Introduction to USP General Chapter Residual Solvents

Updated: May 2021

Pedro López García

Course ID: CM-467-03

Introduction to USP General Chapter

<467> Residual Solvents

Pedro López García

Ph.D.

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Instructor Name Here

Company: DSV LAB consultoria

Education: B.S., Pharmaceutical Chemist, University of San Carlos of Guatemala

M.Sc., Drug and Medicines, University of São Paulo

Ph.D., Drug and Medicines, University of São Paulo

Dr. Pedro López García earned both a Ph.D. and M.Sc. in Drug and Medicines at the

University of São Paulo, Brazil as well as a Bachelor degree in Pharmaceutical Chemist

from the University of San Carlos, Guatemala. Pedro was a Scientist at USP-Brazil from

2012 to 2020 working in the USP-Brazil Collaborative Lab and RSE department.

He has over 20 years of experience in chromatography, capillary electrophoresis and development and validation

of analytical methodologies. His knowledge and experience has enabled him to instruct industry professionals and

healthcare practitioners as well as be a successful academic researcher and professor. He has the ability to work

with residual solvents and knowledge of USP General Chapters <467> and <1467>. His expertise is in HPLC, GC,

GC-MS and CE. He is currently a founding partner of a consulting company in the pharmaceutical field in São

Paulo, Brazil.

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Because USP text and publications may have legal implications in the U.S. and elsewhere, their language must stand on

its own. USP shall not provide an official ex post facto interpretation to one party, thereby placing other parties without

that interpretation at a possible disadvantage. The requirements shall be uniformly and equally available to all parties.

In addition, USP shall not provide an official opinion on whether a particular article does or does not comply with

compendial requirements, except as part of an established USP verification or other conformity assessment program that

is conducted separately from and independent of USP’s standards-setting activities. In addition, except as part of

specified program offerings, USP shall not provide an official opinion on compliance with any applicable regulatory

requirements.

Certain commercial equipment, instruments or materials may be identified in this presentation to specify adequately the

experimental procedure. Such identification does not imply approval, endorsement or certification by USP of a particular

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purpose or that any other brand or product was judged to be unsatisfactory or inadequate. Images of commercial

equipment, instruments or materials in this presentation are copyrighted by their respective owners and are not owned by

USP.

This course material is USP property. Duplication or distribution without USP’s written permission is prohibited.

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error or omission has occurred, please bring it to our attention. We will in good faith correct any error or omission that is

brought to our attention. You may email us at [email protected].

Disclaimer

mailto:[email protected]

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Course Objectives

Upon completion of this course, you will be able to:

Understand the historical approaches and standards contained in USP General

Chapter <467>.

Apply a risk-based strategy concept for complying with residual solvents content

in pharmaceutical requirements of USP <467>.

Illustrate Options 1 and 2, as well as Procedures A, B, and C as described in

USP <467>.

Differentiate between validation and verification and understand when to use

alternative procedures.

Understand validation and verification requirements as described in USP

General Chapter <1467>.

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Course Outline

Modules

History & Scope of the Guideline

Analytical Procedures

Regulatory Aspects

Recent Revisions

– (Major revision of USP <467> and the new USP chapter <1467>, official from November 1, 2019)

– IRA (Reclassification of MIBK as Class 2 solvent and adding Triethylamine as Class 3 solvent)

History & Scope of the

Guideline

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Module Outline

Topics

Pre-ICH Q3C era – USP <467>

Organic Volatile Impurities

ICH Q3C

USP Transition from <467> OVI to

<467> Residual Solvents

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“…residual solvents in pharmaceuticals are defined as organic volatile

chemicals that are used or produced in the manufacture of drug substances,

excipients, or dietary ingredients, or in the preparation of drug products, or

dietary supplement products.”

Residual Solvents — Definition

Current definition from USP Chapter <467>

NOTE: “Residual solvents” refers to the

amount not removed during the purification

of the product.

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Organic Volatile Impurities USP <467>

– Proposed in PF 14(2) (1988)

– Incorporated into 3rd Supplement to USP 22 (1990)

– Based on feedback from Open Conference in 1986

– Revised regularly

– Focused initially on seven solvents (five included in ICH Guidance)

• Acceptance criteria based on relative toxicity

• Applied only to drug substances and some excipients

Pre-ICH Q3C Era – USP <467> Organic Volatile Impurities

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Residual solvents controlled: Benzene – 100 (2) ppm, Ethylene Oxide – 10 (?)

ppm, Chloroform – 50 (60) ppm, Dioxane -100 (380) ppm, Methylene Chloride-

100 (600) ppm, and Trichloroethylene -100 (80) ppm.

Four methods: I, IV, V, and VI

Standards: reagent grade solvents

Direct injection or Headspace (Method IV)

Column: G27 (Method I), G43 (Methods IV and V), various supports and

coatings (Method VI)

Dissolving solvent: “water or the solvent specified in the monograph”

Pre-ICH Q3C Era – USP <467> Organic Volatile Impurities

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ICH: International Council for Harmonization of Technical Requirements for

Pharmaceuticals for Human Use (previously was International Conference on

Harmonization of Technical Requirements for the Registration of Drugs for

Human Use)

ICH Q3C

– Published in July 1997

– Revised in 2002

EP adopted the ICH Q3C guideline in 1999

– General Chapter 5.4 – An introductory paragraph, reproduces the ICH Guideline

– Chapter 2.4.24 – Identification and control of residual solvents (test methods)

History of ICH Q3C and EP

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First proposal to amend USP General Chapter <467> and General Notices

published in PF 29(4), 2003; it incorporates the ICH Q3C classification and

evaluation system and EP procedures.

New chapter became official in USP 28 in 2005 (it still included Methods I, IV, V,

and VI of the previous USP <467> chapter as OTHER ANALYTICAL

PROCEDURES).

USP Transition from <467> OVI to <467> Residual Solvents

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“Residual Solvents – The requirements are stated in USP <467> Residual

Solvents together with information in Impurities in Official Articles <1086>.

USP 29–NF 24 General Notices Text

NOTE: Thus, all drug substances,

excipients, and products are subject to

relevant control of residual solvents, even

when no test is specified in the individual

monograph.

The requirements have been aligned with the ICH

guideline on this topic. If solvents are used during

production, they are of suitable quality. In addition,

the toxicity and residual level of each solvent are

taken into consideration, and the solvents are limited

according to the principles defined and the

requirements specified in USP <467> Residual

Solvents, using the general methods presented

therein or other suitable methods. Official July 1st,

2008).”

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5.60.20 Residual Solvents in USP and NF Articles: “All USP and NF articles

are subject to relevant control of residual solvents, even when no test is

specified in the individual monograph. . .”

ICH: “ . . .nor does it apply to existing marketed drug products.”

USP General Notices

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1. Driving force: Safety of the patient; recommends use of less toxic solvents

“The objective of this general chapter is to define acceptable amounts of residual solvents in pharmaceutical drug products and dietary supplement products for the safety of the patient.”

2. Testing is to be performed only for solvents “likely to be present”

– Used or produced in the final manufacturing step

– Used or produced in earlier manufacturing steps that are not consistently removed by a validated process

– Solvents properly declared by a validated supplier of a drug substance, excipient, or dietary ingredient

3. The limits specified in this chapter do not apply directly to excipients, drug substances, or dietary ingredients except where specified in the individual monographs.

USP <467> Residual Solvents: Main Points

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4. The concentration in the drug product may be:

– Calculated from the contributions of components

– Determined experimentally; mandatory if:

• Cumulative calculation for a given solvent exceeds acceptance criterion

5. Manufacturers of drug products may rely on data provided by the qualified

suppliers of components.

6. Provides identification and quantification methods


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USP <467> Residual Solvents: Main Points – Control Strategy

Control Strategy Options Diagram for Compliance with

USP <467> requirements

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7. Includes options to allow use of materials that exceed the acceptance criteria

established

8. “This chapter provides procedures for the analysis of residual solvents,

although alternative validated methodologies may also be used to demonstrate

compliance with the defined limits. For guidance on verification of USP

procedures or validation of alternative methods for residual solvents, see

Residual Solvents—Verification of Compendial Procedures and Validation of

Alternative Procedures ⟨1467⟩.” (ICH and EP take similar approach.)


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Class 1 – Solvents to be avoided

Known human carcinogens, strongly

suspected human carcinogens, and

environmental hazards

Class 2 – Solvents to be limited

Non-genotoxic animal carcinogens

or possible causative agents of other

irreversible toxicity, such as

neurotoxicity or teratogenicity

Solvents suspected of other

significant but reversible toxicities

Risk-Based Solvent Classification

NOTE: All solvent levels should

be reduced to the extent

possible.

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Risk-Based Solvent Classification

Class 3 – Solvents with low toxic

potential

Solvents with low toxic potential to

man; no health-based exposure limit is

needed

Other residual solvents –

No toxicological data found on which to

base a PDE

NOTE: All solvent levels should

be reduced to the extent

possible.

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Class 1: the concentration limits, in ppm, are provided in Table 2 of the chapter.

Their levels should not be exceeded, “unless otherwise stated in the individual

monograph”.

Class 2: the concentration limits should be calculated from PDE using the

formula:

Concentration (ppm) = 1000 x PDE/Dose, where PDE is given in mg/day, and

dose in g/day

Concentration limits provided in Table 3 are to be used when the daily dose

does not exceed 10 g, it is not known, or is not fixed.

Class 3: PDE is 50 mg/day or more (“unless otherwise stated in the individual

monograph”), corresponding to a concentration limit of ≤0.5% for daily doses not

greater than 10 g.

Limit of Residual Solvents

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Class 1: Should not be employed in the manufacture of

drug substances, excipients, and drug products

because of the unacceptable toxicities or deleterious

environmental effects.

However, if their use is unavoidable, their levels should

be restricted as shown in Table 2.

Limit of Residual Solvents: Class 1

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Solvent Concentration Limit (ppm) Concern

Benzene 2 Carcinogen

Carbon Tetrachloride 4 Toxic,

Env. Hazard

1,2-Dichloroethane 5 Toxic

1,1-Dichloroethene 8 Toxic

1,1,1-Trichloroethane 1,500 Env. Hazard

LIMITS OF RESIDUAL SOLVENTS: Class 1 Solvents

Table 2: Class 1 (5 Residual Solvents)

These solvents should be avoided whenever possible. USP allows their use with justification. Levels must be routinely controlled in either:

Intermediates,

Final active substance, or

Final drug product

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Class 2 residual solvents should be limited in drug substances,

excipients, and drug products because of their inherent toxicities.

Their levels should be restricted as shown in Table 3.

Concentration limits (ppm) vary between 50 (Methylbutylketone)

and 4500 (Methylisobutylketone).

When Class 2 residual solvents are used or produced in the

manufacturing or purification process, they should be identified, and their

levels should be demonstrated to be acceptable.

LIMITS OF RESIDUAL SOLVENTS: Class 2 Solvents

Class 2: 29 solvents

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Class 2 Residual Solvents: Table 3

Solvent Concentration Limit (ppm)PDE

(mg/day)

Acetonitrile 410 4.1

Chlorobenzene 360 3.6

Chloroform 60 0.6

Cumene (USP 36 1supp) 70 0.7

Cyclohexane 3880 38.8

1,2-Dichloroethene 1870 18.7

1,2-Dimethoxyethane 100 1.0

N,N-Dimethylacetamide 1090 10.9

N,N-Dimethylformamide 880 8.8

1,4-Dioxane 380 3.8

2-Ethoxyethanol 160 1.6

Ethylene glycol 620 6.2

Formamide 220 2.2

Hexane 290 2.9

Methanol 3000 30.0

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Class 2 Residual Solvents: Table 3

Solvent Concentration Limit (ppm)PDE

(mg/day)

2-Methoxethanol 50 0.5

Methylbutylketone 50 0.5

Methylcyclohexane 1180 11.8

Methylene chloride 600 6.0

Methylisobutylketone (USP 2020 supp 2) 4500 45

N-Methyl-pyrrolidone 530 5.3

Nitromethane 50 0.5

Pyridine 200 2.0

Sulfolane 160 1.6

Tetrahydrofuran 720 7.2

Tetralin 100 1.0

Toluene 890 8.9

Trichloroethylene 80 0.8

Xylenes 2170 21.7

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Concentration = 1000 X PDE / Dose

Concentration, in ppm

PDE (Permitted Daily Exposure), in mg/day

Dose, in g/day

Permitted Daily Exposure

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Option 1:

Components of the drug product (drug substances and excipients) meet the

concentration acceptance criteria listed in Table 3, and the daily dose does not

exceed 10 g: drug product passes

Option 2:

At least one of the components of the drug product exceeds the concentration

acceptance criteria, or the daily dose exceeds 10 g: the daily exposure to a

solvent (calculated as the sum of the components contributions) should be less

than the PDE

Options for Determining Levels of Class 2

Residual Solvents in Drug Products

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PDE acetonitrile = 4.1 mg/day, thus Option 1 acceptance criterion is 410 ppm (from Table 3)

5.0 g drug product/day: Composed of two excipients

Excipient 1 meets Option 1 acceptance criterion of 410 ppm

Drug substance and excipient 2 do not meet Option 1 acceptance criterion of 410 ppm

Drug product, however, meets Option 2 acceptance criterion of 4.1 mg/day

Example 1: Option 1 and Option 2, with Acetonitrile

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ComponentAmount in

Formulation (g)

Acetonitrile Content Limit

(ppm)

Daily Exposure

(mg)

Drug Substance 0.3 800 (exceeds) 0.24

Excipient 1 0.9 400 (pass) 0.36

Excipient 2 3.8 800 (exceeds) 3.04

Drug Product 5.0 728 3.64 (PASS)

Example 1: Option 1 and Option 2, with Acetonitrile

DE = Concentration X Dose / 1000

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PDE acetonitrile = 4.1 mg/day, thus Option 1 acceptance criterion is 410 ppm

(from Table 3)

5.0 g drug product/day: Composed of two excipients

Drug product does not meet Option 1 or Option 2 acceptance criteria

Manufacturer could test to see if manufacturing did reduce the level of

acetonitrile in drug product below 410 ppm; if so, it passes

Example 2

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Component Amount in Formulation (g)

Acetonitrile Content

Limit

(ppm)

Daily Exposure

(mg)

Drug Substance 0.3 800 0.24

Excipient 1 0.9 2000 1.80

Excipient 2 3.8 800 3.04

Drug Product 5.0 1060 5.08 (FAIL)

Example 2

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Less toxic and of lower risk to human health

Unless otherwise stated in the individual monograph, PDE is 50

mg/day or more, which would render a concentration limit of

5000 ppm or 0.5% as acceptable for daily doses not greater

than 10 g of product.

In some cases, testing can be done by LOD.

If the monograph allows for a concentration resulting in more

than 50 mg/day, Class 3 solvents must be identified and

quantified using procedures similar to those for Classes 1 and 2.

Class 3 Solvents

Class 3: 26 solvents

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Class 3 Residual Solvents

Acetic acid Heptane

Acetone Isobutyl acetate

Anisole Isopropyl acetate

1-Butanol Methyl acetate

2-Butanol 3-Methyl-1-butanol

Butyl acetate Methylethylketone

tert-Butylmethyl ether Methylisobutylketone

Cumene 2-Methyl-l-propanol

Dimethyl sulfoxide Pentane

Ethanol 1-Pentanol

Ethyl acetate 1-Propanol

Ethyl ether 2-Propanol

Ethyl formate Propyl acetate

Formic acid Triethylamine

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For a new solvent (e.g., not listed in Class 1, 2 or 3) or for a level of a listed

solvent higher than the limit currently given in this chapter that are approved by

a competent regulatory authority:

– The manufacturer should notify USP of the identity, the approved acceptance criterion and the

test procedure.

– USP will address the topic in the individual monograph.

For a new solvent approved through the ICH process:

– The solvent will be added to the appropriate list in USP General Chapter <467>.

New Solvents

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Check Your Knowledge

?Knowledge Check

Residual Solvents are defined as

A. Organic volatile chemicals used in

the manufacturing process.

B. Organic volatile chemicals

produced during the manufacturing

process.

C. Organic volatiles used or produced

in the manufacturing that are not

removed during purification.

1

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?Knowledge Check

Which of the following ICH Guidelines

addresses the residual solvents

A. ICH Q2(R1)

B. ICH Q3B

C. ICH Q3C

D. ICH Q3D2

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?Knowledge Check

USP General Chapter <467> is

applicable to

A. Monographs that reference the

chapter

B. All USP and NF articles

C. Monographs that include a test for

solvents3

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?Knowledge Check

The residual solvents limits specified in

USP <467> apply to

A. Drug substance, excipients, dietary

ingredients

B. Drug products and dietary

supplement products4

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?Knowledge Check

The concentration of Residual Solvents

can be determined by

A. Calculating the contribution from

each component of the product and

summing these results

B. Experimentally testing the final

product

C. Either calculating the contribution

from each component of the

product and summing these results

or experimentally testing the final

product

5

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?Knowledge Check

The classification of residual solvents

in three classes is based on

A. The solvent’s relative volatility

B. Difficulty of their removal from the

product

C. The solvent’s risk to human health6

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?Knowledge Check

The compendial requirements for the

content of Class 2 solvents are met by

A. Meeting the concentration acceptance

criteria entered in the chapter for doses

not to exceed 10 grams

B. Ensuring that the daily exposure to the

solvent is not more than the PDE

C. Either meeting the concentration

acceptance criteria entered in the

chapter for doses not to exceed 10

grams or ensuring that the daily

exposure to the solvent is not more than

the PDE

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Analytical Procedures

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Module Outline

Topics

ICH, EP and USP Approaches

Decision tree for Class 1 and

Class 2 Residual Solvents

Chromatographic Systems

– Procedure A

– Procedure B

Limit Test Procedures

– Screening Procedures

– Limit Tests When Solvents LTBP

are Known

Quantitative Tests-Procedure C

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ICH: “Any harmonized procedures for determining levels of residual solvents as

described in the pharmacopoeias should be used, if feasible. Otherwise,

manufacturers are free to select the most appropriate validated analytical

procedure...”

EP: “...The analytical procedures (2.2.24) are to be applied wherever possible.

Otherwise, an appropriate validated procedure should be used.”

Analytical Procedures (ICH, EP)

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USP 2021- Issue 1:

– “...The procedures described in the Identification, Control, and Quantification

of Residual Solvents section of this general chapter are to be applied

wherever possible. Otherwise, an appropriate validated procedure is to be

used...”

– This section describes analytical procedures (Procedures A, B, and C) for

evaluating the levels of all Class 1 and the majority of Class 2 residual

solvents. For each test matrix, verification is needed to demonstrate reliability

of the compendial procedure, as described in ⟨1467⟩.

Analytical Procedures (USP)

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USP31–NF26 General Notices:

Compliance with the USP guidelines can also be determined using alternative methods based on their advantages in terms of accuracy, precision, sensitivity, selectivity, or adaptability to automation or in other special circumstances. Such automated procedures or alternative methods shall be validated.

USP32–NF27 General Notices:

Alternative methods and/or procedures may be used if they provide advantages in terms of accuracy, sensitivity, precision, selectivity, or adaptability to automation, or in other special circumstances. Such alternative procedures and methods shall be validated as described in USP<1225> Validation of Compendial Procedures and must be shown to give equivalent or better results.

USP 2021– Issue 1 General Notices:

An alternative method or procedure is defined as any method or procedure other than the compendial method or procedure for the article in question. The alternative method or procedure must be fully validated (see Validation of Compendial Procedures ⟨1225⟩) and must produce comparable results to the compendial method or procedure within allowable limits established on a case-by-case basis.

Use of Alternative Procedures in USP

https://online.uspnf.com/uspnf/current-document/GUID-E2C6F9E8-EA71-4B72-A7BA-76ABD5E72964_4_en-US

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When the solvents LTBP are not known:

– Use the screening tests of Procedure A and Procedure B as required.

– If the article does not meet the acceptance criteria using Procedure A and Procedure B, then

Procedure C-Quantitative Test must be used to quantify the residual solvent(s) present in the

article.

When the solvents LTBP are known:

– Procedure A and/or Procedure B can be used as the limit test for the targeted solvents as

described above.

– User can go directly to Procedure C using one of the approaches described in the chapter,

general, or targeted test.

Identification, Control, and Quantitation of Residual Solvents

Class 1 and Class 2 Residual Solvents

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Decision Tree — Screening and Limit Test

Procedures A and/or B

* Except 1,1,1-trichloroethane (TEC), which should be smaller than 150 times the size of the corresponding peak response from the Class 1 standard solution

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Decision Tree — Procedure C

Quantitative Tests

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Injector: Headspace

Injection type: Split (Split Ratio: 1:5)

Detector: Flame Ionization

Column: G43 capillary GC column:

– 6% cyanopropyl phenyl-94%

dimethylpolysiloxane

– 0.32 mm x 30m, 1.8 µm

– 0.53 mm X 30m, 3.0 µm

ANALYTICAL PROCEDURES FOR CLASS 1 AND CLASS 2 RESIDUAL

SOLVENTS — Chromatographic Systems

Procedure A

Temperatures:

– Injector temperature: 140oC

– Detector temperature: 250oC

– Oven temperature: See table below

Initial

Temperature

(°)

Temperature

Ramp

(°/min)

Final

Temperature

(°)

Hold Time at

Final

Temperature

(min)

40 0 40 20

40 10 240 —

240 0 240 20

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Injector: Headspace



Column: G16 capillary GC column

– Polyethylene glycol compound (av. mol. wt.

about 15,000)

– 0.32 mm x 30m, 0.25 µm

– 0.53 mm X 30m, 0.25 µm



Procedure B

Temperatures



– Oven temperature: See table below

Initial

Temperature

(°)

Temperature

Ramp

(°/min)

Final

Temperature

(°)

Hold Time at

Final

Temperature

(min)

50 0 50 20

50 6 165 —

165 0 165 20

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SOLVENTS — Headspace Parameters

NOTE: Or follow instrument manufacturer’s

recommendation as long as method criteria

are met. Injecting less than this amount is

allowed as long as adequate sensitivity is

reached.

Procedure Parameters

Headspace Instrumental Setting

Set 1 Set 2 Set 3

Equilibration temperature (°) 80 105 80

Equilibration time (min) 60 45 45

Transfer-line temperature (°)

[if appropriate]a

85 110 105

Syringe temperature (°)

[if appropriate]

80–90 105–115 80–90

Carrier gas: helium, nitrogen,b or

hydrogenb at an appropriate pressureb

— — —

Pressurization time(s) (sec) [if appropriate] ≥60 ≥60 ≥60

Injection volume (mL)c 1 1 1

a It is recommended to increase the temperature of the transfer line between runs to eliminate any potential condensation of solvents.

b The use of nitrogen or hydrogen as the carrier gas requires adjustment and verification.

c Injection volume may be expressed in terms of the injection time.

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Summary of System Suitability Requirements for all Procedures

Flexibility for USP Class 1 RS use

Flexibility for USP Class 2 Mixtures use

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Class 1 Standard Solution

– Prepared by serial dilutions (with DMSO and water) of the USP Class 1 Residual Solvents

Mixture RS

Class 1 System Suitability Solution

– Mixture of components of the Class 1 Standard Solution and of the Stock Sample Solution

Class 2 Mix A and Mix B Standard Solutions

– Prepared by serial dilutions of the respective USP Residual Solvent Class 2 Mixture RS

Test Solution

– Prepared by dissolving in (and diluting with) water the article under test

SCREENING OF WATER-SOLUBLE ARTICLES

Preparations

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– Signal-to-Noise (S/N): 1,1,1 trichloroethane > 5


– Signal-to-Noise (S/N): All peaks NLT 3

Class 2 Mixture A Standard Solution

– Resolution: acetonitrile and methylene chloride > 1.0

Procedure A – Acceptance criteria

If a peak response of any peak in the Test Solution is greater than or equal to a

corresponding peak in either the Class 1 Standard Solution, Class 2 Mixture A,

or B Standard Solutions, proceed to Procedure B to verify the identity of the

peak; otherwise, the article meets the requirements of this test.


Procedure A System Suitability

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Standards and Test Solutions: Procedure A

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WATER-SOLUBLE ARTICLES

PROCEDURE A

SYS SUIT 1 Class 1 std stock Class 2 stock A Class 2 stock B Sample stock

Class 1 Mix RS

DMSO

1 mL

9 mL

1 mL

10 mL

WATER

WATER

WATER WATER WATER WATER

1 mL Class 2

Mixture A RS

1 mL Class 2

Mixture B RS

250 mg sample

1 mL 1 mL 1 mL 5 mL 5 mL

Class 1 SysSuit

Test stock 5 mL

Class 1 STD Class 2 Mix A std Class 2 Mix B std Sample

5 mL WATER 5 mL WATER 1 mL WATER 1 mL WATER

RUN SUIT

RUN

S/N Class 1 is NLT 3 S/N 1,1,1-TCE is NLT 5 R AcN-MC is NLT 1.0 - -

Class 1 STD Class 2 Mix A std Class 2 Mix B std Sample

IF TEST >= CLASS 1 or CLASS 2 A or B, THEN RUN PROCEDURE B (Except 1,1,1-TCE > 150 times)

NEEDED

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Signal-to-Noise

S/N = 2H/h

where H is the height of the peak measured from the peak apex to a baseline extrapolated

over a distance 5 times the peak width at its half-height; and h is the difference between the

largest and smallest noise values observed over a distance 5 times the width at the half-

height of the peak and, if possible, situated equally around the peak of interest

System Suitability

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Procedure A: Class 1

G43


1

2

34

5

Column: Rtx®-1301 Dimensions: 30 m x 0.53 mm x 3 μm

Injection: Split 5:1 @ 140 C, 1 mL Carrier Gas: Helium @ about 35 cm/s linear velocity

Column Temperature: 40 C initial, hold for 20 min, then ramp to 240 C

@ 10 C/min and hold for 20 min.

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Procedure A: Class 2 — Mix A

G43

30meter x 0.32mm x 1.80µm

Column: VF-624 ms Dimensions: 30 m x 0.32 mm x 1.8 μm

Injection: Split 5:1 @ 140 C, 1 mL Carrier Gas: Helium

Column Temperature: 40 C for 20 min, then to 240 C


1. Methanol

2. Acetonitrile

3. Methylene Chloride

4. trans-1,2 Dichloroethene

5. cis-1,2 Dichloroethene

6. Tetrahydrofuran

7. Cyclohexane

8. Methyl cyclohexane

9. 1,4-Dioxane

10. Methylisobutylketone

11. Toluene

12. Chlorobenzene

13. Ethylbenzene

14. m-Xylene & p-Xylene

15. o-Xylene

16. Cumene

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Procedure A: Class 2 — Mix B

G43Column: Rtx®-1301 Dimensions: 30 m x 0.53 mm x 3 μm


Column Temperature: 40 C initial, hold for 20 min, then ramp to 240 C

@ 10 C/min and hold for 20 min. Class 2 Mixture B Standard Solution

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Procedure A: Class 3

G4330meter x 0.32mm x 1.80µm

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Injector: Headspace



Column: G16 capillary GC column

– Polyethylene glycol compound (av. mol. wt. about

15,000)

– 0.32 mm x 30m, 0.25 µm

– 0.53 mm X 30m, 0.25 µm



Procedure B

Column temperature



Initial

Temperature

(°)

Temperature

Ramp

(°/min)

Final

Temperature

(°)

Hold Time at

Final

Temperature

(min)

50 0 50 20

50 6 165 —

165 0 165 20

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– S/N: Benzene > 5


– S/N: All peaks > 3


– Resolution: Resolution between methylisobutylketone and cis-dichloroethene is NLT 1

If the peak response(s) for residual solvents in the Test Solution is/are greater

than or equal to a corresponding peak(s) in either the Class 1 Standard

Solution, Class 2 Mixture A, or B Standard Solutions, proceed to Procedure C to

quantify the peak(s); otherwise, the article meets the requirements of this test.


Procedure B System Suitability

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Water-Soluble Articles, Procedure B

SYS SUIT 1 Class 1 std stock Class 2 stock A Class 2 stock B Sample stock

Class 1 Mix RS

DMSO

1 mL

9 mL

1 mL

10 mL

WATER WATER

WATER WATER WATER WATER

1 mL Class 2 A RS 1 mL Class 2 B RS 250 mg sample

1 mL1 mL 1 mL 5 mL 5 mL

Class 1 SysSuit

Test stock 5 mL

Class 1 STD Class 2 Mix A std Class 2 Mix B std Sample Solution

5 mL WATER 5 mL WATER 1 mL WATER 1 mL WATER

RUN SUIT

RUN

S/N Class 1 is NLT 3 S/N Benzene NLT 5 MIBK-DCE is NLT 1.0 - -

Class 1 STD sol Class 2 Mix A std Class 2 Mix B std Sample Solution

IF ANY PEAK IN TEST SOLUTION >= CLASS 1 or CLASS 2 A or B, THEN RUN PROCEDURE C (Except 1,1,1TCE > 150 times)

PROCEDURE B G16, split 1:5

NEEDED Class 1 SysSuit Class 1 STD Class 2 Mix A std Class 2 Mix B std Sample Solution

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Procedure B: Class 1

G16

30-meter x 0.32 mm x 0.25 µm

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Procedure B: Class 2 — Mix A

G1630 meter x 0.32 mm x 0.25 µm

1. Cyclohexane

2. Methyl cyclohexane

3. THF & trans-1,2 Dichloroethene

4. Methanol

5. Methylene Chloride

6. cis-1,2 Dichloroethene

7. Acetonitrile & Methyl Isobutyl ketone

8. Toluene

9. 1,4-Dioxane

10. Ethylbenzene

11. p-Xylene

12. m-Xylene

13. Cumene

14. o-Xylene

15. Chlorobenzene

Column: Restek Stabilwax Dimensions: 30 m x 0.32 mm x 0.25 μm




Detection: Flame Ionization (FID) @ 250 C

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Procedure B: Class 2 — Mix B

G16

30meter x 0.32mm x 0.25µm

Column: Restek Stabilwax Dimensions: 30 m x 0.32 mm x 0.25 μm




Detection: Flame Ionization (FID) @ 250 C

1. Hexane 2. 1,2-dimethoxyethane 3. Trichloroethylene 4. Chloroform 5. Methylbutylketone 6. Nitromethane 7. Pyridine 8. Tetralin

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Procedure B: Class 3

1. Pentane 2. Ethyl ether

3. Methyl-tert-Butyl ether & Heptane 4. Acetone & Ethyl formate & Methyl acetate

5. Ethyl acetate 6. Isopropyl acetate & Methylethylketone

7. 2-Propanol 8. Dehydrated Alcohol

9. Propyl acetate 10. Methylisobutylketone

11. Isobutyl acetate 12. 2-Butanol

13. 1-Propanol 14. Butyl acetate

15. 2-Methyl-1-propanol 16. 1-Butanol

17. Cumene 18. 3-Methyl-1-butanol

19. 1-Pentanol 20. Anisole

21. Acetic acid

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Procedure A conditions

– Headspace

– G43 capillary GC column:

• 6% cyanopropyl phenyl-94% dimethylpolysiloxane

• 0.32 mm x 30 m, 1.8 µm

• 0.53 mm X 30 m, 3.0 µm

– Split ratio: 1:5

– Oven 40oC: 20 min.

– 10oC/min to 240oC, 20 min.

– Injector temp: 140oC

– FID temp: 250oC

If results from Procedure A are inferior to B, use Procedure B conditions.

USP Method: Procedure C

Instrumental Conditions

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Sample stock solution(s) – Same as for Procedure A

Standard stock solution: For each peak identified and verified by Procedures A and B,

dilute the respective USP Residual Solvent Reference Standard with water to obtain a

final concentration of 1/20 of the value stated in Table 2 or Table 3 under Concentration

Limit.

Standard Solution: Transfer 1.0 mL of Standard stock solution to an appropriate

headspace vial, add 5.0 mL of water, apply the stopper, cap, and mix.

Sample Solution: Same as for Procedure A

Spiked sample solution: A Mixture of 5 mL of each Sample stock solution and 1 mL of

Standard Stock Solution

The use of a vial containing the sample spiked with multiple standards is

permitted for Targeted Test, provided that the procedure is validated accordingly.

Preparations for Procedure C: Water-Soluble Articles

General and Targeted Test:

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– S/N: 1,1,1 trichloroethane > 5


– S/N: All peaks > 3

Class 2 Mixture A Standard Solution

– Resolution: Acetonitrile and methylene chloride > 1.0

If Procedure B is used, follow those system suitability requirements.

Procedure C: System Suitability — Water-Soluble Articles

General

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Class 1 Solvent(s) (if present) in the Standard Solution

– S/N: NLT 10 for any solvent except for 1,1,1 trichloroethane > 5 and Any other Class 1

solvents peaks > 3

Class 2 Solvent (Solvents Mixture) in Standard Solution(s)

– Resolution: NLT 1.0 between a peak of interest and any adjacent peak

Procedure C: System Suitability

Targeted test-Procedure A

Targeted test-Procedure B

Class 1 Solvent(s) (if present) in the Standard Solution

– S/N: NLT 10 for any solvent except for benzene > 5 and any other Class 1 solvents peaks > 3

Class 2 Solvent (Solvents Mixture) in Standard Solution(s)

– Resolution: NLT 1.0 between a peak of interest and any adjacent peak

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PROCEDURE C

NEEDED

G43, split 1:3

Class 1 SysSuit

S/N 1,1,1-TCE is NLT 5 S/N Class 1 is NLT 3 R AcN-MC is NLT 1.0 -

Residual Solvent USP RS

Identified in A/B or known to be present

Water

Dilution 1/20 Conc. Limit

Tables 2 and 3

WATER Water

250 mg sample

SAMPLE STOCKSTANDARD STOCK

5 mL5 mL1 mL

1 mL WATER

Spiked Sample Solution Sample Solution

QUANTIFY RESIDUAL SOLVENTS

Water-Soluble Articles, Procedure C

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Calculate the amount, in ppm, of each residual solvent:

= 5(C/W)[ru/(rst-ru)]

C = Concentration, in ppm, of USP Reference Standard in the Standard Solution

W = Weight, in g, of test article taken to prepare the Test Stock Solution

ru = peak response of Residual Solvent in the chromatogram of the Test Solution

rst = peak response of Residual Solvent in the chromatogram of the Spiked Test

Solution

Water-Soluble Articles — USP Method Specifics: Procedure C

Calculations

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Sample stock solution

– Transfer about 500 mg of the article under test, accurately weighed, to a 10-mL volumetric

flask, dissolve in and dilute with DMF to volume, and mix.

Sample Solution

– Transfer 1.0 mL of Test Stock Solution to an appropriate headspace vial, containing 5.0 mL of

water, apply the stopper, cap, and mix.

Procedure C (Use the requirement for General or Targeted test, as applicable.)

– Spiked Sample solution

• NOTE: Prepare a separate Spiked Sample Solution for each peak identified and verified by

Procedures A and B. (The use of a vial containing the sample spiked with multiple standards is

permitted, provided that the procedure is validated accordingly.)

• Transfer 1.0 mL of Test Stock Solution to an appropriate headspace vial, add 1 mL of Standard Stock

Solution and 4.0 mL of water, apply the stopper, cap, and mix.

Preparations for Water-Insoluble Articles

Procedures A and B

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Water-Insoluble Articles, Procedure A

PROCEDURE A G43, split 1:3

Class 1 Mix RS

1 mL 1 mL

DMF DMF

Sample Stock


S/N 1,1,1-TCE is NLT 5 S/N Class 1 is NLT 3 R AcN-MC is NLT 1.0 - -RUN SUIT

RUN

IF ANY PEAK IN TEST SOLUTION >= CLASS 1 or CLASS 2 A or B, THEN RUN PROCEDURE B (Except 1,1,1TCE > 150 times)

Class 1 SYS SUIT Class 1 std stock Class 2 mix A stock Class 2 mix B stock Sample stock


5 mL WATER 5 mL WATER 5 mL WATER 5 mL WATER 5 mL WATER

DMFDMF DMF DMF

0.5 mL

5 mL

10 mL

1 mL Class 2 Mix A RS 0.5 mL Class 2 Mix B RS 500 mg sampleClass 1Std Stock Intermediate

Class 1 std stock

FID detector

G43 wide bore

HS #3 in table 2

Split 3:1 –variable-

Helium 35 cm/sec

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Water-Insoluble Articles, Procedure B

Class 1 Mix RS

1 mL 1 mL

DMF DMF

SampleStock


S/N class 1,1,1-TCE is NLT 5 S/N Class 1 is NLT 3 R AcN-MC is NLT 1.0 - -RUN SUIT

RUN

SYS SUIT 1 Class 1 std stock Class 2 mix A stock Class 2 Mix B stock SAMPLE STOCK


5 mL WATER 5 mL WATER 5 mL WATER 1 mL WATER 5 mL WATER

DMFDMF DMF DMF

0.5 mL

5 mL

10 mL 1 mL Class 2 A

RS

0.5 mL Class 2 B RS 500 mg sample

Class 1 Std Stock Intermediate

FID detector

G43 wide bore

HS #3 in table 2


Helium 35 cm/sec

Class 1 std stock

IF ANY PEAK IN TEST STOCK >= CLASS 1 or CLASS 2 A or B, THEN RUN PROCEDURE B (Except 1,1,1TCE > 150 times)

PROCEDURE B G16, split 1:3

Class 1 STD sol Class 2 Mix A std Class 2 Mix B std Sample SolutionClass 1 SysSuitNEEDED

RUN SUIT 1 S/N Class 1 NLT 3 S/N Benzene NLT 5 MIBK-DCE is NLT 1.0 - -

Class 1 STD sol Class 2 Mix A std Class 2 Mix B std Sample SolutionRUN

IF PEAK/S ID in Proc A >= CLASS 1 or CLASS 2, THEN RUN PROCEDURE C

FID detector

G16 wide bore

HS #3 in table 2


Helium 35 cm/sec

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PROCEDURE C

NEEDED

G43, split 1:3

Class 1 SysSuit

S/N 1,1,1-TCE is NLT 5 S/N Class 1 is NLT 3 R AcN-MC is NLT 1.0 -

Residual Solvent USP RS

Identified in A/B or known to be present

DMF

Dilution 1/20 Conc. Limit

Tables 2 and 3

WATER DMF

500 mg sample

SAMPLE STOCKSTANDARD STOCK

1 mL1 mL1 mL

5 mL WATER4 mL WATER

Spiked Test Solution Sample Solution

QUANTIFY RESIDUAL SOLVENTS

Water-Insoluble Articles, Procedure C

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Calculate the amount, in ppm, of each residual solvent:

= 10(C/W)[ru/(rst-ru)]

C = Concentration in ug per mL of USP Reference Standard in the Standard

Stock Solution

W = Weight, in g, of test article taken to prepare the Sample Stock Solution

ru = peak response of Residual Solvent in the chromatogram of the Sample Solution

rst = peak response of Residual Solvent in the chromatogram of the Spiked

Sample Solution

Water Insoluble Articles Procedure C Calculations

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The headspace procedures in USP <467> are not suitable for the following

compounds:

Formamide

2-ethoxyethanol

2-methoxyethanol

Ethylene glycol

N-methylpyrrolidone

Sulfolane

N,N-dimethylacetamide

N,N-dimethylformamide

These compounds may be detectable if direct injection is used.

Class 2 Solvents Not Possible Using USP <467> Procedures

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Mixture of Class 1 Residual Solvents (1.2 mL/ampule; 3 ampules)

Class 1 Residual Solvents - Benzene (1.2 mL/ampule; 3 ampules)

Class 1 Residual Solvents - Carbon Tetrachloride (1.2 mL/ampule; 3 ampules)

Class 1 Residual Solvents - 1,2-Dichloroethane (1.2 mL/ampule; 3 ampules)

Class 1 Residual Solvents - 1,1-Dichloroethene (1.2 mL/ampule; 3 ampules)

Class 1 Residual Solvents - 1,1,1-Trichloroethane (1.2 mL/ampule; 3 ampules)

USP Reference Standards of Class 1 Residual Solvents

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Class 2 Residual Solvents - Mixture A (1.2 mL/ampule; 3 ampules)

Class 2 Residual Solvents - Mixture B (1.2 mL/ampule; 3 ampules)

Class 2 Residual Solvents - Mixture C (1.2 mL/ampule; 3 ampules)

Reference Standards for 27 individual Class 2 solvents (solutions in DMSO)

Reference Standards for majority of Class 3 solvents (neat material)

USP Reference Standards of Class 2 Residual Solvents

85

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?Knowledge Check

The Procedures A, B and C of USP

<467> are used for determination of

A. All the solvents listed in the chapter

B. Class 1 Solvents

C. Class 2 solvents

D. Class 1 and majority of Class 2

solvents

8

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?Knowledge Check

If solvents likely to be present (LTBP)

are known, the user

A. can use the limit test when the

LTBP are known

B. either A or can use the screening

test

C. either B or can use Procedure C9

87

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?Knowledge Check

The chapter includes two

chromatographic systems, Procedure A

and Procedure B, because

A. They provide more option to users

B. They ensure the residual solvents

are identified and quantified

adequately

C. GC Experts have different columns

preference

10

88

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?Knowledge Check

If the peak responses from the

chromatograms of sample solution are

greater than or equal to corresponding

peaks in either Class 1 Standard Solution ,

Class 2 Mixture A or B Standard Solution

and the article is a drug substance, excipient

or DS ingredient

A. Article does not meet the

requirement for residual solvents

B. Proceed to Procedure C to quantify

those solvents

C. Both A and B

11

89

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?Knowledge Check

The chromatographic system of

Procedure C is

A. Procedure A system

B. Procedure B system

C. Either Procedure A or Procedure B

system, whichever gives the best

chromatographic results12

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?Knowledge Check

A user may perform Procedure C by

following

A. Targeted test standards and

sample solutions preparations and

requirements

B. General test standard solutions and

sample solutions and requirements

C. Either A or B

13

Regulatory Aspects

92

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Module Outline

Topics

FDA Guidance and Other

Documents related to Residual

Solvents

Code of Federal Regulations (CFR)

pertinent to Residual Solvents in

Pharmaceuticals

93

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21CFR 211.194(a)(2)

21CFR 211.84(d)(2)

Guidance for Industry: Residual Solvents in Drug Products Marketed in the United States

– https://www.fda.gov/regulatory-information/search-fda-guidance-documents/residual-solvents-drug-products-marketed-united-states

– Residual Solvents in ANDAs: Questions and Answers (October 28, 2008)

– http://web.archive.org/web/20170830020957/http://www.fda.gov/downloads/aboutfda/centersoffices/centerfordrugevaluationandresearch/ucm119607.pdf

Regulatory Aspects

FDA documents of interest:

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/residual-solvents-drug-products-marketed-united-states

http://web.archive.org/web/20170830020957/http:/www.fda.gov/downloads/aboutfda/centersoffices/centerfordrugevaluationandresearch/ucm119607.pdf

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21 Code of Federal Regulations:

Parts 210 and 211 — CURRENT GOOD MANUFACTURING PRACTICE

FOR FINISHED PHARMACEUTICALS

21CFR 211.194(a)(2) — A statement of each method used in the

testing of the sample. The statement shall indicate the location of data

that establish that the methods used in the testing of the sample meet

proper standards of accuracy and reliability as applied to the product

tested. (If the method employed is in the current revision of the

United States Pharmacopeia, National Formulary, AOAC

INTERNATIONAL, Book of Methods, or in other recognized standard

references, or is detailed in an approved new drug application and the

referenced method is not modified, a statement indicating the

method and reference will suffice). The suitability of all testing

methods used shall be verified under actual conditions of use.

Regulatory Aspects: Methods

https://www.ecfr.gov/cgi-bin/text-idx?SID=651450d8bb14b753a8b83d65ae9057fa&mc=true&node=se21.4.211_1194&rgn=div8

https://www.ecfr.gov/cgi-bin/text-idx?SID=651450d8bb14b753a8b83d65ae9057fa&mc=true&node=se21.4.211_1194&rgn=div8

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21CFR 211.84(d)(2)

Each component shall be tested for conformity with all appropriate

written specifications for purity, strength, and quality. In lieu of such

testing [i.e., conformity with all appropriate written specifications for

purity, strength, and quality] by the [drug product] manufacturer, a

report of analysis may be accepted from the supplier of a component,

provided that at least one specific identity test is conducted on such

component by the manufacturer, and provided that the manufacturer

establishes the reliability of the supplier’s analyses through

appropriate validation of the supplier’s test results at appropriate

intervals.

Regulatory Aspects: Manufacturer-Supplier Relationship (Supplier

Reliability)

https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=651450d8bb14b753a8b83d65ae9057fa&mc=true&n=pt21.4.211&r=PART&ty=HTML#se21.4.211_184

https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=651450d8bb14b753a8b83d65ae9057fa&mc=true&n=pt21.4.211&r=PART&ty=HTML#se21.4.211_184

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Approved before July 1, 2008: and updated as per ICH Q3C maintenance, are required

to comply with USP <467> if they are the subject of an official USP monograph. ANDAs

approved before July 1, 2008, that are not the subject of an official USP monograph

should conform to the ICH Q3C Guidance.

Approved after July 2008: All products that are subject of a USP monograph (official

products) required to conform to USP <467>.

– FD&C Act, Sec. 501 (b) (All drug products) – “[A drug or device shall be deemed to be

adulterated] if it purports to be or is represented as a drug the name of which is recognized in an

official compendium, and its strength differs from, or its quality or purity falls below, the standards

set forth in such compendium.”

The revised USP <467> does not apply to non-compendial drug products. However, FDA

recommends that NDA and ANDA applicants for non-compendial drug products control

and limit residual solvents as described in guidance for industry Q3C Impurities: Residual

Solvents.

Guidance for Industry: Residual Solvents in Drug Products Marketed

in the United States, November 2009



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Official products not approved under an NDA or ANDA:

– Documentation related to the compliance with the guidelines should be kept in the

manufacturing site following the quality system standards

– Verified during inspection

– GMP applies to all products

Official products approved under an NDA or ANDA:

– FDA Regulations (NDAs/ANDAs) – CFR 314.70 (d) (2) (i) Document any changes in the

specifications of NDAs/ANDAs made to comply with an official compendium in the annual

report unless the specification is increased or the test is deleted

– CDER Guidance for Industry (NDAs/ANDAs) – Changes to an Approved NDA or ANDA

(April 2004) – Section VIII.D.1 recommends the use of an annual report to document changes

made to comply with an official compendium

USP <467> — Compliance with Standards According to FDA

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Analytical methods – The use of methods in <467> is not mandatory.

Alternative methods – Can be used if appropriately described and validated

[21 CFR 211.165(e), 211.194(a)(2) and 21 CFR 314.50(d).]

Analytical data – A summary of data from studies and tests conducted [CFR

314.70 (d) (3) (iv)] should be included in the annual report. Full data should be

kept in the quality system of the company and be available during inspections.

FDA: Annual Report

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Manufacturers of pharmaceutical products need certain information about the

content of residual solvents in drug substances or excipients in order to meet

the criteria of this general chapter.

– Only Class 3 solvents are likely to be present. Loss on drying is less than 0.5%.

– Only Class 2 solvents X, Y,... are likely to be present. All are below the Option 1 limit.

(Here the supplier would name the Class 2 solvents represented by X, Y,...)

– Only Class 2 solvents X, Y,... and Class 3 solvents are likely to be present. Class 2 residual

solvents are below the Option 1 limit, and Class 3 residual solvents are below 0.5%.

Manufacturer-Suppliers Relationship

Recent Revisions

(official from

March 1, 2019)

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Module Outline

Topics

New Chapter <1467> (official 1 March

2019 to current)

Revision of <467> (official 1 March

2019 to 31 October 2019)

<467> Interim Revision Announcement

(IRA) (official 1 November 2019 to 30

November 2020)

<467> IRA Implementation (official 1

December 2020 to current)

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Verification of Compendial Procedures Validation of Alternative Procedures

Validation/Verification

CharacteristicsLimit Test Methods Quantitative Methods Limit Test Methods Quantitative Methods

Specificity Yes Yes Yes Yes

Detection limit Yesa No Yes No

Quantitation limitb No Yesa No Yes

Accuracy No Yes No Yes

Precision/repeatability No Yes No Yes

Linearity No No No Yes

Range No

Demonstrated by

accuracy and

precision

No

Demonstrated by

accuracy and

precision

Intermediate precision No No No Yes

Solution stabilityc Yes Yes Yes Yes

Robustnessd No No Yese Yese

a System suitability may be used instead to demonstrate sensitivity.b In quantitative tests, quantitation limit may be demonstrated by accuracy determination.c Solution stability should be determined for the timeline of the test.d Evaluation of robustness should be considered during the development phase and depends on the type of procedure under study.e The “Yes” quotation here is intended to emphasize the importance of assessing the robustness of the procedure before the implementation.

Official as of 1 March 2019

USP <1467> Residual Solvents—Verification of Compendial

Procedures and Validation of Alternative Procedures

http://www.usppf.com/pf/pub/data/v432/CHA_IPR_432_c1467.html#CHA_IPR_432_c1467-fna

http://www.usppf.com/pf/pub/data/v432/CHA_IPR_432_c1467.html#CHA_IPR_432_c1467-fnb

http://www.usppf.com/pf/pub/data/v432/CHA_IPR_432_c1467.html#CHA_IPR_432_c1467-fna

http://www.usppf.com/pf/pub/data/v432/CHA_IPR_432_c1467.html#CHA_IPR_432_c1467-fnc

http://www.usppf.com/pf/pub/data/v432/CHA_IPR_432_c1467.html#CHA_IPR_432_c1467-fnd

http://www.usppf.com/pf/pub/data/v432/CHA_IPR_432_c1467.html#CHA_IPR_432_c1467-fne

http://www.usppf.com/pf/pub/data/v432/CHA_IPR_432_c1467.html#CHA_IPR_432_c1467-fne

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Procedure A and Procedure B: solvents likely to be present (ltbp) are not known

Samples

– Prepare a reagent blank

– Standard solutions: Prepare Standard solutions as described in Residual Solvents ⟨467⟩

– Spiked sample solution: Prepare the Spiked sample solution as described in Class 1 System suitability

solution in Residual Solvents ⟨467⟩

Specificity

– No significant interference from peaks from a blank

– The procedure must be able to separate acetonitrile and methylene chloride (Procedure A ) or

methylisobutylketone and cis-dichloroethane (Procedure B)

Detection Limit

– The mean signal-to-noise ratio for each solvent in the Standard solution and Spiked sample solution

[after correction for native (original) solvent content] from at least three determinations from a single

preparation is NLT 3

Solution Stability

– Detection limit should meet the requirements throughout the testing period.

USP <1467> Residual Solvents—Verification of Compendial Procedures

and Validation of Alternative Procedures —Limit Procedures

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Procedure A and Procedure B: solvents likely to be present (ltbp) are known

Samples


– Standard solutions: Prepare Standard solutions as described in Residual Solvents ⟨467⟩ using only those solvents

likely to be present (LTBP)

– Spiked sample solution: Prepare the Spiked sample solution as described in Quantitative Procedures: Procedure C

for solvents LTBP

Specificity


– The procedure must be able to separate each of the solvents in the Standard solution(s) from each other and from

other peaks in the Spiked sample solution with a resolution of NLT 1.0.

Detection Limit

– The mean signal-to-noise ratio for each solvent in the Standard solution and the Spiked sample solution [after

correction for native (original) solvent content] from at least three determinations from a single preparation is NLT 3

Solution Stability



and Validation of Alternative Procedures —Limit Procedures

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Procedure C

Samples


– Standard stock solutions: Prepare a solution containing each solvent LTBP or each peak identified and verified by

Procedure A and Procedure B

– Sample stock solution: Prepare as described in Residual Solvents ⟨467⟩

– Spiked sample solutions A, B, C, etc.: Prepare Spiked sample solutions with the sample matrix and spiked with each

solvent LTBP or identified and verified by Procedure A and Procedure B in Residual Solvents ⟨467⟩

Specificity


– The procedure must be able to separate each of the solvents in the Standard solution(s) from each other and from

other peaks in the Spiked sample solution with a resolution of NLT 1.0. If the resolution between any pair of peaks is

less than 1.5, then verification must demonstrate that the method is suitable for its intended use.

Quantitation Limit

– The mean signal-to-noise ratio for each solvent in the Standard solution and the Spiked sample solution [after

correction for native (original) solvent content] from at least three determinations is NLT 10, or the Quantitation Limit

may be demonstrated by Accuracy and Precision.

.


and Validation of Alternative Procedures —Quantitative Procedures

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Procedure C

Accuracy

– The mean recovery for Spiked sample solutions A, B, and C, etc., when calculated relative to the

Spiked sample solution, is 80%–120% of the expected theoretical amount. [Note—Recoveries should

be corrected for native (original) content of any solvent under test.]

Precision/Repeatability

– Use at least six independent Spiked sample solution preparations from the same lot, prepared as

described in the Spiked sample solution in the Accuracy test above, or use nine independent

preparations as described in Spiked sample solutions A, B, C, etc.

– Relative standard deviation is NMT 20% for each solvent present.

Solution Stability



and Validation of Alternative Procedures —Quantitative Procedures

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Validation of Alternative Procedures:

Chromatographic alternative procedures should meet the acceptance criteria for the

analytical performance characteristics shown below. When non-chromatographic

alternative procedures are validated, the analytical performance characteristics listed

should be addressed, although, it may be appropriate to apply other analytical

performance characteristics. For more information, refer to Validation of Compendial

Procedures ⟨1225⟩.

Limit Procedures

Analytical characteristics to be validated are specificity, detection limit, and solution

stability. The same criteria used for Verification when solvents LTBP are known, as

described above, may be used.


and Validation of Alternative Procedures —Limit Test Procedures

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Validation of Alternative Procedures: Quantitative Procedures

Samples


– Spiked sample solutions P, Q, R, etc.: Prepare Spiked sample solutions with the sample matrix and spiked

with each solvent LTBP at NLT 5 levels covering the range of interest. [Note—Results should be corrected

for native (original) content of any solvent under test.]

Specificity

– The analytical procedure must have the ability to assess unequivocally the analytes of interest in the

presence of the components expected to be present.

Linearity and Range

– Perform linear regression analysis on the results for Spiked sample solutions P, Q, R, etc. The coefficient of

determination, r2, is NLT 0.90.

Quantitation Limit

– The mean signal-to-noise ratio for each solvent in the standard solution and the Spiked sample solution

[after correction for native (original) solvent content] from at least three determinations is NLT 10. The

Quantitation Limit may also be demonstrated by Accuracy and Precision.


and Validation of Alternative Procedures

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Validation of Alternative Procedures: Quantitative Procedures

Accuracy

– The mean recovery for each Spiked sample solution should be 80%–120%. [Note—

Recoveries should be corrected for native (original) content of any solvent under test.]

Precision/Repeatability

– Prepare at least six independent Spiked sample solution preparations from the same lot.

– Relative standard deviation is NMT 20% for each solvent present.

Precision/Intermediate Precision

– Perform the Repeatability test over at least two independent events, e.g., on different days, and/or

using different instruments and/or analysts.

– Testing for intermediate precision should demonstrate that the method is suitable for its intended use.

Solution Stability

– Standard solutions and Spiked sample solutions should be stable throughout the testing period.

– NMT 20% variation


and Validation of Alternative Procedures

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?Knowledge Check

The Analytical Performance

Characteristics give in Table 1 of

<1467> represent

A. Recommended best practices

values specific for residual solvents

testing.

B. Regulatory mandatory

requirements13

111

© 2021 USP


?Knowledge Check

The verification of <467> procedures is

performed

A. To ensure that the chromatographic

system is working properly in a

laboratory.

B. To demonstrate that the procedure

conducted in the laboratory is

suitable for testing a specific

sample for the content of residual

solvents when the test is first

implemented in the laboratory

14

112

© 2021 USP


?Knowledge Check

When performing verification of <467>

procedures or Validation of alternative

procedures, the solution stability must

be checked

A. At the beginning of the run

B. Throughout the entire testing period

C. At the middle of the run

D. Only at the end of the testing period

15

Recent Revision to USP <467>, Official as of 1 March 2019

In addition, the application of this

chapter to dietary supplement (DS)

monographs is clarified in the

chapter where appropriate. As per

DS GMPs [21 CFR 111.70(b) for

each component used in the

manufacture of a DS, and 21 CFR

111.70(e) for each DS that is

manufactured], the manufacturer

must establish product

specifications for quality attributes.

113

© 2020 USP


These specifications must include

limits on those types of

contamination that may cause

adulteration, such as the limits for

residual solvents. However, the

regulations do not provide guidance

on tolerance limits or methods to be

used to measure solvent residues

as contaminants that may

adulterate the finished batch of the

DS.

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© 2020 USP


DS industry trade and professional

associations may ask their members to

adopt specifications such as those

provided in this chapter to limit the

residual solvents in botanical extracts

and other DS where there might be

solvent residues, in a risk-based

approach.

DS claiming compliance with USP

specifications must meet the

requirements of this chapter.

This revision also lists the USP

Reference Standards required for

performing procedures described in this

chapter115

© 2020 USP

Recent Revision to USP <467>, Official as of 1 November 2019

Methylisobytylketone reclassified from

Class 3 Residual Solvent to Class 2

Residual Solvent with a delayed

implementation date of 1 December

2020.

Triethylamine added as a new Class 3

Residual Solvent with a delayed

implementation date of 1 December

2020.

System suitability resolution

requirement for Procedure B revised

from the resolution between AcN and

cis-dichloroethane to the resolution

between methylisobutylketone and cis-

dichloroethane

116

© 2020 USP

https://education.usp.org | [email protected]

http://education.usp.org/

mailto:[email protected]

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