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Guidance for Industry 
 
Residual Solvents in Animal Drug Products 
Questions and Answers 
 
Submit comments on this guidance at any time.  Submit  electronic comments to 
http://www.regulations.gov.   Submit written comments to the Division  of Dockets Management 
(HFA-305), Food and Drug Administration,  5630 Fishers Lane, Rm. 1061, Rockville,  MD 
20852.  All comments should be identified  with the Docket No. FDA-2010-D-0566. 
 
For further information  regarding this document, contact Heather Longstaff, Center for 
Veterinary Medicine, (HFV-145), Food and Drug Administration,  7500 Standish Place, 
Rockville,  MD 20855, 240-402-0651,  e-mail:  heather.longstaff@fda.hhs.gov. 
 
Additional  copies of this guidance document may be requested from the Policy and Regulations 
Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration,  7519 Standish 
Place, Rockville,  MD 20855, and may be viewed on the Internet at either 
http://www.fda.gov/AnimalVeterinary/default.htm  or http://www.regulations.gov. 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine 
April 2015  Contains Non-Binding  Recommendations 
Table of Contents 
 
INTRODUCTION ................................................................................................................... 3 
DRUG PRODUCT .................................................................................................................. 3 
Q1.  What information should be submitted to demonstrate compliance with USP <467>? ..... 3 
Q2.  Are commitments to submit residual solvent data in a future submission allowed?.......... 4 
Q3.  If a formulation  of a drug product contains a solvent, is that solvent held to the limits  in 
USP <467>?................................................................................................................. 4 
Q4.  There are currently some differences in solvent classifications/limits  between USP <467> 
and VICH GL18(R).  How should differences in USP and VICH classifications be 
addressed? ................................................................................................................... 4 
Q5.  There are situations where the USP monograph for the active ingredient in a formulation 
includes a specification  for a class 2 or class 3 solvent.  If the active ingredient is the only 
source for the solvent in the formulation,  and the active ingredient  meets the 
specifications of the USP monograph,  does the drug product still have to comply with the 
limits in USP <467> for this solvent? ............................................................................ 4 
Q6.  When is it acceptable to use a Class 1 solvent? .............................................................. 5 
Q7.  How should the acceptance criterion be established for a residual solvent that is not 
classified (as Class 1, 2 or 3) in USP <467>?................................................................. 5 
Q8.  If a drug product utilizes  raw materials supplied  in solvents and the solvent is then driven 
off during the drug product manufacturing steps, does the final drug product need to be 
tested and do all the limits in USP <467> apply? ........................................................... 5 
DRUG PRODUCT TESTING ................................................................................................. 5 
Q9.  Should residual solvent test methods used for testing of the drug product be validated or 
verified?....................................................................................................................... 5 
Q10.  Would it be acceptable to use a high purity solvent in place of the USP reference 
standard?...................................................................................................................... 5 
Q11.  Can loss on drying (LOD) be used to control Class 3 solvents even if Class 2 solvents are 
present providing that the total of both classes is <0.5%? ............................................... 5 
RAW MATERIALS ................................................................................................................ 6 
Q12.  Are raw materials required to meet the residual solvent levels stated in USP <467>? ...... 6 
Q13.  What should a raw material manufacturers statement regarding residual solvents 
contain? ....................................................................................................................... 6 
Q14.  How does CVM define likely to be present? .............................................................. 7 
Q15.  Sometimes excipient manufacturers do not provide information  in a customary Certificate 
of Analysis.  Many firms obtain this information  through surveys of their suppliers.  Is 
this an acceptable format to demonstrate compliance with USP <467? ........................... 7 
Q16.  How can a sponsor verify raw material manufacturer statements? .................................. 7 
Q17.  What information  should be submitted by a sponsor if the raw material manufacturer will 
not provide any residual solvent information? ............................................................... 8 
Q18.  How should residual solvents in coating materials, colorants, flavors, capsules, and 
imprinting inks be characterized? .................................................................................. 8 
   
  2  Contains Non-Binding  Recommendations 
Guidance for Industry 
 
Residual Solvents in Animal  Drug Products 
Questions and Answers 
 
This guidance represents the Food and Drug Administrations (FDA or Agency) 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 using the contact information on the title page of this guidance. 
 
INTRODUCTION 
 
On July 1, 2008, the United States Pharmacopeia (USP) implemented  a requirement for the 
control of residual solvents in drug products marketed in the United States.  Once implemented, 
the requirement, USP General Chapter <467> Residual Solvents, became a statutory requirement 
under section 501(b) of the Federal Food, Drug, and Cosmetic Act. 
 
The USP General Chapter <467> Residual Solvents applies to both human and veterinary drugs 
and to compendial  and non-compendial  drug products.  Because the drug products CVM 
regulates are administered to a number of different animal species, CVM allows for a flexible 
approach to the implementation  of USP <467> Residual Solvents.  This document answers 
questions regarding CVMs implementation  of USP <467> Residual Solvents.  
 
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. 
 
Drug Product 
 
Q1.  WHAT INFORMATION SHOULD BE SUBMITTED TO DEMONSTRATE COMPLIANCE WITH 
USP <467>? 
 
A.  For each raw material in a formulation,  you should submit the following  information:   
  Raw material manufacturers statement regarding residual solvents (See Q13, 14, and 15) 
  Sponsor's verification  of raw material manufacturers statement (See Q15, 16, 17) 
 
For the drug product, information  in the submission  should include:   
  A finished product specification  or certificate of analysis stating complies with USP 
<467> 
  For each residual solvent identified  by the drug substance manufacturer, raw material 
manufacturer, or used by the sponsor: 
  3  Contains Non-Binding  Recommendations 
 
  A statement that indicates which option was used to demonstrate compliance with 
o
USP <467> and a summary of the appropriate calculation,  if Option 2 or 3 was used, 
indicate the source of data used in the calculation; 
  The results of any residual solvent testing on the drug product, if applicable,  and 
o
  Method validation  if the finished product is tested (See Q8) 
o
 
  Suitable information  to support the safety of residual solvents that are not defined as 
being Class 1, Class 2, or Class 3 solvents (See Q6) 
 
Q2.  ARE COMMITMENTS TO SUBMIT RESIDUAL SOLVENT DATA IN A FUTURE SUBMISSION 
ALLOWED? 
 
A.  CVM stopped accepting commitments on July 1, 2010, and will incomplete  any submissions 
that do not include data that demonstrate compliance with USP <467> or do not reference a 
previous commitment  to provide this data. 
 
Q3.  IF A FORMULATION OF A DRUG PRODUCT CONTAINS A SOLVENT, IS THAT SOLVENT HELD 
TO THE LIMITS IN USP <467>? 
 
A.  No, USP <467> does not apply to the actual component in the formulation;  however, any 
residual solvents in that component should meet USP <467> limits. 
 
Q4.  THERE ARE CURRENTLY SOME DIFFERENCES IN SOLVENT CLASSIFICATIONS/LIMITS 
BETWEEN USP <467> AND VICH GL18(R).  HOW SHOULD DIFFERENCES IN USP AND VICH 
CLASSIFICATIONS BE ADDRESSED? 
 
A.  Any proposed differences from USP classifications  must be justified  for compendial 
products. Where there are differences in residual solvent classification  between USP <467> 
and VICH GL18(R), CVM will continue to accept the justification  that residual solvent limits 
conform to recommendations contained in VICH GL18(R).  
 
Q5.  THERE ARE SITUATIONS WHERE THE USP MONOGRAPH FOR THE ACTIVE INGREDIENT 
IN A FORMULATION INCLUDES A SPECIFICATION FOR A CLASS 2 OR CLASS 3 SOLVENT.  IF THE 
ACTIVE INGREDIENT IS THE ONLY SOURCE FOR THE SOLVENT IN THE FORMULATION, AND THE 
ACTIVE INGREDIENT MEETS THE SPECIFICATIONS OF THE USP MONOGRAPH, DOES THE DRUG 
PRODUCT STILL HAVE TO COMPLY WITH THE LIMITS IN USP <467> FOR THIS SOLVENT? 
 
A.  In this case, it is sufficient to comply with the solvent limits  in the USP monograph for the 
active ingredient for the drug product to demonstrate compliance with USP <467>. 
   
  4  Contains Non-Binding  Recommendations 
Q6.  WHEN IS IT ACCEPTABLE TO USE A CLASS 1 SOLVENT? 
 
A.  Class 1 solvents should be avoided whenever possible.  However, a sponsor or raw material 
manufacturer may use them if the user has diligently  evaluated other solvents and provided 
valid reasons why alternative solvents are not appropriate.  Compliance with USP <467> 
limits  is not, in itself, considered adequate justification.   The raw material manufacturer 
should provide a list of Class 1 solvents with specifications and data used in the 
manufacturing of raw materials. 
 
Q7.  HOW SHOULD THE ACCEPTANCE CRITERION BE ESTABLISHED FOR A RESIDUAL 
SOLVENT THAT IS NOT CLASSIFIED (AS CLASS 1, 2 OR 3) IN USP <467>? 
 
A.  Scientific literature and toxicology  data can be used to support the proposed acceptance 
criterion. 
 
Q8.  IF A DRUG PRODUCT UTILIZES RAW MATERIALS SUPPLIED IN SOLVENTS AND THE 
SOLVENT IS THEN DRIVEN OFF DURING THE DRUG PRODUCT MANUFACTURING STEPS, DOES THE 
FINAL DRUG PRODUCT NEED TO BE TESTED AND DO ALL THE LIMITS IN USP <467> APPLY? 
 
A.  For raw materials supplied in solutions,  the solvent is considered a component in the drug 
product manufacturing process and therefore USP <467> applies to this solvent. The removal 
of the solvent by the drug product manufacturing process should be demonstrated by either 
drug product testing or an ICH Q8(R) Quality by Design (QbD)-based approach. 
 
Drug Product Testing 
 
Q9.  SHOULD RESIDUAL SOLVENT TEST METHODS USED FOR TESTING OF THE DRUG PRODUCT 
BE VALIDATED OR VERIFIED? 
 
A.  Non-USP methods should be validated.  USP methods should be verified (see USP <1226>). 
The sponsor should submit summary data in support of the validation  of a non-USP method 
or verification  of the USP method. 
 
Q10.  WOULD IT BE ACCEPTABLE TO USE A HIGH PURITY SOLVENT IN PLACE OF THE USP 
REFERENCE  STANDARD? 
 
A.  Yes, a high purity solvent may be used in lieu of the reference standard if the sponsor 
provides suitable documentation  (i.e., certificate of analysis) of the purity and source. 
 
Q11.  CAN LOSS ON DRYING (LOD) BE USED TO CONTROL CLASS 3 SOLVENTS EVEN IF CLASS 
2 SOLVENTS ARE PRESENT PROVIDING THAT THE TOTAL OF BOTH CLASSES IS <0.5%? 
 
A.  Yes, provided that all Class 2 solvents likely  to be present are addressed separately and 
suitable controls are in place to ensure that the likely  to be present Class 2 solvents are 
below the Option 1 limits  from USP <467>.  Sponsors should be aware that unidentified 
  5  Contains Non-Binding  Recommendations 
Class 3 solvents may interfere with analytical methods to measure Class 2 solvents. See Q14 
for a definition  of likely  to be present. 
 
Raw Materials 
 
Q12.  ARE RAW MATERIALS REQUIRED TO MEET THE RESIDUAL SOLVENT LEVELS STATED IN 
USP <467>? 
 
A.  No, the residual solvent levels stated in USP <467> are specifically for finished dosage 
forms.  Raw material manufacturers should provide a statement specifying the residual 
solvents likely  to be present so the drug product manufacturer can demonstrate that the drug 
product complies with USP <467>.  If all raw materials meet the residual solvent levels 
stated in USP <467>, then Option 1 can be used for the finished dosage form. If any raw 
material does not meet the residual solvent levels stated in USP <467>, then Options 2, 3, or 
finished dosage form testing can be used for the finished dosage form. 
 
Q13.  WHAT SHOULD A RAW MATERIAL  MANUFACTURERS STATEMENT REGARDING 
RESIDUAL SOLVENTS CONTAIN? 
 
A.  A raw material manufacturers statement regarding residual solvents should contain: 
  All Class 1 solvents used or generated, 
  All Class 2 solvents likely  to be present, 
  Whether Class 3 solvents are likely  to be present and the identity  of all Class 3 solvents 
present at greater than 0.5%, and 
  All other solvents likely  to be present, as applicable. 
 
Also, in all circumstances: 
  You should include numerical values for the limits  of all solvents identified  above.  
These results can be reported as equal to or less than the limits  specified in USP <467> 
and need not be the actual values of the concentrations in the raw materials. For example:  
If the USP limit  for a solvent is 20 ppm and the actual testing provides a result of 3 ppm 
present in the raw material, the numerical value for the result can be stated as < 20 ppm. 
 
We prefer that the raw material manufacturers statement regarding residual solvents be 
included in the raw material manufacturers COA, although a separate raw material 
manufacturers statement may be used. 
 
Examples of such statements include: 
  Only Class 3 solvents are likely  to be present. Loss on drying is less than 0.5 percent. 
  Only Class 2 solvents X and Y are likely  to be present. All are below the Option 1 limit. 
(Here the raw material manufacturer should name the Class 2 solvents represented by X 
and Y and provide the Option 1 limit  for each solvent). 
  Only Class 2 solvents X and Y and Class 3 solvents are likely  to be present. Residual 
Class 2 solvents are below the Option 1 limit  and residual Class 3 solvents are below 0.5 
percent. 
  No Class 1, Class 2, Class 3, or other solvents are used. 
  6  Contains Non-Binding  Recommendations 
 
Q14.  HOW DOES CVM DEFINE LIKELY TO BE PRESENT? 
 
A.  Likely  to be present refers to the solvents used or produced in the final manufacturing step 
and to solvents that are used or produced in earlier manufacturing steps and not removed 
consistently by a validated process.  CVM would consider listed solvents which are removed 
or present in the raw materials at less than 10% of the listed limit  to be NOT likely  to be 
present. Therefore, these solvents do not have to be reported on the raw material vendors 
COA as part of the residual solvents compliance information  in an application.   Whenever 
possible,  the raw material vendor should demonstrate that their process will consistently 
remove the residual solvents at the level they are purporting  and justify why it is acceptable 
to omit the residual solvents testing. 
 
Q15.  SOMETIMES EXCIPIENT MANUFACTURERS DO NOT PROVIDE INFORMATION IN A 
CUSTOMARY CERTIFICATE  OF ANALYSIS.  MANY FIRMS OBTAIN THIS INFORMATION THROUGH 
SURVEYS OF THEIR SUPPLIERS.  IS THIS AN ACCEPTABLE FORMAT TO DEMONSTRATE 
COMPLIANCE WITH USP <467? 
 
A.  Any format that has been used to obtain the information  from the excipient supplier is 
acceptable.  The suppliers statement about the residual solvents likely  to be present should 
be submitted to CVM as part of the application.   The information  included  in the suppliers 
statement is used to demonstrate compliance regardless of the format received from the 
supplier.  The suppliers information  should be verified by the drug product sponsor.  Note 
that the drug sponsor is ultimately  responsible for the quality of all materials used to 
manufacture drugs.  If residual solvent information  is provided in a statement or survey 
rather than on the COA, the drug sponsor should demonstrate that they have an agreement 
with the supplier  to update the statement regarding any changes in the residual solvents 
information  and that this updated information  will  be provided  to CVM. 
 
Q16.  HOW CAN A SPONSOR VERIFY RAW MATERIAL  MANUFACTURER  STATEMENTS? 
 
A.  The sponsor tests the residual solvents as a part of the complete testing protocol in order to 
demonstrate that it is capable of performing the tests and to verify the raw material 
manufacturers data for each identified  residual solvent.1  Once the raw material 
manufacturers data is validated and verified, the sponsor can implement  a vendor 
qualification  program as set forth in 21 CFR 211.84(d)(2).  The sponsor should submit 
complete COAs for all raw materials, including  residual solvent data, to demonstrate 
verification  and compliance with USP <467>. 
 
                                              
1 The reasons for requesting sponsors to perform the complete testing protocol are twofold, i.e., to verify the actual 
testing results but, more importantly, to ensure that the sponsor is capable of performing the tests, so that it can run 
specific tests when problems arise.  Without this capability, many firms are inadequately prepared when a problem 
does arise.  
 
  7  Contains Non-Binding  Recommendations 
A raw material manufacturers statement that solvents are not used does not require the 
sponsors verification.   However, the statement from the vendor should be referenced in the 
raw material specification. 
 
Q17.  WHAT INFORMATION SHOULD BE SUBMITTED BY A SPONSOR IF THE RAW MATERIAL 
MANUFACTURER  WILL NOT PROVIDE ANY RESIDUAL SOLVENT INFORMATION? 
 
A.  If the raw material manufacturer will not provide residual solvent information,  then it is the 
sponsors responsibility  to test for all residual solvents listed in USP <467> for each batch of 
material received.  An appropriately  validated LOD test may be used as an initial  qualitative 
test only for Class 3 residual solvents, however, more extensive quantitative testing for Class 
3 solvents will be required if the LOD indicates presence of solvents.  An LOD test will not 
reveal Class 1 or 2 solvents above the USP <467> levels, and these should be tested for by a 
quantitative  method. 
 
Q18.  HOW SHOULD RESIDUAL SOLVENTS IN COATING MATERIALS, COLORANTS, FLAVORS, 
CAPSULES, AND IMPRINTING INKS BE CHARACTERIZED? 
 
A.  Information on residual solvents in flavors should be included.  Information on residual 
solvents in coating materials, colorants, capsules, and imprinting  inks is generally not needed 
unless Class 1 solvents are used in the manufacture of these components. 
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