Guidance for Industry
 

Q4B Evaluation and Recommendation
 

of Pharmacopoeial Texts for Use in the
 

ICH Regions
 

Annex 3
 

Test for Particulate Contamination:
 

Subvisible Particles General Chapter
 

U.S. Department of Healtb and Human Services
 

Food and Drug Administration
 

Center for Drug Evaluation and Researcb (CDER)
 

Center for Biologics Evaluation and Researcb (CBER)
 

January 2009
 

ICH
 
Guidance for Industry 

Q4B Evaluation and Recommendation of 

Pharmacopoeial Texts for Use in the 

ICH Regions 

Annex 3 

Test for Particulate Contamination: 

Subvisible Particles General Chapter 

Additional copies are available from: 

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Division of Drug Information 

Center for Drug Evaluation and Research 

Food and Drug Administration 

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(Tel) 301-796-3400 

 http://www.fda.gov/cder/guidance/index.htm 

or 

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Center for Biologics Evaluation and Research 

 Food and Drug Administration 

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 http://www.fda.gov/cber/guidelines.htm. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

Center for Biologics Evaluation and Research (CBER) 

January 2009 

ICH 
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TABLE OF CONTENTS 

I. INTRODUCTION (1)....................................................................................................... 1

II. Q4B OUTCOME (2)......................................................................................................... 2

A. Analytical Procedures (2.1) ...........................................................................................................2

B. Acceptance Criteria (2.2)...............................................................................................................2

III. TIMING OF ANNEX IMPLEMENTATION (3) .......................................................... 2

IV. CONSIDERATIONS FOR IMPLEMENTATION (4).................................................. 2

A. General Consideration (4.1)..........................................................................................................2

B. FDA Consideration (4.2) ...............................................................................................................2

C. EU Consideration (4.3) ..................................................................................................................3

D. MHLW Consideration (4.4) ..........................................................................................................3

V. REFERENCES USED FOR THE Q4B EVALUATION (5) ........................................ 3

ATTACHMMENT........................................................................................................................ 4
Contains Nonbinding Recommendations

1

Guidance for Industry1

Q4B Evaluation and Recommendation of Pharmacopoeial Texts 

for Use in the ICH Regions 

Annex 3 

Test for Particulate Contamination: Subvisible Particles 

General Chapter 

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 (1)2

This annex is one in a series of guidance documents that describe the evaluations and 

recommendations by the Q4B Expert Working Group (EWG) of selected pharmacopoeial texts 

to facilitate their recognition by regulatory authorities for use as interchangeable in the ICH 

regions. Implementation of the Q4B annexes is intended to avoid redundant testing by industry. 

For general information on the Q4B process, the reader is referred to the core guidance Q4B 

Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions.

3

This annex is the result of the Q4B process for the Test for Particulate Contamination: Subvisible 

Particles General Chapter. The proposed texts were submitted by the Pharmacopoeial 

Discussion Group (PDG). 

 

1 This guidance was developed within the Expert Working Group (Quality) of the International Conference on 

Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been 

subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been 

endorsed by the ICH Steering Committee at Step 4 of the ICH process, June 2008. At Step 4 of the process, the final 

draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States. 

2

 Arabic numbers reflect the organizational breakdown of the document endorsed by the ICH Steering Committee at 

Step 4 of the ICH process, June 2008. 

3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER 

guidance page at http://www.fda.gov/cder/guidance/index.htm or the CBER guidance page at 

http://www.fda.gov/cber/guidelines.htm..
Contains Nonbinding Recommendations

2

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 

cited. The use of the word should in Agency guidances means that something is suggested or 

recommended, but not required.

II. Q4B OUTCOME (2) 

A. Analytical Procedures (2.1) 

The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group 

(EWG), recommends that the official pharmacopoeial texts, Ph. Eur. 2.9.19. Particulate 

Contamination: Sub-visible Particles, JP 6.07 Insoluble Particulate Matter Test for Injections, 

and USP <788> Particulate Matter in Injections, can be used as interchangeable in the ICH 

regions subject to the following condition: 

• Condition (2.1.1): Instrument calibration and system suitability measurements should 

follow regional good manufacturing practice (GMP) requirements. 

B. Acceptance Criteria (2.2) 

Except for nominal 100-milliliter (mL) parenteral products, the acceptance criteria are 

interchangeable. At the 100-mL nominal volume, the criteria specified in JP are more stringent 

than those in the Ph. Eur. and the USP pharmacopoeias; therefore, the criteria are not 

interchangeable in all three regions at that volume. 

III. TIMING OF ANNEX IMPLEMENTATION (3) 

When this annex has been implemented (incorporated into the regulatory process at ICH Step 5) 

in a region, it can be used in that region. Timing might differ for each region. 

IV. CONSIDERATIONS FOR IMPLEMENTATION (4) 

A. General Consideration (4.1) 

 

When sponsors or manufacturers change their existing methods to the implemented Q4Bevaluated pharmacopoeial texts that are referenced in section II.A (2.1) of this annex, any change 

notification, variation, and/or prior approval procedures should be handled in accordance with 

established regional regulatory mechanisms pertaining to compendial changes. 

B. FDA Consideration (4.2) 
Contains Nonbinding Recommendations

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Based on the recommendation above, and with reference to the conditions set forth in this annex, 

the pharmacopoeial texts referenced in section II.A (2.1) of this annex can be considered 

interchangeable. However, FDA might request that a company demonstrate that the chosen 

method is acceptable and suitable for a specific material or product, irrespective of the origin of 

the method. For nominal 100-mL parenteral products, the FDA considers testing criteria from all 

three pharmacopoeias as interchangeable. 

C. EU Consideration (4.3) 

For the European Union, the monographs of the Ph. Eur. have mandatory applicability. 

Regulatory authorities can accept the reference in a marketing authorization application, renewal 

or variation application citing the use of the corresponding text from another pharmacopoeia as 

referenced in section II.A (2.1), in accordance with the conditions set out in this annex, as 

fulfilling the requirements for compliance with the Ph. Eur. Chapter, Particulate Contamination: 

Sub-visible Particles: 2.9.19., on the basis of the declaration of interchangeability made above. 

For nominal 100-mL parenteral products, the EU considers testing criteria from all three 

pharmacopoeias as interchangeable. 

D. MHLW Consideration (4.4) 

The pharmacopoeial texts referenced in section II.A (2.1) of this annex can be used as 

interchangeable in accordance with the conditions set out in this annex. Details of 

implementation requirements will be provided in the notification by MHLW when this annex is 

implemented. 

V. REFERENCES USED FOR THE Q4B EVALUATION (5) 

A. (5.1) The PDG Stage 5B sign-off document: Japanese Pharmacopoeial Forum, 

Volume 13, Number 3 (August 2004). 

B. (5.2) The pharmacopoeial references for Particulate Matter for this annex are: 

1. (5.2.1) European Pharmacopoeia (Ph. Eur.): 5th Edition (official on January 

2005), Particulate Contamination: Sub-visible Particles (reference 01/2005:20919). 

2. (5.2.2) Japanese Pharmacopoeia (JP): 6.07 Insoluble Particulate Matter Test for 

Injections as it appears in the JP Fifteenth Edition (March 31, 2006, The Ministry of 

Health, Labour and Welfare Ministerial Notification No. 285). The method was 

changed in September 2007 to correct a sentence in the introduction as underlined in the text 

that is provided by MHLW which is attached.

3. (5.2.3) United States Pharmacopeia (USP): <788> Particulate Matter in Injections, 

Revision Bulletin, April 4, 2007. 
Contains Nonbinding Recommendations

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ATTACHMMENT 
Contains Nonbinding Recommendations

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Contains Nonbinding Recommendations

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