Guideline No. 92
Guidance for Industry #92: Impurities In New Veterinary Drug Substances (Revision), VICH GL10 ( R) , Revised Guidance
Revised November 21, 2007
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR VETERINARY MEDICINE
Guidance for Industry
IMPURITIES IN NEW VETERINARY
DRUG SUBSTANCES (Revision)
VICH GL10(R)
REVISED GUIDANCE
Comments and suggestions regarding the document should be submitted to Division of Dockets Management (HFA-305), Food and Drug Administration,
For questions regarding this document, contact Dennis Bensley, Center for Veterinary Medicine, (HFV-143), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-6956, e-mail:dbensley@cvm.fda.gov.
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.
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,
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 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 (
Identification of impurities present at an apparent level of not more than (
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 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 (
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.
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 (
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 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 thresholdTotal 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., 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.
8. Glossary
(The following definitions are presented for the purpose of this Revised Guidance.)
Chemical Development Studies
Enantiomeric Impurity
Extraneous Contaminant
Herbal Products
Identified Impurity
Identification Threshold
Impurity
Impurity Profile
Intermediate
Ligand
New Veterinary Drug Substance
New Veterinary Medicinal Product
Polymorphic Forms
Potential Impurity
Qualification
Qualification Threshold
Reagent
Reporting Threshold:
Solvent:
Specified Impurity
Starting Material
Unidentified Impurity
Unspecified Impurity
Attachment 1: Thresholds
New Veterinary Drug Substance
Identification 2
As per ICH*
Reporting 1,2
As per ICH*
Qualification 2
0.50%
0.20%**
0.10%**
* new veterinary drug substance used in veterinary and human medicine
** new veterinary drug substance not used in human medicine
1
2
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).
Attachment 3: Decision Tree for Identification and Qualification
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?
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