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, (HFV143), 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 

IMPURITIES IN NEW VETERINARY DRUG 

SUBSTANCES (REVISION) 

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

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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. 

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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 

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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 

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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. 

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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 

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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., 

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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. 

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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 nonsuperimposable 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. 

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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. 

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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. 

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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). 

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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 

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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?