Guidance for Industry 
Residual Solvents in Drug 
Products Marketed in the 
United States 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
November 2009 
 
CMC 
 
      Guidance for Industry 
Residual Solvents in Drug 
Products Marketed in the 
United States 
 
 
Additional copies are available from: 
Office of Communication 
Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Avenue 
Bldg. 51, rm. 2201 
Silver Spring, MD  20993-0002 
(Tel) 301-796-3400 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
November 2009 
 
CMC  
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND/POLICY...............................................................................................2 
III.  RECOMMENDATIONS..................................................................................................2 
A.  Compendial Drug Products Approved Under an NDA or ANDA............................................2 
B.  Compendial Drug Products Not Approved Under an NDA or ANDA.....................................3 
C.  Non-compendial NDA or ANDA Drug Products........................................................................3   
1
Guidance for Industry  
Residual Solvents in Drug Products Marketed in the United States 
 
 
This guidance represents the Food and Drug Administration's (FDA's) 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.  
 
 
 
I.  INTRODUCTION 
 
This guidance is intended to assist manufacturers in responding to the issuance of the United 
States Pharmacopeia (USP) requirement2 for the control of residual solvents in drug products 
marketed in the United States.  Specifically, this guidance makes recommendations on the 
following: 
 
1.  How new drug application (NDA) and abbreviated new drug application (ANDA) 
applicants for noncompendial drug products should limit residual solvents as described in 
the International Conference on Harmonisation (ICH) guidance for industry Q3C 
Impurities: Residual Solvents (Q3C).  This guidance contains recommendations on 
solvent classification and permitted daily exposure.3 
2.   How manufacturers of compendial drug products that are not marketed under an 
approved NDA or ANDA can comply with USP General Chapter <467> Residual 
Solvents and the Federal Food, Drug, and Cosmetic Act (the Act). 
3.  How holders of NDAs or ANDAs for compendial drug products should report changes in 
chemistry, manufacturing, and controls specifications to FDA to comply with General 
Chapter <467> and 21 CFR 314.70. 
 
For recommendations on solvent classification and permitted daily exposure, please refer to the 
ICH Q3C. 
 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
                                                 
1  This guidance has been prepared by the Office of Pharmaceutical Science in the Center for Drug Evaluation and 
Research (CDER) at the Food and Drug Administration.  
2  USP; General Chapter <467> Residual Solvents. 
3 The levels in ICH Q3C and General Chapter <467> should also be considered for products that are not subject to 
an NDA or ANDA (e.g., over-the-counter monograph products).  
     
cited.  The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required. 
 
 
II.  BACKGROUND 
 
On July 1, 2008, the USP implemented a requirement for the control of residual solvents in drug 
products marketed in the United States.  The requirement, General Chapter <467> Residual 
Solvents, replaced General Chapter <467> Organic Volatile Impurities.  The effective date of 
this change was July 1, 2008. 
 
III.  RECOMMENDATIONS  
 
FDA makes the following recommendations concerning implementation of the USP requirement 
General Chapter <467> Residual Solvents. 
 
A.  Compendial Drug Products Approved Under an NDA or ANDA 
 
1.  Beginning July 1, 2008, U.S. marketed drug products with an official USP 
monograph were required to meet the requirements for control of residual solvents as 
described in General Chapter <467>.4   
 
General Chapter <467> requires control of residual solvents in finished drug products.  Although 
manufacturers may choose to test the drug product, General Chapter <467> also provides options 
for evaluating the active pharmaceutical ingredient and excipient components of the finished 
drug product for residual solvents.  FDA can accept residual solvent test data on components 
from tests performed by the drug product manufacturer or the manufacturer may provide test 
data or, if applicable, appropriate statements obtained from properly qualified suppliers as 
described in 21 CFR 211.84(d)(2).  For example, reports of analysis can be accepted from a 
properly qualified5 supplier of a drug product component and will be used by the drug product 
manufacturer to determine whether the finished drug product complies with the General Chapter 
<467> defined limits.  If the test limits are met for the drug product components, finished 
product testing is unnecessary.   
 
2.  FDA will accept the use of appropriate analytical procedures other than those 
included in General Chapter <467>. 
 
The USP General Notices section on Tests and Assays  Residual Solvents references the use 
of suitable methods other than the specific analytical methods included in General Chapter 
<467>.  FDA will accept the use of such other analytical procedures as referenced in  21 CFR 
314.50(d) provided that all such procedures are properly described and validated and their 
                                                 
4  The Federal Food, Drug, and Cosmetic Act, section 501(b) (21 U.S.C. 351). 
5 As part of ongoing supplier management, a drug product manufacturer is expected to monitor a supplier to assure 
that the component it produces continues to be of consistent quality and laboratory results reported on the COA 
remain reliable.   
     
suitability verified under actual conditions of use as described in the current good manufacturing 
practices (CGMPs) regulations at 21 CFR 211.165(e) and 211.194(a)(2).   
 
For compendial drug products approved under an NDA or ANDA, changes made to the 
specifications in the approved application regarding General Chapter <467> should be in 
accordance with applicable regulations described in 21 CFR 314.70 and the recommendations in 
the guidance for industry on Changes to an Approved NDA or ANDA.  
 
Generally, an annual report, if needed, can be used to report changes such as adding a test to a 
finished product specification or adding an alternative analytical procedure to a specification to 
comply with the USP.  The annual report must contain the information described in 21 CFR 
314.70(d)(3).  As described in 21 CFR parts 210 and 211, detailed data and information related 
to control of residual solvents and compliance with General Chapter <467> should be 
documented and kept available at the manufacturing site for the Agency to review upon request 
during an inspection. 
  
The annual report should be submitted in accordance with applicable regulations described in 21 
CFR 314.70 and the recommendations in the guidance for industry on Changes to an Approved 
NDA or ANDA.  
 
3.  Applicants can submit an amendment to their pending NDA or ANDA to document 
any changes made to implement General Chapter <467> if the drug products are the 
subject of an official USP monograph and the applicants have already submitted 
NDAs or ANDAs to the Agency for approval.   
 
The amendment should be submitted as soon as possible.  Similarly, this same information 
should be included in all new NDAs and ANDAs submitted for compendial drug products. 
 
B.  Compendial Drug Products Not Approved Under an NDA or ANDA   
 
Marketed compendial drug products not approved under an NDA or ANDA (e.g., over-the-
counter (OTC) drug products marketed under an FDA OTC monograph) are also subject to the 
provisions of the Act, General Chapter <467>, and CGMP documentation requirements 
described in 21 CFR parts 210 and 211.  Manufacturers can use appropriate analytical 
procedures other than those in General Chapter <467> provided they properly describe and 
validate their procedures and verify their suitability under actual conditions of use as described in 
21 CFR 211.165(e) and 211.194(a)(2).    
 
C.  Non-compendial NDA or ANDA Drug Products 
 
General Chapter <467> does not apply to noncompendial drug products.  However, FDA 
recommends that NDA and ANDA applicants for noncompendial drug products limit residual 
solvents as described in guidance for industry Q3C Impurities: Residual Solvents.  Applicants 
who have not included limits for residual solvents in their NDA or ANDA, as described in 21 
CFR 314.50(d), should amend their pending applications as soon as possible.