176 
 
Guidance for Industry  
 
 
Specifications: Test Procedures And Acceptance 
Criteria For New Veterinary Drug Substances And New 
Medicinal Products: Chemical Substances 
VICH GL39 
 
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. 2005D-0199.   
 
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 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/ucm04
2450.htm 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine 
June 14, 2006 
 
  Contains Non-Binding Recommendations 
 
 
VICH GL39 (QUALITY) 
November 2005 
For Implementation at Step 7 
 
 
 
 
 
 
S : T P
PECIFICATIONS   EST  ROCEDURES AND 
A C
CCEPTANCE  RITERIA FOR NEW 
V
ETERINARY DRUG SUBSTANCES AND NEW 
M P : C
EDICINAL  RODUCTS   HEMICAL 
S  
UBSTANCES 
 
 
Recommended for Adoption 
at Step 7 of the VICH Process 
in November 2005 by the VICH SC  
for implementation in November 2006 
 
 
 
 
 
 
 
This 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 7 of the Process the final draft will 
be recommended for adoption to the regulatory bodies of the European Union, Japan and USA. 
  - 2 - Contains Non-Binding Recommendations 
 
 
SPECIFICATIONS: TEST PROCEDURES AND ACCEPTANCE CRITERIA 
FOR NEW VETERINARY DRUG SUBSTANCES AND NEW MEDICINAL 
PRODUCTS: 
CHEMICAL SUBSTANCES 
 
VICH Harmonized Tripartite Guidance 
 
TABLE OF CONTENTS 
1.   INTRODUCTION.......................................................................... 5 
  1.1   Objective of the Guidance 
  1.2   Background .......................................................................................5 
  1.3 Scope of the Guidance 
2.   GENERAL CONCEPTS..................................................................  6 
  2.1 Periodic or Skip Testing ........................................................... 6 
  2.2 Release vs. Shelf-life Acceptance Criteria ................................... 6 
  2.3 In-process Tests..................................................................... 7 
  2.4 Design and Development Considerations.................................... 7 
  2.5 Limited Data Available at Filing................................................. 7 
  2.6 Parametric Release ................................................................. 7 
  2.7 Alternative Procedures............................................................. 8 
  2.8 Pharmacopoeial Tests and Acceptance Criteria ............................ 8 
  2.9 Evolving Technologies.............................................................. 8 
  2.10 Impact of Drug Substance on Medicinal Product Specifications..... 8 
  2.11 Reference Standard............................................................... 8 
3.  GUIDANCES  .......................................................................................8 
  3.1   Specifications: Definition and Justification .................... 8 
     3.1.1  Definition of Specifications......................................... 9 
     3.1.2  Justification of Specifications...................................... 9 
  3.2 Universal Tests / Criteria.......................................................... 9 
     3.2.1  New Drug Substances ............................................... 9 
     3.2.2  New Medicinal Products ........................................... 10 
  - 3 - Contains Non-Binding Recommendations 
 
 
  3.3 Specific Tests / Criteria.......................................................... 11 
     3.3.1  New Drug Substances ............................................. 11 
     3.3.2  New Medicinal Products ............................................13 
 
4.   GLOSSARY  ............................................................................. 19 
 
5.   REFERENCES
 .......................................................................................21 
 
6.   ATTACHMENTS: Decision Trees #1 Through #8........................ 22 
 
 
 
 
  - 4 - Contains Non-Binding Recommendations 
 
SPECIFICATIONS: TEST PROCEDURES AND ACCEPTANCE CRITERIA 
FOR NEW VETERINARY DRUG SUBSTANCES AND NEW MEDICINAL 
PRODUCTS:  CHEMICAL SUBSTANCES 
 
This guidance respresents the Food and Drug Administrations (FDAs) current thinking on this topic.  
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 statutes and regulations.  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 
1.1 Objective of the Guidance 
This guidance is intended to assist to the extent possible, in the establishment of a single 
set of global specifications for new veterinary drug substances and medicinal products. It 
provides guidance on the setting and justification of acceptance criteria and the selection 
of test procedures for new drug substances of synthetic chemical origin, and new 
medicinal products produced from them, which have not been registered previously in the 
United States, the European Union, or Japan. 
 
FDAs guidance documents, including this guidance, do not establish legally 
enforceable responsibilities.  Instead, guidances describe the Agencys 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. 
 
1.2  Background 
A specification is defined as a list of tests, references to analytical procedures, and 
appropriate acceptance criteria which are numerical limits, ranges, or other criteria for the 
tests described. It establishes the set of criteria to which a drug substance or medicinal 
product should conform to be considered acceptable for its intended use. "Conformance 
to specifications" means that the drug substance and/or medicinal product, when tested 
according to the listed analytical procedures, will meet the listed acceptance criteria.  
Specifications are critical quality standards that are proposed and justified by the 
manufacturer and approved by regulatory authorities as conditions of approval.  
 
Specifications are one part of a total control strategy for the drug substance and medicinal 
product designed to ensure product quality and consistency. Other parts of this strategy 
include thorough product characterization during development, upon which specifications 
are based, and adherence to Good Manufacturing Practices (GMPs); e.g., suitable 
facilities, a validated manufacturing process, validated test procedure, raw material 
testing, in-process testing, stability testing, etc. 
 
Specifications are chosen to confirm the quality of the drug substance and medicinal 
product rather than to establish full characterization, and should focus on those 
characteristics found to be useful in ensuring the safety and efficacy of the drug substance 
and medicinal product. 
 
1.3 Scope of the Guidance 
The quality of drug substances and medicinal products is determined by their design, 
development, in-process controls, GMP controls, and process validation, and by 
-- 5  -- Contains Non-Binding Recommendations 
 
specifications applied to them throughout development and manufacture. This guidance 
addresses specifications, i.e., those tests, procedures, and acceptance criteria which play 
a major role in assuring the quality of the new veterinary drug substance and medicinal 
product at release and during shelf life. Specifications are an important component of 
quality assurance, but are not its only component. All of the considerations listed above 
are important to ensure consistent production of drug substances and medicinal products 
of high quality. 
This guidance addresses only the marketing approval of new medicinal products 
(including combination products) and, where applicable, new drug substances; it does not 
address drug substances or medicinal products during the clinical research stages of drug 
development.  This guidance may be applicable to synthetic and semi-synthetic antibiotics 
and synthetic peptides of low molecular weight; however, it is not sufficient to adequately 
describe specifications of higher molecular weight peptides and polypeptides, and 
biotechnological/biological products. The draft VICH GL10 Guidance Specifications: Test 
Procedures and Acceptance Criteria for New Biotechnological/Biological Veterinary 
Products addresses guidance specifications, tests and procedures for 
biotechnological/biological products. Radiopharmaceuticals, products of fermentation, 
oligonucleotides, herbal products and crude products of animal or plant origin are similarly 
not covered.  
 
Guidance is provided with regard to acceptance criteria which should be established for all 
new drug substances and new medicinal products, i.e. universal acceptance criteria, and 
those that are considered specific to individual drug substances and/or dosage forms. 
This guidance should not be considered all encompassing.  New analytical technologies, 
and modifications to existing technology, are continually being developed.  Such 
technologies should be used when justified. 
Dosage forms addressed in this guidance include solid oral dosage forms, powders, liquid 
oral dosage forms, and parenterals (small and large volume). This is not meant to be an 
all-inclusive list, or to limit the number of dosage forms to which this guidance applies. The 
dosage forms presented serve as models, which may be applicable to other dosage forms 
which have not been discussed. The extended application of the concepts in this guidance 
to other dosage forms, e.g., to topical formulations (pour-on, spot-on, creams, ointments, 
gels) is encouraged.  
2.  GENERAL CONCEPTS 
The following concepts are important in the development and setting of harmonized 
specifications. They are not universally applicable, but each should be considered in 
particular circumstances. This guidance presents a brief definition of each concept and an 
indication of the circumstances under which it may be applicable. Generally, proposals to 
implement these concepts should be justified by the applicant and approved by the 
appropriate regulatory authority before being put into effect according to 21 CFR 
514.1(b)(5). 
2.1 Periodic or Skip Testing 
Periodic or skip testing is the performance of specified tests at release on pre-selected 
batches and/or at predetermined intervals, rather than on a batch-to-batch basis with the 
understanding that those batches not being tested still meet all acceptance criteria 
established for that product. This represents a less than full schedule of testing and 
should therefore be justified and presented to and approved by the regulatory authority 
prior to implementation.  This concept may be applicable to, for example, residual solvents 
and microbiological testing, for solid oral dosage forms.  It is recognized that only limited 
data may be available at the time of submission of an application (see section 2.5). This 
concept should therefore generally be implemented post-approval.  When tested, any 
failure to meet acceptance criteria established for the periodic test should be handled by 
proper notification of the appropriate regulatory authority(ies).  If these data demonstrate a 
need to restore routine testing, then batch by batch release testing should be reinstated. 
- 6 -  Contains Non-Binding Recommendations 
 
 
2.2 Release vs. Shelf-life Acceptance Criteria 
The concept of different acceptance criteria for release vs. shelf-life specifications applies 
to medicinal products only; it pertains to the establishment of more restrictive criteria for 
the release of a medicinal product than are applied to the shelf-life. Examples where this 
may be applicable include assay and impurity (degradation product) levels.  In some 
regions, the concept of release limits may only be applicable to in-house limits and not to 
the regulatory shelf-life limits.   Thus, in these regions, the regulatory acceptance criteria 
are the same from release throughout shelf-life; however, an applicant may choose to 
have tighter in-house limits at the time of release to provide increased assurance to the 
applicant that the product will remain within the regulatory acceptance criterion throughout 
its shelf-life.  In the European Union, there is a regulatory requirement for distinct 
specifications for release and for shelf-life where different. 
 
2.3 In-process Tests 
In-process tests, as presented in this guidance, are tests which may be performed during 
the manufacture of either the drug substance or medicinal product, rather than as part of 
the formal battery of tests which are conducted prior to release. 
 
In-process tests which are only used for the purpose of adjusting process parameters 
within an operating range, e.g., hardness and friability of tablet cores which will be coated 
and individual tablet weights, are not included in the specification. 
 
Certain tests conducted during the manufacturing process, where the acceptance criterion 
is identical to or tighter than the release requirement, (e.g., pH of a solution) may be 
sufficient to satisfy specification requirements when the test is included in the 
specification.  However, this approach should be validated to show that test results or 
product performance characteristics do not change from the in-process stage to finished 
product. 
 
2.4 Design and Development Considerations 
The experience and data accumulated during the development of a new drug substance 
or product should form the basis for the setting of specifications. It may be possible to 
propose excluding or replacing certain tests on this basis. Some examples are:   
  microbiological testing for drug substances and solid dosage forms which have 
been shown during development not to support microbial viability or growth 
(see Decision Trees #6 and #8). 
  extractables from product containers where it has been reproducibly shown that 
either no extractables are found in the medicinal product or the levels meet 
accepted standards for safety. 
  particle size testing may fall into this category, may be performed as an in-process 
test, or may be performed as a release test, depending on its relevance to product 
performance. 
  dissolution testing for immediate release solid oral medicinal products made from 
highly water soluble drug substances may be replaced by disintegration testing, if 
these products have been demonstrated during development to have consistently 
rapid drug release characteristics (see Decision Trees #7(1) and #7(2)). 
 
 
2.5  Limited Data Available at Filing 
 
- 7 -  Contains Non-Binding Recommendations 
 
It is recognized that only a limited amount of data may be available at the time of filing, 
which can influence the process of setting acceptance criteria. As a result it may be 
important to propose revised acceptance criteria as additional experience is gained with 
the manufacture of a particular drug substance or drug product (example: acceptance 
limits for a specific impurity). The basis for the acceptance criteria at the time of filing 
should necessarily focus on safety and efficacy. 
 
When only limited data are available, the initially approved tests and acceptance criteria 
should be reviewed as more information is collected, with a view towards possible 
modification. This could involve loosening, as well as tightening, acceptance criteria as 
appropriate. 
 
2.6 Parametric Release 
Parametric release can be used as an operational alternative to routine release testing for 
the medicinal product in certain cases when approved by the regulatory authority (see 21 
CFR 514.1(b)(5)). Sterility testing for terminally sterilized medicinal products is one 
example. In this case, the release of each batch is based on satisfactory results from 
monitoring specific parameters, e.g., temperature, pressure, and time during the terminal 
sterilization phase(s) of medicinal product manufacturing. These parameters can generally 
be more accurately controlled and measured, so that they are more reliable in predicting 
sterility assurance than is end-product sterility testing.  Appropriate laboratory tests (e.g., 
chemical or physical indicator) may be included in the parametric release program.  It is 
important to note that the sterilization process should be adequately validated before 
parametric release is proposed and maintenance of a validated state should be 
demonstrated by revalidation at established intervals. When parametric release is 
performed, the attribute which is indirectly controlled (e.g., sterility), together with a 
reference to the associated test procedure, still should be included in the specifications. 
 
2.7 Alternative Procedures 
Alternative procedures are those which may be used to measure an attribute when such 
procedures control the quality of the drug substance or medicinal product to an extent that 
is comparable or superior to the official procedure.  
 
2.8 Pharmacopoeial Tests and Acceptance Criteria 
References to certain procedures are found in pharmacopoeias in each region.  Wherever 
they are appropriate, pharmacopoeial procedures should be utilized.  Whereas differences 
in pharmacopoeial procedures and/or acceptance criteria have existed among the 
regions, a harmonized specification is possible only if the procedures and acceptance 
criteria defined are acceptable to regulatory authorities in all regions. 
 
The full utility of this Guidance is dependent on the successful completion of 
harmonization of pharmacopoeial procedures for several attributes commonly considered 
in the specification for new drug substances or new medicinal products.  The 
Pharmacopoeial Discussion Group (PDG) of the European Pharmacopoeia, the Japanese 
Pharmacopoeia (JP), and the United States Pharmacopeia has expressed a commitment 
to achieving harmonization of the procedures in a timely fashion. 
 
Where harmonization has been achieved, an appropriate reference to the harmonized 
procedure and acceptance criteria is considered acceptable for a specification in all three 
regions.  For example, after harmonization, sterility data generated using the JP 
procedure, as well as the JP procedure itself and its acceptance criteria, are considered 
acceptable for registration in all three regions.  To signify the harmonized status of these 
- 8 -  Contains Non-Binding Recommendations 
 
procedures, the pharmacopoeias have agreed to include a statement in their respective 
texts which indicates that the procedures and acceptance criteria from all three 
pharmacopoeias are considered equivalent and are, therefore, interchangeable. 
 
Since the overall value of this Guidance is linked to the extent of harmonization of the 
analytical procedures and acceptance criteria of the pharmacopoeias, none of the three 
pharmacopoeias should change a harmonized monograph unilaterally.  According to the 
PDG procedure for the revision of harmonized monographs and chapters, no 
pharmacopoeia shall revise unilaterally any monograph or chapter after sign-off or after 
publication. 
 
2.9 Evolving Technologies 
New analytical technologies, and modifications to existing technology, are continually 
being developed. Such technologies should be used when they are considered to offer 
additional assurance of quality, or are otherwise justified. 
2.10  Impact of Drug Substance on Medicinal Product Specifications 
In general, it should not be important to test the medicinal product for quality attributes 
uniquely associated with the drug substance. Example: it is normally not considered 
important to test the medicinal product for synthesis impurities which are controlled in the 
drug substance and are not degradation products. Refer to the VICH GL 11 Guidance 
Impurities in New Veterinary Medicinal Products, for detailed information. 
 
2.11  Reference Standard 
A reference standard, or reference material, is a substance prepared for use as the 
standard in an assay, identification, or purity test.  It should have a quality appropriate to 
its use. It is often characterized and evaluated for its intended purpose by additional 
procedures other than those used in routine testing.  For new drug substance reference 
standards intended for use in assays, the impurities should be adequately identified 
and/or controlled, and purity should be measured by a quantitative procedure.  
 
3.  GUIDANCES 
3.1 Specifications: Definition and Justification 
3.1.1  Definition of Specifications 
A specification is defined as a list of tests, references to analytical procedures, and 
appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the 
tests described. It establishes the set of criteria to which a new drug substance or new 
medicinal product should conform to be considered acceptable for its intended use. 
"Conformance to specifications" means that the drug substance and/or medicinal product, 
when tested according to the listed analytical procedures, will meet the listed acceptance 
criteria. Specifications are critical quality standards that are proposed and justified by the 
manufacturer and approved by regulatory authorities as conditions of approval. 
 
It is possible that, in addition to release tests, a specification may list in-process tests as 
defined in 2.3, periodic (skip) tests, and other tests which are not always conducted on a 
batch-by-batch basis. In such cases the applicant should specify which tests are routinely 
conducted batch-by-batch, and which tests are not, with an indication and justification of 
the actual testing frequency. In this situation, the drug substance and/or medicinal product 
should meet the acceptance criteria if tested. 
 
It should be noted that changes in the specification after approval of the application may 
need prior approval by the regulatory authority (see 21 CFR 514.8) 
- 9 -  Contains Non-Binding Recommendations 
 
 
3.1.2  Justification of Specifications 
When a specification is first proposed, justification should be presented for each 
procedure and each acceptance criterion included. The justification should refer to 
relevant development data, pharmacopoeial standards, test data for drug substances and 
medicinal products used in toxicology, residue (when relevant) and clinical studies, and 
results from accelerated and long term stability studies, as appropriate. Additionally, a 
reasonable range of expected analytical and manufacturing variability should be 
considered. It is important to consider all of this information. 
 
Approaches other than those set forth in this guidance may be applicable and acceptable. 
The applicant should justify alternative approaches. Such justification should be based on 
data derived from the new drug substance synthesis and/or the new medicinal product 
manufacturing process. This justification may consider theoretical tolerances for a given 
procedure or acceptance criterion, but the actual results obtained should form the primary 
basis for whatever approach is taken. 
 
Test results from stability and scale-up/validation batches, with emphasis on the primary 
stability batches, should be considered in setting and justifying specifications. If multiple 
manufacturing sites are planned, it may be valuable to consider data from these sites in 
establishing the initial tests and acceptance criteria. This is particularly true when there is 
limited initial experience with the manufacture of the drug substance or medicinal product 
at any particular site. If data from a single representative manufacturing site are used in 
setting tests and acceptance criteria, product manufactured at all sites should still comply 
with these criteria (see 21 CFR 514.1(b)(5)).  
 
Presentation of test results in graphic format may be helpful in justifying individual 
acceptance criteria, particularly for assay values and impurity levels. Data from 
development work should be included in such a presentation, along with stability data 
available for new drug substance or new medicinal product batches manufactured by the 
proposed commercial processes. Justification for proposing exclusion of a test from the 
specification should be based on development data and on process validation data (where 
appropriate). 
 
3.2 Universal Tests / Criteria  
Implementation of the recommendations in the following section should take into account 
the VICH GL 1 and 2 Guidances Validation of Analytical Procedures: Definition and 
Terminology and Validation of Analytical Procedures: Methodology. 
3.2.1  New Drug Substances 
The following tests and acceptance criteria are considered generally applicable to all new 
drug substances. 
 
a) Description: a qualitative statement about the state (e.g. solid, liquid) and color of the 
new drug substance. If any of these characteristics change during storage, this change 
should be investigated and appropriate action taken.  
 
b) Identification: identification testing should optimally be able to discriminate between 
compounds of closely related structure which are likely to be present. Identification tests 
should be specific for the new drug substance, e.g., infrared spectroscopy. Identification 
solely by a single chromatographic retention time, for example, is not regarded as being 
specific.  However, the use of two chromatographic procedures, where the separation is 
based on different principles or a combination of tests into a single procedure, such as 
HPLC/UV diode array, HPLC/MS, or GC/MS is generally acceptable.  If the new drug 
- 10 -  Contains Non-Binding Recommendations 
 
substance is a salt, identification testing should be specific for the individual ions.  An 
identification test that is specific for the salt itself should suffice.  Identification should be 
retained in the specification; however testing during a stability study is not recommended 
unless the identification test is stability indicating. 
 
New drug substances which are optically active may also call for specific identification 
testing or performance of a chiral assay.  Please refer to 3.3.1.d in this Guidance for 
further discussion of this topic. 
 
c) Assay: A specific, stability-indicating procedure should be included to determine the 
content of the new drug substance. In many cases it is possible to employ the same 
procedure (e.g., HPLC) for both assay of the new drug substance and quantitation of 
impurities. 
 
In cases where use of a non-specific assay is justified, other supporting analytical 
procedures should be used to achieve overall specificity. For example, where titration is 
adopted to assay the drug substance, the combination of the assay and a suitable test for 
impurities should be used. 
 
d) Impurities: Organic and inorganic impurities and residual solvents are included in this 
category. Refer to the VICH GL18 Guidances Impurities in New Veterinary Drug 
Substances and Residual Solvents in New Veterinary Medicinal Products, Active 
Substances and Excipients for detailed information.  
 
Decision tree #1 addresses the extrapolation of meaningful limits on impurities from the 
body of data generated during development. At the time of filing it is unlikely that sufficient 
data will be available to assess process consistency. Therefore it is not recommended to 
establish acceptance criteria which tightly encompass the batch data at the time of filing. 
(see section 2.5) 
 
3.2.2  New Medicinal Products 
The following tests and acceptance criteria are considered generally applicable to all new 
medicinal products: 
 
a) Description: A qualitative description of the dosage form should be provided (e.g., size, 
shape, and color). If any of these characteristics change during manufacture or storage, 
this change should be investigated and appropriate action taken. The acceptance criteria 
should include the final acceptable appearance. If color changes during storage, a 
quantitative procedure may be appropriate. 
 
b) Identification: Identification testing should establish the identity of the new drug 
substance(s) in the new medicinal product and should be able to discriminate between 
compounds of closely related structure which are likely to be present. Identity tests should 
be specific for the new drug substance, e.g., infrared spectroscopy.  Identification solely 
by a single chromatographic retention time, for example, is not regarded as being specific.  
However, the use of two chromatographic procedures, where the separation is based on 
different principles, or combination of tests into a single procedure, such as HPLC/UV 
diode array, HPLC/MS, or GC/MS, is generally acceptable.  Identification should be 
retained in the specification; however testing during a stability study is not recommended 
unless the identification test is stability indicating.  
 
c) Assay: A specific, stability-indicating assay to determine strength (content) should be 
included for all new medicinal products. In many cases it is possible to employ the same 
procedure (e.g., HPLC) for both assay of the new drug substance and quantitation of 
- 11 -  Contains Non-Binding Recommendations 
 
impurities.  Results of content uniformity testing for new medicinal products can be used 
for quantitation of medicinal product strength, if the methods used for content uniformity 
are also appropriate as assays. 
 
In cases where use of a non-specific assay is justified, other supporting analytical 
procedures should be used to achieve overall specificity. For example, where titration is 
adopted to assay the drug substance for release, the combination of the assay and a 
suitable test for impurities can be used.  A specific procedure should be used when there 
is evidence of excipient interference with the non-specific assay.  
 
d) Impurities: Organic and inorganic impurities (degradation products) and residual 
solvents are included in this category.  Refer to the VICH GL18 Guidances Impurities in 
New Veterinary Medicinal Products and Residual Solvents for detailed information.    
Organic impurities arising from degradation of the new drug substance and impurities that 
arise during the manufacturing process for the medicinal product should be monitored in 
the new medicinal product.  Acceptance limits should be stated for individual specified 
degradation products, which may include both identified and unidentified degradation 
products as appropriate, and total degradation products.  Process impurities from the new 
drug substance synthesis are normally controlled during drug substance testing, and 
therefore are not included in the total impurities limit.  However, when a synthesis impurity 
is also a degradation product, its level should be monitored and included in the total 
degradation product limit.  When it has been conclusively demonstrated via appropriate 
analytical methodology, that the drug substance does not degrade in the specific 
formulation, and under the specific storage conditions proposed in the new drug 
application, degradation product testing may be reduced or eliminated upon approval by 
the regulatory authorities. 
 
Decision tree #2 addresses the extrapolation of meaningful limits on degradation products 
from the body of data generated during development. At the time of filing it is unlikely that 
sufficient data will be available to assess process consistency. Therefore it is not 
recommended to establish acceptance criteria which tightly encompass the batch data at 
the time of filing. (see section 2.5) 
 
3.3 Specific Tests / Criteria 
In addition to the universal tests listed above, the following tests may be considered on a 
case by case basis for drug substances and/or medicinal products. Individual tests/criteria 
should be included in the specification when the tests have an impact on the quality of the 
drug substance and medicinal product for batch control. Tests other than those listed 
below may be recommended in particular situations or as new information becomes 
available.  
3.3.1  New Drug Substances 
a) Physicochemical properties: These are properties such as pH of an aqueous solution, 
melting point / range, and refractive index. The procedures used for the measurement of 
these properties are usually unique and do not need much elaboration, e.g., capillary 
melting point, Abbe refractometry. The tests performed in this category should be 
determined by the physical nature of the new drug substance and by its intended use.  
 
b) Particle size: For some new drug substances intended for use in solid or suspension 
medicinal products, particle size can have a significant effect on dissolution rates, 
bioavailability, residue depletion if appropriate, and/or stability. In such instances, testing 
for particle size distribution should be carried out using an appropriate procedure, and 
acceptance criteria should be provided. 
 
- 12 -  Contains Non-Binding Recommendations 
 
Decision tree #3 provides additional guidance on when particle size testing should be 
considered.  
 
c) Polymorphic forms: Some new drug substances exist in different crystalline forms which 
differ in their physical properties. Polymorphism may also include solvation or hydration 
products (also known as pseudopolymorphs) and amorphous forms.  Differences in these 
forms could, in some cases, affect the quality or performance of the new medicinal 
products. In cases where differences exist which have been shown to affect medicinal 
product performance, bioavailability, residue depletion if appropriate, or stability, then the 
appropriate solid state should be specified.  
 
Physicochemical measurements and techniques are commonly used to determine 
whether multiple forms exist.  Examples of these procedures are: melting point (including 
hot-stage microscopy), solid state IR, X-ray powder diffraction, thermal analysis 
procedures (like DSC, TGA and DTA), Raman spectroscopy, optical microscopy, and 
solid state NMR (nuclear magnetic resonance) spectroscopy. 
 
Decision trees #4(1) through 4(3) provide additional guidance on when, and how, 
polymorphic forms should be monitored and controlled. 
 
Note: These decision trees should be followed sequentially. Trees 1 and 2 consider 
whether polymorphism is exhibited by the drug substance, and whether the different 
polymorphic forms can affect performance of the medicinal product. Tree 3 should only be 
applied when polymorphism has been demonstrated for the drug substance, and shown to 
affect these properties. Tree 3 considers the potential for change in polymorphic forms in 
the medicinal product, and whether such a change has any effect on product 
performance.  
 
It is generally technically very difficult to measure polymorphic changes in medicinal 
products. Therefore, a surrogate test (e.g., dissolution) (see Decision tree 4(3)) can 
generally be used to monitor product performance. Polymorph content should only be 
measured in cases where a surrogate test is not possible. 
 
d) Tests for chiral new drug substances: Where a new drug substance is predominantly 
one enantiomer, the opposite enantiomer is excluded from the qualification and 
identification thresholds given in the VICH GL10 and GL11 Guidances on Impurities in 
New Veterinary Drug Substances and Impurities in New Veterinary Medicinal Products 
because of practical difficulties in quantifying it at those levels.  However, that impurity in 
the chiral new drug substance and the resulting new medicinal product(s) should 
otherwise be treated according to the principles established in those Guidances. 
 
Decision tree #5 summarizes when and if chiral identity tests, impurity tests, and assays 
may be important for both new drug substances and new medicinal products, according to 
the following concepts:  
 
  Drug Substance: Impurities. For chiral drug substances which are developed as a 
single enantiomer, control of the other enantiomer should be considered in the same 
manner as for other impurities. However, technical limitations may preclude the same 
limits of quantification or qualification from being applied.  Assurance of control also 
could be given by appropriate testing of a starting material or intermediate, with 
suitable justification.  
 
  Assay. An enantioselective determination of the drug substance should be part of the 
specification. It is considered acceptable for this to be achieved either through use of 
- 13 -  Contains Non-Binding Recommendations 
 
a chiral assay procedure or by the combination of an achiral assay together with 
appropriate methods of controlling the enantiomeric impurity. 
 
  Identity. For a drug substance developed as a single enantiomer, the identity test(s) 
should be capable of distinguishing both enantiomers and the racemic mixture.  For a 
racemic drug substance, there are generally two situations where a stereospecific 
identity test is appropriate for release/acceptance testing: 1) where there is a 
significant possibility that the enantiomer might be substituted for the racemate, or 2) 
when there is evidence that preferential crystallization may lead to unintentional 
production of a non-racemic mixture. 
   
Medicinal Product: Degradation products. Control of the other enantiomer in a 
medicinal product is considered appropriate unless racemization has been shown to 
be insignificant during manufacture of the dosage form, and on storage. 
 
  Assay: An achiral assay may be sufficient where racemization has been shown to be 
insignificant during manufacture of the dosage form, and on storage.  Otherwise a 
chiral assay should be used, or alternatively, the combination of an achiral assay plus 
a validated procedure to control the presence of the opposite enantiomer may be 
used. 
 
  Identity: A stereospecific identity test is not generally recommended in the medicinal 
product release specification.  When racemization is insignificant during manufacture 
of the dosage form, and on storage, stereospecific identity testing is more 
appropriately addressed as part of the drug substance specification.  When 
racemization in the dosage form is a concern, chiral assay or enantiomeric impurity 
testing of the medicinal product will serve to verify identity. 
 
e) Water content: This test is important in cases where the new drug substance is known 
to be hygroscopic or degraded by moisture or when the drug substance is known to be a 
stoichiometric hydrate. The acceptance criteria may be justified with data on the effects of 
hydration or moisture absorption. In some cases, a Loss on Drying procedure may be 
considered adequate; however, a detection procedure that is specific for water (e.g., Karl 
Fischer titration) is preferred. 
 
f) Inorganic impurities: The need for inclusion of tests and acceptance criteria for inorganic 
impurities (e.g., catalysts) should be studied during development and based on knowledge 
of the manufacturing process.  Procedures and acceptance criteria for sulfated 
ash/residue on ignition should follow pharmacopoeial precedents; other inorganic 
impurities may be determined by other appropriate procedures, e.g., atomic absorption 
spectroscopy. 
 
g) Microbial limits: There may be a need to specify the total count of aerobic 
microorganisms, the total count of yeasts and molds, and the absence of specific 
objectionable bacteria (e.g., Staphylococcus aureus, Escherichia coli, Salmonella, 
Pseudomonas aeruginosa). These should be suitably determined using pharmacopoeial 
procedures.  The type of microbial test(s) and acceptance criteria should be based on the 
nature of the drug substance, method of manufacture, and the intended use of the 
medicinal product.  For example, sterility testing may be appropriate for drug substances 
manufactured as sterile and endotoxin testing may be appropriate for drug substances 
used to formulate an injectable medicinal product.  
 
Decision tree #6 provides additional guidance on when microbial limits should be 
included. 
 
- 14 -  Contains Non-Binding Recommendations 
 
3.3.2  New Medicinal Products 
Additional tests and acceptance criteria generally should be included for particular new 
medicinal products.  The following section presents a representative sample of both the 
medicinal products and the types of tests and acceptance criteria which may be 
appropriate. The specific dosage forms addressed include solid oral medicinal products, 
liquid oral medicinal products, and parenterals (small and large volume).  Application of 
the concepts in this guidance to other dosage forms is encouraged.  Note that issues 
related to optically active drug substances and to solid state considerations for medicinal 
products are discussed in part 3.3.1. of this guidance.  
 
3.3.2.1 Solid Oral Medicinal Products: The following tests are applicable to tablets 
(coated and uncoated) and hard capsules.  One or more of these tests may also be 
applicable to soft capsules, powders, and granules. 
 
a) Dissolution: The specification for solid oral dosage forms normally includes a test to 
measure release of drug substance from the medicinal product.  Single-point 
measurements are normally considered to be suitable for immediate-release dosage 
forms.  For modified-release dosage forms, appropriate test conditions and sampling 
procedures should be established.  For example, multiple time point sampling should be 
performed for extended-release dosage forms, and two-stage testing (using different 
media in succession or in parallel, as appropriate) may be appropriate for delayed-release 
dosage forms.  In some cases (see 3.3.2.1 b) Disintegration) dissolution testing may be 
replaced by disintegration testing (see Decision Tree #7 (1)). 
 
For immediate-release medicinal products where changes in dissolution rate have been 
demonstrated to significantly affect bioavailability, it is desirable to develop test conditions 
which can distinguish batches with poor bioavailability.  If changes in formulation or 
process variables significantly affect dissolution and such changes are not controlled by 
another aspect of the specification, it may also be appropriate to adopt dissolution test 
conditions which can distinguish these changes  (see Decision Tree #7(2)).  
 
Where dissolution significantly affects bioavailability, the acceptance criteria should be set 
to reject batches with unacceptable bioavailability.  Otherwise, test conditions and 
acceptance criteria should be established which pass clinically acceptable batches (see 
Decision Tree #7(2)). 
 
For extended-release medicinal products, in vitro/in vivo correlation may be used to 
establish acceptance criteria when bioavailability data are available for formulations 
exhibiting different release rates.  Where such data are not available, and drug release 
cannot be shown to be independent of in vitro test conditions, then acceptance criteria 
should be established on the basis of available batch data.  Normally, the permitted 
variability in mean release rate at any given time point should not exceed a total numerical 
difference of +/-10% of the labeled content of drug substance (i.e., a total variability of 
20%: a requirement of 50 +/- 10% thus means an acceptable range from 40% to 60%), 
unless a wider range is supported by a bioequivalency study (see Decision Tree #7(3)). 
 
b) Disintegration: For rapidly dissolving (dissolution >80% in 15 minutes at pH 1.2, 4.0 and 
6.8, or as appropriate for specific veterinary species) products containing drugs which are 
highly soluble throughout the physiological range (dose/solubility volume < 250 mL from 
pH 1.2 to 6.8, or as appropriate for specific veterinary species), disintegration may be 
substituted for dissolution.  Disintegration testing is most appropriate when a relationship 
to dissolution has been established or when disintegration is shown to be more 
discriminating than dissolution.  In such cases dissolution testing may not be appropriate. 
Development information should be provided to support the robustness of the formulation 
- 15 -  Contains Non-Binding Recommendations 
 
and manufacturing process with respect to the selection of dissolution vs. disintegration 
testing  (see Decision Tree #7(1)). 
 
c) Hardness/friability: It is normally appropriate to perform hardness and/or friability testing 
as an in-process control (see section 2.3).  Under these circumstances, it is normally not 
important to include these attributes in the specification.  If the characteristics of hardness 
and friability have a critical impact on medicinal product quality (e.g., chewable tablets), 
acceptance criteria should be included in the specification.  
 
d) Uniformity of dosage units: This term includes both the mass of the dosage form and 
the content of the active substance in the dosage form; a pharmacopoeial procedure 
should be used.  In general, the specification should include one or the other but not both.  
If appropriate, these tests may be performed in-process; the acceptance criteria should be 
included in the specification.  When weight variation is applied for new medicinal products 
exceeding the threshold value to allow testing uniformity by weight variation, applicants 
should verify during drug development that the homogeneity of the product is adequate. 
 
e) Water content: A test for water content should be included when appropriate.  The 
acceptance criteria may be justified with data on the effects of hydration or water 
absorption on the medicinal product. In some cases, a Loss on Drying procedure may be 
considered adequate; however, a detection procedure which is specific for water (e.g., 
Karl Fischer titration) is preferred. 
 
f) Microbial limits: Microbial limit testing is seen as an attribute of Good Manufacturing 
Practice (21 CFR 211.165(b)), as well as of quality assurance. In general, it is advisable to 
test the medicinal product unless its components are tested before manufacture and the 
manufacturing process is known, through validation studies, not to carry a significant risk 
of microbial contamination or proliferation.  It should be noted that, whereas this guidance 
does not directly address excipients, the principles discussed here may be applicable to 
excipients as well as to new medicinal products. Skip testing may be an appropriate 
approach in both cases where permissible.  (See Decision Tree #6 for microbial testing of 
excipients.) 
 
Acceptance criteria should be set for the total count of aerobic microorganisms, the total 
count of yeasts and molds, and the absence of specific objectionable bacteria (e.g., 
Escherichia coli and Salmonella; testing of additional organisms may be appropriate 
according to the U.S. Pharmacopeia (USP)). These should be determined by suitable 
procedures, using pharmacopoeial procedures, and at a sampling frequency or time point 
in manufacture which is justified by data and experience.  The type of microbial test(s) and 
acceptance criteria should be based on the nature of the drug substance, method of 
manufacture, and the intended use of the medicinal product. With acceptable scientific 
justification, it should be possible to propose no microbial limit testing for solid oral dosage 
forms.  
 
Decision tree #8 provides additional guidance on the use of microbial limits testing.    
3.3.2.2 Oral liquids: One or more of the following specific tests will normally be applicable 
to oral liquids and to powders intended for reconstitution as oral liquids. 
 
a) Uniformity of dosage units: This term includes both the mass of the dosage form and 
the content of the active substance in the dosage form; a pharmacopoeial procedure 
should be used. In general, the specification should include one or the other but not both.  
When weight variation is applied for new medicinal products exceeding the threshold 
value to allow testing uniformity by weight variation, applicants should verify during drug 
development that the homogeneity of the product is adequate. 
 
- 16 -  Contains Non-Binding Recommendations 
 
If appropriate, tests may be performed in-process; however, the acceptance criteria 
should be included in the specification. This concept may be applied to both single-dose 
and multiple-dose packages. 
 
The dosage unit is considered to be a representative dose that would be administered to 
an animal. If the actual unit dose is controlled, it may either be measured directly or 
calculated, based on the total measured weight or volume of drug divided by the total 
number of doses expected. If dispensing equipment (such as medicine droppers or 
dropper tips for bottles) is an integral part of the packaging, this equipment should be 
used to measure the dose. Otherwise, a standard volume measure should be used. The 
dispensing equipment to be used is normally determined during development. 
 
For powders for reconstitution, uniformity of mass testing is generally considered 
acceptable. 
 
b) pH: Acceptance criteria for pH should be provided where applicable and the proposed 
range justified. 
 
c) Microbial limits: Microbial limit testing is seen as an attribute of Good Manufacturing 
Practice (21 CFR 211.165(b)), as well as of quality assurance. In general, it is advisable to 
test the medicinal product unless its components are tested before manufacture and the 
manufacturing process is known, through validation studies, not to carry a significant risk 
of microbial contamination or proliferation.  It should be noted that, whereas this Guidance 
does not directly address excipients, the principles discussed here may be applicable to 
excipients as well as to new medicinal products.  Skip testing may be an appropriate 
approach in both cases where permissible.  With acceptable scientific justification, it may 
be possible to propose no microbial limit testing for powders intended for reconstitution as 
oral liquids.  
 
Acceptance criteria should be set for the total count of aerobic microorganisms, total count 
of yeasts and molds, and the absence of specific objectionable bacteria (e.g., Escherichia 
coli and Salmonella,; testing of additional organisms may be appropriate according to the 
U.S. Pharmacopeia (USP)). These should be determined by suitable procedures, using 
pharmacopoeial procedures, and at a sampling frequency or time point in manufacture 
which is justified by data and experience.  
 
Decision tree #8 provides additional guidance on the use of microbial limits testing. 
 
d) Antimicrobial preservative content: For oral liquids needing an antimicrobial 
preservative, acceptance criteria for preservative content should be established.  
Acceptance criteria for preservative content should be based upon the levels of 
antimicrobial preservative necessary to maintain microbiological quality of the product at 
all stages throughout its proposed usage and shelf-life. The lowest specified concentration 
of antimicrobial preservative should be demonstrated to be effective in controlling 
microorganisms by using a pharmacopoeial antimicrobial preservative effectiveness test.  
 
Testing for antimicrobial preservative content should normally be performed at release.  
Under certain circumstances, in-process testing may suffice in lieu of release testing. 
When antimicrobial preservative content testing is performed as an in-process test, the 
acceptance criteria should remain part of the specification.  
 
Antimicrobial preservative effectiveness should be demonstrated during development and 
throughout the shelf-life and the in-use period (e.g., in stability testing: see the VICH GL3 
Guidance, Stability Testing of New Veterinary Drug Substances and Products), although 
- 17 -  Contains Non-Binding Recommendations 
 
chemical testing for preservative content is the attribute normally included in the 
specification. 
 
e) Antioxidant preservative content: Release testing for antioxidant content should 
normally be performed. Under certain circumstances, where justified by developmental 
and stability data, shelf-life testing may not be important, and in-process testing may 
suffice in lieu of release testing where permitted.  When antioxidant content testing is 
performed as an in-process test, the acceptance criteria should remain part of the 
specification. If only release testing is performed, this decision should be reinvestigated 
whenever either the manufacturing procedure or the container/closure system changes. 
 
f) Extractables: Generally, where development and stability data show evidence that 
extractables from the container/closure systems are consistently below levels that are 
demonstrated to be acceptable and safe, elimination of this test can normally be 
accepted.  This should be reinvestigated if the container/closure system or formulation 
changes. 
Where data demonstrate the need, tests and acceptance criteria for extractables from the 
container/closure system components (e.g., rubber stopper, cap liner, plastic bottle, etc.) 
are considered appropriate for oral solutions packaged in non-glass systems, or in glass 
containers with non-glass closures. The container/closure components should be listed, 
and data collected for these components as early in the development process as possible. 
 
g) Dissolution: In addition to the attributes recommended immediately above, it may be 
appropriate (e.g., insoluble drug substance) to include dissolution testing and acceptance 
criteria for oral suspensions and dry powder products for resuspension.  Dissolution 
testing should be performed at release. This test may be performed as an in-process test 
when justified by product development data. The testing apparatus, media, and conditions 
should be pharmacopoeial, if possible, or otherwise justified. Dissolution procedures using 
either pharmacopoeial or non-pharmacopoeial apparatus and conditions should be 
validated.  
 
Single-point measurements are normally considered suitable for immediate-release 
dosage forms. Multiple-point sampling, at appropriate intervals, should be performed for 
modified-release dosage forms. Acceptance criteria should be set based on the observed 
range of variation, and should take into account the dissolution profiles of the batches that 
showed acceptable performance in vivo. Developmental data should be considered when 
determining the need for either a dissolution procedure or a particle size distribution 
procedure.  
 
h) Particle size distribution: Quantitative acceptance criteria and a procedure for 
determination of particle size distribution may be appropriate for oral suspensions. 
Developmental data should be considered when determining the importance of either a 
dissolution procedure or a particle size distribution procedure for these formulations.  
 
Particle size distribution testing should be performed at release.  It may be performed as 
an in-process test when justified by product development data. If these products have 
been demonstrated during development to have consistently rapid drug release 
characteristics, exclusion of a particle size distribution test from the specification may be 
proposed.  
 
Particle size distribution testing may also be proposed in place of dissolution testing; 
justification should be provided. The acceptance criteria should include acceptable particle 
size distribution in terms of the percent of total particles in given size ranges. The mean, 
upper, and/or lower particle size limits should be well defined.  
 
- 18 -  Contains Non-Binding Recommendations 
 
Acceptance criteria should be set based on the observed range of variation, and should 
take into account the dissolution profiles of the batches that showed acceptable 
performance in vivo, as well as the intended use of the product. The potential for particle 
growth should be investigated during product development; the acceptance criteria should 
take the results of these studies into account.  
 
i) Redispersibility: For oral suspensions which settle on storage (produce sediment), 
acceptance criteria for redispersibility may be appropriate. Shaking may be an appropriate 
procedure.   
 
The procedure (mechanical or manual) should be indicated. Time required to achieve 
resuspension by the indicated procedure should be clearly defined. Data generated during 
product development may be sufficient to justify skip lot testing, or elimination of this 
attribute from the specification may be proposed. 
 
j) Rheological properties: For relatively viscous solutions or suspensions, it may be 
appropriate to include rheological properties (viscosity/specific gravity) in the specification. 
The test and acceptance criteria should be stated. Data generated during product 
development may be sufficient to justify skip lot testing, or elimination of this attribute from 
the specification may be proposed. 
 
k)  Reconstitution time: Acceptance criteria for reconstitution time should be provided for 
dry powder products which require reconstitution. The choice of diluent should be justified. 
Data generated during product development may be sufficient to justify skip lot testing or 
elimination of this attribute from the specification may be proposed. 
 
l) Water content: For oral products requiring reconstitution, a test and acceptance criterion 
for water content should be proposed when appropriate. Loss on Drying is generally 
considered sufficient if the effect of absorbed moisture vs. water of hydration has been 
adequately characterized during the development of the product. In certain cases a more 
specific procedure (e.g., Karl Fischer titration) may be preferable. 
 
3.3.2.3 Parenteral Medicinal Products: The following tests may be applicable to 
parenteral medicinal products. 
 
a) Uniformity of dosage units: This term includes both the mass of the dosage form and 
the content of the active substance in the dosage form; a pharmacopoeial procedure 
should be used.  In general, the specification should include one or the other but not both 
and is applicable to powders for reconstitution. When weight variation is applied for new 
medicinal products exceeding the threshold value to allow testing uniformity by weight 
variation, applicants should verify during drug development that the homogeneity of the 
product is adequate. 
 
If appropriate (see section 2.3), these tests may be performed in-process; the acceptance 
criteria should be included in the specification. This test may be applied to both single-
dose and multiple-dose packages. 
 
For powders for reconstitution, uniformity of mass testing is generally considered 
acceptable. 
 
b) pH: Acceptance criteria for pH should be provided where applicable and the proposed 
range justified. 
 
c) Sterility: All parenteral products should have a test procedure and acceptance criterion 
for evaluation of sterility. Where data generated during development and validation 
- 19 -  Contains Non-Binding Recommendations 
 
justifies parametric release, this approach may be proposed for terminally sterilized 
medicinal products (see section 2.6).  
 
d) Endotoxins/Pyrogens: A test procedure and acceptance criterion for endotoxins, using 
a procedure such as the limulus amoebocyte lysate test, should be included in the 
specification in accordance with regional requirements.  Pyrogenicity testing may be 
proposed as an alternative to endotoxin testing where justified. 
 
e) Particulate matter: Parenteral products should have appropriate acceptance criteria for 
particulate matter. This will normally include acceptance criteria for visible particulates 
and/or clarity of solution, as well as for sub-visible particulates as appropriate.  
 
f) Water content: For non-aqueous parenterals, and for parenteral products for 
reconstitution, a test procedure and acceptance criterion for water content should be 
proposed when appropriate. Loss on Drying is generally considered sufficient for 
parenteral products, if the effect of absorbed moisture vs. water of hydration has been 
adequately characterized during development. In certain cases a more specific procedure 
(e.g., Karl Fischer titration) may be preferred. 
 
g) Antimicrobial preservative content: For parenteral products needing an antimicrobial 
preservative, acceptance criteria for preservative content should be established. 
Acceptance criteria for preservative content should be based upon the levels of 
antimicrobial preservative necessary to maintain microbiological quality of the product at 
all stages throughout its proposed usage and shelf life. The lowest specified concentration 
of antimicrobial preservative should be demonstrated to be effective in controlling 
microorganisms by using a pharmacopoeial antimicrobial preservative effectiveness test.   
 
Testing for antimicrobial preservative content should normally be performed at release.  
Under certain circumstances, in-process testing may suffice in lieu of release testing 
where permitted.  When antimicrobial preservative content testing is performed as an in-
process test, the acceptance criteria should remain part of the specification.  
 
Antimicrobial preservative effectiveness should be demonstrated during development and 
throughout the shelf-life and the in-use period (e.g., in stability testing: see the VICH GL 3 
Guidance, Stability Testing of New Animal Drug Substances and Products), although 
chemical testing for preservative content is the attribute normally included in the 
specification. 
 
h) Antioxidant preservative content: Release testing for antioxidant content should 
normally be performed. Under certain circumstances, where justified by developmental 
and stability data, shelf-life testing may not be important and in-process testing may 
suffice in lieu of release testing. When antioxidant content testing is performed as an in-
process test, the acceptance criteria should remain part of the specification. If only release 
testing is performed, this decision should be reinvestigated whenever either the 
manufacturing procedure or the container/closure system changes. 
 
i) Extractables: Control of extractables from container/closure systems is considered 
significantly more important for parenteral products than for oral liquids. However, where 
development and stability data show evidence that extractables are consistently below the 
levels that are demonstrated to be acceptable and safe, elimination of this test can 
normally be accepted. This should be reinvestigated if the container/closure system or 
formulation changes. 
 
Where data demonstrate the need, acceptance criteria for extractables from the 
container/closure components are considered appropriate for parenteral products 
- 20 -  Contains Non-Binding Recommendations 
 
packaged in non-glass systems or in glass containers with elastomeric closures.  This 
testing may be performed at release only, where justified by data obtained during 
development. The container/closure system components (e.g., rubber stopper, etc.) 
should be listed, and data collected for these components as early in the development 
process as possible. 
 
j) Functionality testing of delivery systems: Parenteral formulations packaged in pre-filled 
syringes, autoinjector cartridges, or the equivalent should have test procedures and 
acceptance criteria related to the functionality of the delivery system.  These may include 
control of syringeability, pressure, and seal integrity (leakage), and/or parameters such as 
tip cap removal force, piston release force, piston travel force, and power injector function 
force.  Under certain circumstances these tests may be performed in-process.  Data 
generated during product development may be sufficient to justify skip lot testing or 
elimination of some or all attributes from the specification.  
 
k) Osmolarity: When the tonicity of a product is declared in its labeling, appropriate control 
of its osmolarity should be performed. Data generated during development and validation 
may be sufficient to justify performance of this procedure as an in-process control, skip lot 
testing, or direct calculation of this attribute. 
 
l) Particle size distribution: Quantitative acceptance criteria and a procedure for 
determination of particle size distribution may be appropriate for injectable suspensions. 
Developmental data should be considered when determining the importance of either a 
dissolution procedure or a particle size distribution procedure.  
 
Particle size distribution testing should be performed at release.  It may be performed as 
an in-process test when justified by product development data.  If the product has been 
demonstrated during development to have consistently rapid drug release characteristics, 
exclusion of particle size controls from the specification may be proposed.  
 
Particle size distribution testing may also be proposed in place of dissolution testing, when 
development studies demonstrate that particle size is the primary factor influencing 
dissolution; justification should be provided. The acceptance criteria should include 
acceptable particle size distribution in terms of the percent of total particles in given size 
ranges. The mean, upper, and / or lower particle size limits should be well defined.  
 
Acceptance criteria should be set based on the observed range of variation, and should 
take into account the dissolution profiles of the batches that showed acceptable 
performance in vivo and the intended use of the product.  The potential for particle growth 
should be investigated during product development; the acceptance criteria should take 
the results of these studies into account. 
 
m) Redispersibility: For injectable suspensions which settle on storage (produce 
sediment), acceptance criteria for redispersibility may be appropriate.  Shaking may be an 
appropriate procedure.  The procedure (mechanical or manual) should be indicated.  Time 
required to achieve resuspension by the indicated procedure should be clearly defined.  
Data generated during product development may be sufficient to justify skip lot testing, or 
elimination of this attribute from the specification may be proposed. 
 
n) Reconstitution time: Acceptance criteria for reconstitution time should be provided for 
all parenteral products which require reconstitution.  The choice of diluent should be 
justified.  Data generated during product development and process validation may be 
sufficient to justify skip lot testing or elimination of this attribute from the specification for 
rapidly dissolving products. 
 
- 21 -  Contains Non-Binding Recommendations 
 
 
 
4.  GLOSSARY 
(The following definitions are presented for the purpose of this Guidance) 
Acceptance criteria: Numerical limits, ranges, or other suitable measures for acceptance 
of the results of analytical procedures. 
Chiral: Not superimposable with its mirror image, as applied to molecules, conformations, 
and macroscopic objects, such as crystals.  The term has been extended to samples of 
substances whose molecules are chiral, even if the macroscopic assembly of such 
molecules is racemic. 
Combination product: A medicinal product which contains more than one drug 
substance. 
Degradation product: A molecule resulting from a chemical change in the drug molecule 
brought about over time and/or by the action of e.g., light, temperature, pH, water, or by 
reaction with an excipient and/or the immediate container/closure system. Also called 
decomposition product. 
Delayed Release: Release of a drug (or drugs) at a time other than immediately following 
oral administration.   
Enantiomers: Compounds with the same molecular formula as the drug substance, 
which differ in the spatial arrangement of atoms within the molecule and are 
nonsuperimposable mirror images. 
Extended Release: Products which are formulated to make the drug available over an 
extended period after administration. 
Highly Water Soluble Drugs: Drugs with a dose/solubility volume of less than or equal to 
250 mL over a pH range of 1.2 to 6.8, or as appropriate for specific veterinary species. 
(Example: Compound A has as its lowest solubility at 37 0.5C, 1.0 mg/mL at pH 6.8, 
and is available in 100 mg, 200 mg, and 400 mg strengths.  This drug would be 
considered a low solubility drug as its dose/solubility volume is greater than 250 mL (400 
mg/1.0 mg/mL = 400 mL). 
Immediate Release: Allows the drug to dissolve in the gastrointestinal contents, with no 
intention of delaying or prolonging the dissolution or absorption of the drug. 
Impurity: (1) Any component of the new drug substance which is not the chemical entity 
defined as the new drug substance. (2) Any component of the medicinal productwhich is 
not the chemical entity defined as the drug substance or an excipient in the medicinal 
product. 
Identified impurity: An impurity for which a structural characterization has been 
achieved. 
In-process tests: Tests which may be performed during the manufacture of either the 
drug substance or medicinal product, rather than as part of the formal battery of tests 
which are conducted prior to release. 
Modified Release: Dosage forms whose drug-release characteristics of time course 
and/or location are chosen to accomplish therapeutic or convenience objectives not 
offered by conventional dosage forms such as a solution or an immediate release dosage 
form.  Modified release solid oral dosage forms include both delayed and extended 
release medicinal products. 
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. 
- 22 -  Contains Non-Binding Recommendations 
 
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. 
Polymorphism: The occurrence of different crystalline forms of the same drug substance.  
This may include solvation or hydration products (also known as pseudopolymorphs) and 
amorphous forms.  
Quality: The suitability of either a drug substance or medicinal product for its intended 
use.  This term includes such attributes as the identity, strength, and purity. 
Racemate: A composite (solid, liquid, gaseous, or in solution) of equimolar quantities of 
two enantiomeric species.  It is devoid of optical activity. 
Rapidly Dissolving Products: An immediate release solid oral medicinal product is 
considered rapidly dissolving when not less than 80% of the label amount of the drug 
substance dissolves within 15 minutes in each of the following media: (1) pH 1.2, (2) pH 
4.0, and (3) pH 6.8, or as appropriate for specific veterinary species.  
Reagent: A substance, other than a starting material or solvent, which is used in the 
manufacture of a new veterinary drug substance. 
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 or the 
manufacture of a new medicinal product. 
Specification: A list of tests, references to analytical procedures, and appropriate 
acceptance criteria which are numerical limits, ranges, or other criteria for the tests 
described.  It establishes the set of criteria to which a drug substance or medicinal product 
should conform to be considered acceptable for its intended use.  "Conformance to 
specifications" means that the drug substance and/or medicinal product, when tested 
according to the listed analytical procedures, will meet the listed acceptance criteria.  
Specifications are critical quality standards that are proposed and justified by the 
manufacturer and approved by regulatory authorities. 
Specific test: A test which is considered to be applicable to particular new drug 
substances or particular new medicinal products depending on their specific properties 
and/or intended use.Specified impurity: An identified or unidentified impurity that is 
selected for inclusion in the new drug substance or new medicinal product specification 
and is individually listed and limited in order to assure the quality of the new drug 
substance or new medicinal product. 
Unidentified impurity: An impurity which is defined solely by qualitative analytical 
properties, (e.g., chromatographic retention time). 
Universal test: A test which is considered to be potentially applicable to all new drug 
substances, or all new medicinal products; e.g., appearance, identification, assay, and 
impurity tests. 
 
 
5.  REFERENCES 
 
VICH GL10 (R); "Impurities in New Veterinary Drug Substances", 2006 
VICH GL11 (R); "Impurities in New Veterinary Medicinal Products", 2006 
VICH GL3 (R); "Stability Testing of New Veterinary Drug Substances and Products", 2006 
VICH GL1; " Validation of Analytical Procedures: Definition and Terminology", 1999. 
VICH GL2; "Validation of Analytical Procedures: Methodology", 1999. 
- 23 -  Contains Non-Binding Recommendations 
 
VICH GL18, "Impurities: Residual Solvents in New Veterinary Medicinal Products, Active 
Substances and Excipients", 2000. 
 
6.  ATTACHMENTS 
Decision Trees #1 through #8 
 
For the decision trees referenced in this guidance, see the following pages. 
 
- 24 -  Contains Non-Binding Recommendations 
 
DECISION TREE #1: ESTABLISHING ACCEPTANCE CRITERION 
FOR A SPECIFIED IMPURITY IN A NEW DRUG SUBSTANCE
Determine impurity level in 
relevant batches1
Is Estimate maximum increase in impurity
Determine mean + upper confidence  impurity also YES at retest date using data from relevant
limit for the impurity (Let this = A) a degradation accelerated and long-term stability 
product? studies
NO
Is
Acceptance criterion = A or B NO greatAer o trh Ban  the AD +e itnecrmreiansee m ina dxiemguramd alitkioelny  plerovedlu acst :at
(as appropriate) qualified appropriate storage conditions.
level? (Let this = B)
YES
Acceptance criterion = qualified level
or establish new qualified level2
1Relevant batches are those from development, pilot and scale-up studies.
2Refer to VICHGuideline on Impurities in New Drug Substances
Definition: upper confidence limit = three times the standard deviation of batch analysis data
 
 
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DECISION TREE #2: ESTABLISHING ACCEPTANCE CRITERION 
FOR A DEGRADATION PRODUCT IN A NEW MEDICINALPRODUCT
Does Estimate maximum increase in 
degradation NO degradation product at shelf life using
occur during product data from relevant accelerated and
manufacture? long-term stability studies.  
(Let this = D)
YES
Determine maximum likely level as 
Estimate maximum increase in degradation drug substance acceptance criterion2.
product during manufacture from relevant ((A or B)+ C + D)
batches1.  (Let this = C)
Is
maximum
NO likely level greater
Acceptance criterion = maximum likely level. than the
qualified
level?
YES
Acceptance criterion = qualified level
or establish new qualified level3
or new storage conditions
or reduce shelf life.
1 Relevant batches are those from development, pilot and scale-up studies.
2Refer to Decision Tree 1 for information regarding A and B.
3Refer to VICH Guideline on Impurities in New Veterinary Medicinal Products. 
 
 
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DECISION TREE #3: SETTING ACCEPTANCE CRITERIA FOR 
DRUG SUBSTANCE PARTICLE SIZE DISTRIBUTION
No drug substance particle
Is the drug product a solid
dosage form or liquid  NO size acceptance criterion 
required for solution dosage 
containing undissolved
forms.
drug substance?
YES
1.  Is the particle size critical to dissolution,
solubility, or bioavailability?
2.  Is the particle size critical to drug product
If NO to all
processability?
3.  Is the particle size critical to drug product stability?
4.  Is the particle size critical to drug product 
content uniformity? 
5. Is particle size critical for maintaining 
product appearance?
6. Is particle size critical for residue depletion?
If YES to any
No Acceptance Criterion 
Required
Set Acceptance Criterion
 
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DECISION TREE #4: INVESTIGATING THE NEED TO SET
ACCEPTANCE CRITERIA FOR POLYMORPHISM
IN DRUG SUBSTANCES AND MEDICINAL PRODUCTS
Drug Substance
Conduct polymorphism Can NO
1. screen on drug substance. different polymorphs No further action
be formed?
YES
Characterize the forms:
e.g., -X-ray Powder Diffraction 2.
-DSC / Thermoanalysis GO TO 
-Microscopy
-Spectroscopy
2.
Do the
forms have NO
different properties?
(solubility, stability,
melting point)
No further test or
YES
acceptance criterion
for drug substance
Is medicinal
product safety, NO
performance or 
efficacy affected?
YES
Set acceptance criterion
for polymorph content GO TO 3.
in drug substance
 
 
 
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DECISION TREE #4: INVESTIGATING THE NEED TO SET 
ACCEPTANCE CRITERIA FOR POLYMORPHISM
IN DRUG SUBSTANCES AND MEDICINAL PRODUCTS
MedicinalProduct -Solid Dosage Form or Liquid Containing UndissolvedDrug Substance
N.B.: Undertake the following processes only if technically possible
to measure polymorph content in themedicinal product.
3.
Does
medicinal product
performance testing Establish acceptance criteria
provide adequate control if  YES for the relevant performance 
polymorph ratio changes test(s).
(e.g., dissolution)? 
NO
Monitor polymorph form during
stability ofmedicinalproduct.
Does a
change occur NO No need to set acceptance criteria
which could affect  for polymorph change in medicinal 
safety or efficacy? product.
YES
Establish acceptance criteria
which are consistent with 
safety and/or efficacy.
 
 
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DECISION TREE #5: ESTABLISHING IDENTITY, ASSAY 
AND ENANTIOMERIC IMPURITY PROCEDURES FOR CHIRAL 
NEW DRUG SUBSTANCES AND NEW MEDICINALPRODUCTS
CONTAINING CHIRAL DRUG SUBSTANCES
Consider the need for
verifying chiralidentity in YES Is the new NO Chiralidentity, assay 
drug substance release drug substance and impurity procedures 
and/or acceptance  chiral1? are not needed.
testing. AND RACEMIC
YES
AND ONE ENANTIOMER
Needed for drug substance specification:2
-chiralidentity3
-chiralassay4
-enantiomericimpurity5
Needed for medicinal product specification6:
-chiralassay4
-enantiomericimpurity5
1 Chiralsubstances of natural origin are not addressed in this Guideline.
2 As with other impurities arising in and from raw materials used in drug substance synthesis, control
of chiralquality could be established alternatively by applying limits to appropriate starting materials 
or intermediates when justified from developmental studies.  This essentially will be the case when 
there are multiple chiralcenters (e.g., three or more), or when control at a step prior to production 
of the final drug substance is desirable.
3 A chiralassay or an enantiomericimpurity procedure may be acceptable in lieu of a chiralidentity 
procedure.
4 An achiralassay combined with a method for controlling the opposite enantiomeris acceptable in lieu of a 
chiralassay.
5 The level of the opposite enantiomerof the drug substance may be derived from chiralassay data or from 
a separate procedure.
6 Stereospecifictesting of medicinalproduct may not be necessary if racemizationhas been demonstrated 
to be insignificant during drug product manufacture and during storage of the finished dosage form.
 
 
 
- 30 -  Contains Non-Binding Recommendations 
 
ES OF DRUG SUBSTANCE AND EXCIPIENTS  Provide supporting data. Microbial limits acceptance criteria and testing may not be necessary. No further microbial limits testing or acceptance criteria are necessary. Establish microbial limit acceptance criteriaas per the harmonized pharmacopeialmonograph.  Does scientific evidence demonstrate thatreduction steps result in microorganism levels < acceptance criteria limits (and the absence of compendialindicator organisms)in the drug substance/excipient?  NOYES Provide supporting data. Microbial limits acceptance criteria and testing may not be necessary.
T
U
B
RI
T
T
A
LITY  NO YES YES
GICAL QUA microbial limits m compendialganisms.
DECISION TREE #6: MICROBIOLO Is the drug substance/excipientcapable of supporting microbial growth or viability? YES Is the drug substance/excipientsterile? NO Does drug substance/excipientsynthesis/processing involvesteps which inherently reduce microorganisms? NO Establish microbial limit acceptance criteriaas per the harmonized pharmacopoeialmonograph. Are monitoring microorganism/indicator levels consistently below acceptance criteria levels? YESNO Test each lot for Test lots on a skip-lot basis for and freedom fromicrobial limits and freedom fromindicator orcompendialindicator organisms.
 
 
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DECISION TREES #7: SETTING ACCEPTANCE CRITERIA 
FORMEDICINAL PRODUCT DISSOLUTION
1. What type of drug release acceptance criteria are appropriate?
Establish drug release acceptance criteria.
form dIess tihgen eddo stoa gperoduce YES EDxetleanydeedd r ereleleaassee: :t wmou slttipalgee tsim, pea praolilnetls 
modified release? or sequential
NO
Is drug solubility
at 37 0.5C high throughout
the physiological pH range?
(Dose/ solubility <250 mL NO
(pH 1.2 -6.8*))
YES
Is dosage form
dissolution rapid?
NO Generally single-point dissolution
(Dissolution > 80% in 15 minutes acceptance criteria with a lower limit
at pH 1.2, 4.0, and 6.8*)   are acceptable.
YES
NO
Has a relationship been
determined between disintegration Generally disintegration acceptance 
and dissolution? YES criteria with an upper time 
limit are acceptable.
* -use appropriate pH for specific veterinary species
Continued on next page.
 
 
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DECISION TREES #7: SETTING ACCEPTANCE CRITERIA 
FOR MEDICINAL PRODUCT DISSOLUTION
2. What specific test conditions and acceptance criteria are appropriate? [immediate release]
Does
dissolution significantly
affect bioavailability? YES Attempt to develop test conditions and acceptance
(e.g., have relevant developmental criteria which can distinguish batches 
batches exhibited unacceptable with unacceptable bioavailability.
bioavailability?) 
NO
Do changes in
formulation or
manufacturing variables 
YES Are these changes controlled
affect dissolution?
by another procedure and acceptance
(Use appropriate  ranges.
criterion?
Evaluate dissolution
within pH 1.2 -6.8*)
YES
NO
NO
Adopt appropriate test conditions
and acceptance criteria without 
regard to discriminating power, to
Adopt test conditions and acceptance criteria
pass clinically acceptable batches.
which can distinguish these changes. 
Generally, single point acceptance criteria
are acceptable. 
* -use appropriate pH for specific veterinary species
 
 
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DECISION TREES #7: SETTING 
ACCEPTANCE CRITERIA 
FOR MEDICINAL PRODUCT DISSOLUTION
3. What are appropriate acceptance ranges? [extended release]
Are bioavailability
NO
data available for batches Is drug release independent of
with different drug release rates? in vitrotest conditions?
YES
YES
NO
Can an in vitro / in vivo
Use all available stability, clinical, and
relationship be established? NO
bioavailability data to establish 
appropriate acceptance ranges.
(Modify in vitrotest conditions
if appropriate.)
YES
Use the in vitro / in vivo Are acceptance Provide appropriate
YES
correlation, along with ranges >20% of the bioavailability data
appropriate batch data, to  labeled content? to validate the
establish acceptance ranges. acceptance ranges.
NO
Finalize acceptance ranges.
 
 
 
- 34 -  Contains Non-Binding Recommendations 
 
O
N
N-STERILE MEDICINAL PRODUCTS YES Establish preservative chemical acceptance criteria and perform preservative effectiveness validation of product containing less than or equal to the minimum specified preservative concentration, or demonstrate the inherent antimicrobial activity of the medicinal product.  Establish microbial limit acceptance criteriaas per the harmonized pharmacopoeialmonograph. Perform microbial limits testing on a lot-by-lot basis. Do production lots consistently meet microbial limits acceptance criteria? YES Perform skip-lot testing for microbial limits, or provide scientific justification for no routine microbial limits testing. 
O
N
F 
O
S 
E
T
U
8: MICROBIOLOGICAL ATTRIB Does the medicinal product contain antimicrobial preservatives or possess inherent antimicrobial activity? NO NO
#
DECISION TREE  NO Is the medicinal product a dry dosage form (e.g. solid oral or dry powder)? YES Does scientific evidence demonstrategrowth inhibitory properties of the medicinalproduct? YES Microbial limits acceptance criteria and testing may not be necessary.
 
 
 
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