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Interpretation of the New USP General Chapter <467> Residual Solvents

Chair: USP Residual Solvents Project Team

Thomas E. Chapman, Ph.D.

Allergan Inc.

USP-WCDG August 1st, 2008

Introduction: USP Mission

“The United States Pharmacopeia promotes the public health and benefits practitioners and patients by disseminating authoritative standards and information developed by its volunteers for medicines, other health care technologies, and related practices used to maintain and improve health and promote optimal health care delivery.”

History: Residual Solvents

“…..residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products.”

ICH, USP, EP

[Note: “residual solvents” refers to the amount not removed during the purification of the product”]

Residual Solvents

Residual solvents are one of the three main types of impurities in pharmaceutical articles, the other two being organic and inorganic impurities.

Therefore, standards to control the strength,

quality, and purity of official pharmaceutical articles in the United States Pharmacopeia (USP) and the National Formulary (NF) frequently include a test for residual solvents, together with procedures for the test and acceptance criteria.

Residual Solvents

The implementation of modern standards to control these types of impurities has occupied regulatory agencies, pharmaceutical manufacturers, and pharmacopeias for many years.

Substantial progress in the overall effort came with development of the ICH Q3C Guideline in 1997 (Impurities: Guideline for Residual Solvents) and subsequent adoption of this Guideline as a FDA guidance.

ICH Q3C and EP

ICH Q3C Published in July 1997 Revised in 2002

EP adopts the ICH Q3C guideline in 1999. General Chapter 5.4. An introductory

paragraph and reproduces the ICH Guideline

Chapter 2.4.24 Identification and control of residual solvents (Test methods for Class 1, 2 and 3 Residual Solvents)

<467> Organic Volatile Impurities

Individual monographs specify which <467> method to follow.

Residual solvents controlled: Chloroform (60 ppm), Dioxane (380 ppm), Methylene Chloride (600 ppm) and Trichloroethylene (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”

USP incorporates ICH Q3C classification and evaluation system and EP procedures

USP was not consistent with Q3C Impurity guideline (1997)

First proposal to amend General Chapter <467> and General Notices published in PF 29(4), 2003

USP: Residual Solvents

General Notices and Requirements statement: ….”all drug substances, excipients, and products are subject to relevant control of residual solvents”……..

Monograph Changes<467>OVI: Removed

USP: Residual Solvents

USP 29-NF 24 General Notices Text

“ Residual solvents – The requirements are stated in Residual solvents

<467> together with information in Impurities in Official Articles <1086>.

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 Residual solvents <467>, using the general

methods presented therein or other suitable methods. (Official July 1,

2008)

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

2. Testing is to be performed only for solvents “likely to be present” used or produced in the final manufacturing step used in previous steps and not removed by a validated

procedure

3. The limits for acceptable concentrations listed in the Chapter are for drug products, not for its components.

Residual Solvents <467>: Main Points

Residual Solvents <467>: Main Points, continued

4. The concentration in the drug product may be calculated from the contributions of components determined experimentally; mandatory if

• solvents are used in its manufacture• cumulative calculation exceeds limits

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

6. Provides unambiguous identification and quantification methods

7. Includes options to allow use of materials that exceed the limits established.

8. “The procedures described in this general chapter are to be applied wherever possible. Otherwise, manufacturers may select the most appropriate validated analytical procedure for a particular application.” (ICH and EP take similar approach) (see <1225> Validation of Compendial Procedures).

9. Submission of alternative methods is not required

Residual Solvents <467>: Main Points, continued

Risk-based classification of solvents

Three classes of solvents:

Class 1 – Unacceptable toxicities; should be avoided, unless their use can be strongly justified in a risk- based assessment.

Class 2 – Less severe toxicities; should be limited.Class 3 – Less toxic; should be used where practical.

• [Note: Other solvents may be used but only after approval from a regulatory agency.]

Establishing Exposure Limits (Appendix 3 in the General Chapter)

Permitted Daily Exposure (PDE) derived from the No-observed-effect level (NOEL) in animal studies.

For Class 1 solvents, exposure limits were determined using a large safety factor (10,000 to 100,000)

For Class 2 solvents, PDE was calculated from NOEL, weight adjustments, and correction factors (e.g. extrapolating between species and accounting for variability between individuals)

Limits of Residual Solvents

Class 1: concentration limits, in ppm, are provided in a Table. They should not be exceeded “unless otherwise stated in the individual monograph.”

Class 2: concentration limits are to be calculated from PDE with the formula:

Concentration (ppm) = 1000 PDE/dose, where PDE is in mg/day and dose is in g/day

A table is provided, to be used when the daily dose is 10 g or less, or when the daily dose is not known or fixed.

Class 3: PDE is 50 mg/day (“unless otherwise stated in the individual monograph.”), corresponding to a concentration of 0.5% for daily doses of 10 g or less

Limit of Residual Solvents: Class 1

Class 1 Residual Solvents (Table 1): Should not be used in the manufacturing of drug substances, excipients or drug products because of unacceptable toxicities or deleterious environmental effects of the residual solvents.

However if their use is unavoidable, their levels should be restricted as shown in Table 1.

Table 1. Class 1 Residual Solvents

Solvent Concentration Limit

(ppm)

Concern

Benzene 2 Carcinogen

Carbon tetrachloride 4 Toxic and environmental Hazard

1,2-Dichloroethane 5 Toxic

1,1-Dichloroethene 8 Toxic

1,1,1-Trichloroethane 1500 Environmental Hazard


Class 2: 26 solvents 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 2. Concentration limits (ppm) vary between 50 (methylbutylketone) and 3880 (cyclohexane).

When Class 2 residual solvents are used (or produced) in the manufacturing or purification process, they should be identified and quantified

SolventPDE

(mg/day)Concentration

Limit (ppm)

Acetonitrile 4.1 410

Chlorobenzene 3.6 360

Chloroform 0.6 60

Cyclohexane 38.8 3880

1,2-Dichloroethene 18.7 1870

1,2-Dimethoxyethane

1.0 100

N,N-Dimethylacetamide

10.9 1090

N,N-Dimethylformamide

8.8 880

1,4-Dioxane 3.8 380

2-Ethoxyethanol 1.6 160

Ethylene glycol 6.2 620

Formamide 2.2 220

Hexane 2.9 290

Methanol 30.0 3000

SolventPDE

(mg/day)

Concentration

Limit (ppm)

2-Methoxyethanol 0.5 50

Methylbutylketone 0.5 50

Methylcyclohexane 11.8 1180

Methylene chloride 6.0 600

N-Methylpyrrolidone

5.3 530

Nitromethane 0.5 50

Pyridine 2.0 200

Sulfolane 1.6 160

Tetrahydrofuran 7.2 720

Tetralin 1.0 100

Toluene 8.9 890

Trichloroethylene 0.8 80

Xylenes 21.7 2170


Options for Determining Levels of Class 2 Residual Solvents in Drug Products

Option 1:

All the components of the drug product (drug substances and excipients) meet the concentration limits (ppm) listed in Table 2, 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 limits (ppm), 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 (mg).

Example 1: Option 1 and Option 2, with acetonitrile

PDE acetonitrile = 4.1 mg/day, thus Option 1 limit is 410 ppm (from Table 2). 5.0 g drug product/day. Composed of two excipients

Excipient 1 meets Option 1 limit of 410 ppm. Drug substance, excipient 2, and drug product do not meet Option 1 limit of 410

ppm. Drug product however, does meet Option 2 limit of 4.1 mg/day.

Component Amount 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

Calculated data*

5.0 728 (exceeds)* 3.64 (PASS)*

Example 2: Option 1 and Option 2, with acetonitrile

PDE acetonitrile = 4.1 mg/day, thus Option 1 limit is 410 ppm (from Table 2). 5.0 g drug product/day. Composed of two excipients

Drug product does not meet Option 1 limit (410 ppm) or Option 2 limit (4.1 mg/day).

Manufacturer could test to see if manufacturing reduced the level of acetonitrile in the drug product below 410 ppm; if so it passes.

Component Amount in Formulation

(g)

Acetonitrile Content-Limit

(ppm)

Daily Exposure

(mg)

Drug Substance

0.3 800 (exceeds) 0.24



Drug Product

Calculated data*

5.0 1016 (exceeds)* 5.08 (FAIL)*


Class 3: 28 solvents Less toxic and of lower risk to human health Unless otherwise stated in the individual

monograph, PDE is nmt 50 mg/day, corresponding to a concentration limit of 5000 ppm for daily doses not greater than 10 g of product.

Use Loss on Drying in NMT 0.5%. If the monograph allows for a concentration

resulting in more than 50 mg/day, Class 3 solvents must be identified and quantified.


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

Analytical Procedures (ICH, EP)

ICH: “Any harmonized procedures for determining levels of residual solvents as described in the pharmacopoeias should be used, if feasible. Otherwise, manufacturers would be free to select the most appropriate validated analytical procedure . . .”

EP: “. . . The methodology in the general analytical method (2.2.24) is to be applied wherever possible. Otherwise an appropriate validated method is to be employed.”

Analytical Procedures (USP)

USP: “. . . The procedures described in . . . This

general chapter are to be applied whenever possible. Otherwise manufacturers may select the most appropriate validated analytical procedure for a particular application . . .”

Identification, Control, and Quantitation of Residual Solvents

Class 1 and Class 2 Residual Solvents● Procedure A-Identification and Limit Test● Procedure B-Confirmatory Test● Procedure C-Quantitative Test

Class 3 Residual Solvents●LOD, followed if necessary by Gas

Chromatography analysis if it exceeds 0.5%

Rationale for Two Procedures

Procedure A and B are orthogonal approaches

Co-elutions occur in both procedures, but Co-eluting peaks in Procedure A are

resolved in Procedure B, and vice versa

Final quantification by Procedure C

Decision Tree

yes

no

yes

no

Procedure C

Calculate amountof Residual

Solvents found

Is this aproduct

Meet option 1Label to indicateRS and amount

found

Meet option 2 Pass

Fail

Decision Tree, continued

no no

yes yes

yes

no

USP Method Specifics: Procedure A

Headspace 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

Split ratio: 1:5 Oven 40oC: 20 mins 10oC/min to 240oC, 20 mins Injector temp: 140oC FID temp: 250oC

USP Method Specifics

Head Space Operating Parameters

1 2 3

Equilibration temperature (°C) 80 105 80

Equilibration time (min.) 60 45 45

Transfer-line temperature (°C) 85 110 105

Carrier gas (35 cm/sec) Nitrogen or Helium

Pressurization time (sec.) 30 30 30

Injection volume (mL) 1 1 1

USP Method Specifics: Procedure A, Continued

System Suitability: Class 1 Standard Solution

• Signal-to-Noise (S/N): 1,1,1 trichloroethane NLT 5

Class 1 System Suitability Solution• Signal-to-Noise (S/N): All peaks NLT 3

Class 2 Mixture A Standard Solution• Resolution: Acetonitrile and methylene chloride

NLT 1.0.

USP Method Specifics: Procedure A,continued

Procedure: Class 1 Standard Solution Class 2 Mixture A Standard Solution Class 2 Mixture B Standard Solution Test Solution

If a peak response of any peak in the Test Solution is greater 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.

USP Method Specifics: Procedure B

Only run Procedure B, to confirm procedure A If the peak response(s) in the Test Solution in the peaks

identified in Procedure A 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), other wise the article meets the requirements of this test.

Preparations for Procedure C

Same as for Procedure A (If results from Procedure A are inferior to B, use Procedure B conditions ), plus

Standard solution(s) – for each peak identified and verified by Procedures A and B by dilution of the respective USP Residual Solvent Reference Standard

Spiked Test Solution – mixture of Test Solution and Standard solution

Method Specifics: Procedure C, continued

Calculate the ppm of each residual solvent:

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

C= Concentration in ppm of USP StandardW=Weight in g of test articleru =peak response of RS in the Test Solution

rst =peak response of RS in the Spiked Test Solution (allows for recovery issues).

Residual Solvents Class 1 – Procedure A

min0 2 4 6 8 10 12 14

Norm.

5

6

7

8

9

FID2 B, (03234A\03234A16.D)

artifact

1,1-Dichloroethene

1,1,1-Trichloroethane

Carbon Tetrachloride

Benzene

1,2-Dichloroethane

Residual Solvents Class 1 – Procedure B

min1 2 3 4 5 6 7 8 9

pA

6

8

10

12

14

16

18

FID2 B, (03234B\03234B47.D)

1,1-Dichloroethene

1,1,1-Trichloroethane & Carbon Tetrachloride

Benzene

1,2-Dichloroethane

Residual Solvents Class 2A – Procedure A

1 Methanol 8 Methylcyclohexane

2 Acetonitrile 9 1,4-Dioxane

3 Dichloromethane 10 Toluene4 Trans-1,2-Dichloroethene 11 Chlorobenzene5 Cis-1,2-Dichloroethene 12 Ethylbenzene6 Tetrahydrofuran 13 m-xylene, p-xylene7 Cyclohexane 14 o-xylene

min0 5 10 15 20 25

Norm.

6

8

10

12

14

FID2 B, (03234A\03234A29.D)

a

1

2

3 4 5 6 7 8

9

1011

12

13

14

Regulatory Aspects-1

21 Code of Federal Regulations

Parts 210 and 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS

21 CFR 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.

http://www.fda.gov/cder/dmpq


FDA Statement-OGD

All drug substances, excipients, and products are subject to relevant control of residual solvents, even when no test is supplied in the individual monograph.

Starting July 1, 2008: Any new ANDA must provide information and data as necessary to demonstrate

control of residual solvents prior to approval or tentative approval. ANDA’s currently under review but not approved by July 1, 2008, must also

contain this information and data. Residual Solvent information and data for approved products should be submitted

in the next annual report for the ANDA.

http://www.fda.gov/cder/ogd/ResidualSolvents.pdf


FDA Statement OGD-Continued

Ensure that all Drug Substance and excipients must have limits (ppm) that fall within ICH Q3C (option 1) limit or ,

Ensure that all Drug Substances and excipients weighted by their amount in the drug product, result in a cumulative daily exposure for residual solvents (PDE) that falls within the ICH Q3C (option 2) limit or ,

Ensure via direct testing of the drug product, that the total Daily Exposure falls within ICH Q3C (option 2) limit.



FDA Statement OGD-Continued

Sponsors include a commitment to re-assess suppliers if a new vendor is chosen.

Although above statements are for compendial materials in the USP, the OGD expects ANDA’s for products not official in the USP to contain information and data that assures safe levels of residual solvents in the drug product consistent with USP <467>.


Supplier/End-User

USP <467> Limits in Excipients Limits are not specifications for each

excipient. • If C of A states levels well below ICH Q3C, FDA

expects if this is tested by end-user that specifications will be set there too.

Some excipients used as drug products. Manufacturer of drug product has to

calculate, based upon limit and PDE.

Supplier

Generally, Class 1 Solvents such as benzene are no longer being used in producing excipients.

Many produced with Class 2 or 3. Eliminating or lowering solvent levels may

change quality and performance for certain functions.

Take advantage of USP calculation option, i.e PDE rather than limit (ppm).

Supplier and C of A

Need information exchange between user and supplier. However there are confidentiality concerns. Trust needed between two parties A supplier audit may be needed, GMP concern

for regulatory department and FDA. Not just rely on C of A. The C of A may not specify what residual

solvents are present or cite meets ICH Q3C guidelines.• Screening then needed

Contract Lab

Perform Residual Solvent testing per USP. Can also screen with GC/MS

Co-elution not a problem Use qualifier ions in SIM mode

Release testing: GC/MS, however is not the USP <467>

method, and as such would have to be validated if it is to be used as a release assay.

Future of <467>

USP may revise the chapter in response to additional comments received regarding the analytical method.

USP has not discussed separating methods in <467> to a separate chapter. (Similar to Ph Eur)

http://www.usp.org/USPNF/notices/faq.html

Strategy-Summary-1

Read C of A: No solvents, no test needed. Solvents, use C of A or test

Test for known solvents: Use USP method

• Verify Suitability per USP Verification <1226> • Establish LOQ, by S/N or RSD• Linearity from LOQ to ICH Limit or limit on C

of A. n=5• Precision: n=6• Accuracy at levels on C of A or levels found

Release testing

Strategy-Summary-2

Residual Solvents (indicated but not listed): Screen by GC/MS Then proceed with:

• Verification of USP method USP <1226>• Release testing using USP <467>

FDA expects three lots per year to be tested FDA will expect audit of supplier to assess

confidence in methods (validation) and data if C of A information alone is used.

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