levels
of impurities. In cases where the response factors of the new veterinary drug substance and the
relevant impurity are not close, this practice can still be appropriate, provided a correction factor
is applied or the impurities are, in fact, being overestimated. Acceptance criteria and analytical
procedures used to estimate identified or unidentified impurities can be based on analytical
assumptions (e.g., equivalent detector response). These assumptions should be discussed in the
registration application.
5. 	REPORTING IMPURITY CONTENT OF BATCHES
Analytical results should be provided in the application for all batches of the new veterinary drug
substance used for clinical, safety, and stability testing, as well as for batches representative of
the proposed commercial process. Quantitative results should be presented numerically as
opposed to in general terms such as “complies,” “meets limit,” etc. Any impurity at a level
greater than (>) the reporting threshold (see Attachment 1) and total impurities observed in these
batches of the new veterinary drug substance should be reported with the analytical procedures
indicated. Below 1.0%, the results should be reported to two decimal places (e.g., 0.06%, 0.13%);
at and above 1.0%, the results should be reported to one decimal place (e.g., 1.3%). Results
should be rounded using conventional rules (see Attachment 2). A tabulation (e.g., spreadsheet)
of the data is recommended. Impurities should be designated by code number or by an
appropriate descriptor, e.g., retention time. If a higher reporting threshold is proposed, it should
be fully justified. All impurities at a level greater than (>) the reporting threshold should be
summed and reported as total impurities.
When analytical procedures change during development, reported results should be linked to the
procedure used, with appropriate validation information provided. Representative chromatograms
should be provided. Chromatograms of representative batches from analytical validation studies
showing separation and detectability of impurities (e.g., on spiked samples), along with any other
impurity tests routinely performed, can serve as the representative impurity profiles. The
applicant should ensure that complete impurity profiles (e.g., chromatograms) of individual
batches are available, if requested.
7

Contains Non-Binding Recommendations
A tabulation should be provided that links the specific new veterinary drug substance batch to
each safety study and each clinical study in which the new veterinary drug substance has been
used.
For each batch of the new veterinary drug substance, the report should include:
• 	Batch identity and size
• 	Date of manufacture
• 	Site of manufacture
• 	Manufacturing process
• 	Impurity content, individual and total
• 	Use of batches
• 	Reference to analytical procedure used
6. 	LISTING OF IMPURITIES IN SPECIFICATIONS
The specification for a new veterinary drug substance should include a list of impurities. Stability
studies, chemical development studies, and routine batch analyses can be used to predict those
impurities likely to occur in the commercial product. The selection of impurities in the new
veterinary drug substance specification should be based on the impurities found in batches
manufactured by the proposed commercial process. Those individual impurities with specific
acceptance criteria included in the specification for the new veterinary drug substance are
referred to as "specified impurities" in this guidance. Specified impurities can be identified or
unidentified.
A rationale for the inclusion or exclusion of impurities in the specification should be presented.
This rationale should include a discussion of the impurity profiles observed in the safety and
clinical development batches, together with a consideration of the impurity profile of batches
manufactured by the proposed commercial process. Specified identified impurities should be
included along with specified unidentified impurities estimated to be present at a level greater
than (>) the identification threshold given in Attachment 1. For impurities known to be unusually
potent or to produce toxic or unexpected pharmacological effects, the quantitation/detection limit
of the analytical procedures should be commensurate with the level at which the impurities
should be controlled. For unidentified impurities, the procedure used and assumptions made in
establishing the level of the impurity should be clearly stated. Specified, unidentified impurities
should be referred to by an appropriate qualitative analytical descriptive label (e.g., “unidentified
A", “unidentified with relative retention of 0.9”). A general acceptance criterion of not more than
(≤) the identification threshold (Attachment 1) for any unspecified impurity and an acceptance
criterion for total impurities should be included.
Acceptance criteria should be set no higher than the level that can be justified by safety data, and
should be consistent with the level achievable by the manufacturing process and the analytical
capability. Where there is no safety concern, impurity acceptance criteria should be based on data
generated on batches of the new veterinary drug substance manufactured by the proposed
commercial 	process, 	allowing 	sufficient 	latitude 	to 	deal 	with 	normal 	manufacturing 	and
8

Contains Non-Binding Recommendations
analytical variation and the stability characteristics of the new veterinary drug substance.
Although normal manufacturing variations are expected, significant variation in batch-to-batch
impurity levels can indicate that the manufacturing process of the new veterinary drug substance
is not adequately controlled and validated (see guidance VICH GL39 on Specifications and
Decision Tree #1 for establishing an acceptance criterion for a specified impurity in a new
veterinary drug substance). The use of two decimal places for thresholds does not necessarily
indicate the precision of the acceptance criteria for specified impurities and total impurities.
In summary, the new veterinary drug substance specification should include, where applicable,
the following list of impurities:
Organic Impurities
• 	Each specified identified impurity
• 	Each specified unidentified impurity
• 	Any unspecified impurity with an acceptance criterion of not more than (≤) the
identification threshold
• 	Total impurities
Residual Solvents
Inorganic Impurities
7. 	QUALIFICATION OF IMPURITIES
Qualification is the process of acquiring and evaluating data that establishes the biological safety
of an individual impurity or a given impurity profile at the level(s) specified. The applicant
should provide a rationale for establishing impurity acceptance criteria that includes safety
considerations. The level of any impurity present in a new veterinary drug substance that has
been adequately tested in safety and/or clinical studies would be considered qualified. Impurities
that are also significant metabolites present in animal and/or human studies are generally
considered qualified. A level of a qualified impurity higher than that present in a new veterinary
drug substance can also be justified based on an analysis of the actual amount of impurity
administered in previous relevant safety studies.
If data are unavailable to qualify the proposed acceptance criterion of an impurity, studies to
obtain such data can be appropriate when the usual qualification thresholds given in Attachment
1 are exceeded.
Higher or lower thresholds for qualification of impurities can be appropriate for some individual
drugs based on scientific rationale and level of concern, including drug class effects and clinical
experience. For example, qualification can be especially important when there is evidence that
such impurities in certain drugs or therapeutic classes have previously been associated with
adverse 	reactions 	in 	animals. 	In 	these 	instances, 	a 	lower 	qualification 	threshold 	can 	be
appropriate. Conversely, a higher qualification threshold can be appropriate for individual drugs
when the level of concern for safety is less than usual based on similar considerations (e.g.,
9

Contains Non-Binding Recommendations
animal species, drug class effects, clinical considerations). Proposals for alternative thresholds
would be considered on a case-by-case basis.
The "Decision Tree for Identification and Qualification" (Attachment 3) describes considerations
for the qualification of impurities when thresholds are exceeded. In some cases, decreasing the
level of impurity to not more than the threshold can be simpler than providing safety data.
Alternatively, adequate data could be available in the scientific literature to qualify an impurity.
If neither is the case, additional safety testing should be considered. The studies considered
appropriate to qualify an impurity will depend on a number of factors, including the animal
species, daily dose, and route and duration of drug administration. Such studies can be conducted
on the new veterinary drug substance containing the impurities to be controlled, although studies
using isolated impurities can sometimes be appropriate.
Although this guidance does not address the clinical research stage of development, in the later
stages of development the thresholds in this guidance can be useful in evaluating new impurities
observed in the new veterinary drug substance batches prepared by the proposed commercial
process. 	Any new impurity observed in later stages of development should be identified if its
level is greater than (>) the identification threshold given in Attachment 1 (see the “Decision
Tree for Identification and Qualification” in Attachment 3). 	Similarly, the qualification of the
impurity should be considered if its level is greater than (>) the qualification threshold given in
Attachment 1. Safety assessment studies to qualify an impurity should compare the new
veterinary 	drug 	substance 	containing 	a 	representative 	amount 	of 	the 	new 	impurity 	with
previously qualified material. Safety assessment studies using a sample of the isolated impurity
can also be considered.
10

Contains Non-Binding Recommendations
8. 	GLOSSARY
(The following definitions are presented for the purpose of this Revised Guidance.)
Chemical Development Studies: Studies conducted to scale-up, optimize, and validate the
manufacturing process for a new veterinary drug substance.
Degradation Product: An impurity resulting from a chemical change in the drug substance
brought about during its manufacture and/or storage by the effect of, for example, light,
temperature, pH or water.
Enantiomeric Impurity: 	A compound with the same molecular formula as the new veterinary
drug substance that differs in the spatial arrangement of atoms within the molecule and is a non-
superimposable mirror image.
Extraneous 	Contaminant: 	An 	impurity 	arising 	from 	any 	source 	extraneous 	to 	the
manufacturing process.
Herbal Products: 	Medicinal products containing, exclusively, plant material and/or vegetable
drug preparations as active ingredients. In some traditions, materials of inorganic or animal origin
can also be present.
Identified Impurity: An impurity for which a structural characterization has been achieved.
Identification Threshold: A limit above (>) which an impurity should be identified.
Impurity: 	Any component of the new veterinary drug substance that is not the chemical entity
defined as the new veterinary drug substance.
Impurity Profile: 	A description of the identified and unidentified impurities present in a new
veterinary drug substance.
Intermediate: 	A material produced during steps of the synthesis of a new veterinary drug
substance that undergoes further chemical transformation before it becomes a new veterinary
drug substance.
Ligand: An agent with a strong affinity to a metal ion.
New Veterinary Drug Substance: 	The designated therapeutic moiety that has not been
previously registered in a region or member state in a veterinary medicinal product (also referred
to as a new molecular entity or new chemical entity). It can be a complex, simple ester, or salt of
a previously approved drug substance.
New Veterinary Medicinal Product: 	A pharmaceutical product type, for example, tablet,
capsule, solution, cream, etc., containing a new or existing drug substance which has not
previously been registered in a region or member state, and which contains a drug ingredient
generally, but not necessarily, in association with excipients.
Polymorphic Forms: 	Different crystalline forms of the same new veterinary drug substance.
These can include solvation or hydration products (also known as pseudo-polymorphs) and
amorphous forms.
11

Contains Non-Binding Recommendations
Potential Impurity: 	An impurity that theoretically can arise during manufacture or storage. It
may or may not actually appear in the new veterinary drug substance.
Qualification: The process of acquiring and evaluating data that establishes the biological safety
of an individual impurity or a given impurity profile at the level(s) specified.
Qualification Threshold: A limit above (>) which an impurity should be qualified.
Reagent: 	A substance other than a starting material, intermediate, or solvent that is used in the
manufacture of a new veterinary drug substance.
Reporting Threshold: A limit above (>) which an impurity should be reported. Reporting
threshold is the same as reporting level in VICH GL2, Guidance on Validation of Analytical
Procedures.
Solvent: An inorganic or an organic liquid used as a vehicle for the preparation of solutions or
suspensions in the synthesis of a new veterinary drug substance.
Specified Impurity: 	An impurity that is individually listed and limited with a specific
acceptance criterion in the new veterinary drug substance specification. A specified impurity can
be either identified or unidentified.
Starting Material: 	A material used in the synthesis of a new veterinary drug substance that is
incorporated as an element into the structure of an intermediate and/or of the new veterinary drug
substance. Starting materials are normally commercially available and of defined chemical and
physical properties and structure.
Unidentified Impurity: 	An impurity for which a structural characterization has not been
achieved and that is defined solely by qualitative analytical properties (e.g., chromatographic
retention time).
Unspecified Impurity: An impurity that is limited by a general acceptance criterion, but not
individually listed with its own specific acceptance criterion, in the new veterinary drug
substance specification.
12

Contains Non-Binding Recommendations
Attachment 1: Thresholds
New Veterinary Drug Substance
Identification 2 As per ICH*
0.20%**
Reporting 1,2 As per ICH*
0.10%**
Qualification 2 0.50%
* new veterinary drug substance used in veterinary and human medicine
** new veterinary drug substance not used in human medicine
________________________
1 Higher reporting thresholds should be scientifically justified.
2 Lower thresholds can be appropriate if the impurity is unusually toxic.
13

Contains Non-Binding Recommendations
Attachment 	2: 	Illustration 	of 	Reporting 	Impurity 	Results 	for 	Identification 	and
Qualification 	in 	an 	Application 	(substances 	used 	in 	veterinary 	medicine 	only 	(see
attachment 1); for substances used in human and veterinary medicine see also relevant ICH
guidance)
‘Raw’ Result 	Reported Result 	Action
(%) 	(%) 	Identification
(Threshold 0.20%)
Qualification
(Threshold 0.50%)
0.166 	0.17 	None 	None
0.1963 	0.20 	None 	None
0.22 	0.22* 	Yes 	None
0.649 	0.65* 	Yes 	Yes*
* * After identification, if the response factor is determined to differ significantly from the
original assumptions, it may be appropriate to re-measure the actual amount of the impurity
present and re-evaluate against the qualification threshold (see Attachment 1).
14

Contains Non-Binding Recommendations
Attachment 3: Decision Tree for Identification and Qualification
Is impurity greater
than identification
thresholdc
?
Yes
No
Consider animal species, duration of use and
consider conducting:
• 	Genotoxicity 	studies 	(point 	mutation,
chromosomal aberration)a
• 	General toxicity studies (one species, usually
14 to 90 days)b
• 	Other 	specific 	toxicity 	endpoints, 	as
appropriate
Yes 	No No action
Yes
Yes
No
Structure
identified?
Reduce to safe level or
remove impurity or
conduct additional
safety studies
Any
clinically
relevant adverse
effects?
No
No action
No
Greater
than qualification
thresholdc
?
Yes
Reduce to
safe level
No
Reduce
to not more than
(≤) identification
thresholdc
?
Reduce
to not more than
(≤) qualification
thresholdc
?
No further
action
Yes
No
Yes
Toxicity documented
and sufficient/acceptable
justification for relation to
other substances with known
toxicity?
Any
known human
or animal
relevant risksd?
Qualified
Yes
No
15

Contains Non-Binding Recommendations
16
Notes on Attachment 3
a) 	If considered desirable, a minimum screen (e.g., genotoxic potential), should be conducted.
A study to detect point mutations and one to detect chromosomal aberrations, both in vitro,
are considered an appropriate minimum screen.
b) 	If general toxicity studies are desirable, one or more studies should be designed to allow
comparison of unqualified to qualified material. 	The study duration should be based on
available relevant information and performed in the species most likely to maximise the
potential to detect the toxicity of an impurity. On a case-by-case basis, single-dose studies
can be appropriate, especially for single-dose drugs. In general, a minimum duration of 14
days and a maximum duration of 90 days would be considered appropriate.
c) 	Lower thresholds can be appropriate if the impurity is unusually toxic.
d) 	For example, do known safety data for this impurity or its structural class preclude human
or animal exposure at the concentration present?