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
Guidance for Industry1

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-thecounter (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.