Q4B Annex 3: Test for Particulate Contamination: Subvisible Particles General Chapter

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Q4B Evaluation and Recommendation
of Pharmacopoeial Texts for Use in the
ICH Regions
Annex 3(R1)
Test for Particulate Contamination:
Subvisible Particles General Chapter
Guidance for Industry
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)
September 2017
ICH
Revision 1

Q4B Evaluation and Recommendation of
Pharmacopoeial Texts for Use in the
ICH Regions
Annex 3(R1)
Test for Particulate Contamination:
Subvisible Particles General Chapter
Guidance for Industry
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Email: ocod@fda.hhs.gov
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.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)
September 2017
ICH
Revision 1

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) ............................................................................................................... 3
C. 	EU Consideration (4.3) .................................................................................................................. 3
D. 	MHLW Consideration (4.4) .......................................................................................................... 3
E. 	Canada Consideration (4.5) ......................................................................................................... 3
V. 	REFERENCES USED FOR THE Q4B EVALUATION (5) ........................................ 3
ATTACHMMENT ........................................................................................................................ 4

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Q4B Evaluation and Recommendation of Pharmacopoeial Texts
for Use in the ICH Regions
Annex 3(R1)
Test for Particulate Contamination: Subvisible Particles
General Chapter
Guidance for Industry1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the
title page.
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
1 This guidance was developed within the Expert Working Group (Quality) of the International Council for
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), formerly the International
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 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, September 2010. At Step 4 of the
process, the final draft is recommended for adoption to the regulatory agencies.
2 Arabic numbers reflect the organizational breakdown of the document endorsed by the ICH Steering Committee at
Step 4 of the ICH process, September 2010.
3 We update guidance documents periodically. To make sure you have the most recent version of a guidance, check
the FDA Drugs guidance page at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/default.htm or the FDA Biologics guidance page at
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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Discussion Group (PDG). This revision, Q4B Annex 3(R1), adds the Health Canada
interchangeability statement in section IV.E (4.5).
In general, FDA’s guidance documents 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 is 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 Q4B-
evaluated 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.

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B. 	FDA Consideration (4.2)
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 (EU), 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.
E. 	Canada Consideration (4.5)
In Canada, any of the pharmacopoeial texts cited in section II.A (2.1) of this annex and used in
accordance with the conditions set out in this annex can be considered interchangeable.
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.): 5 th 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

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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.

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ATTACHMMENT

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