Q4B Evaluation and Recommendation 
of Pharmacopoeial Texts for Use in the 
ICH Regions 
 
Annex 4C(R1) 
Microbiological Examination of 
Nonsterile Products: Acceptance 
Criteria for Pharmaceutical 
Preparations and Substances for 
Pharmaceutical Use 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 4C(R1) 
Microbiological Examination of Nonsterile 
Products: Acceptance Criteria for 
Pharmaceutical Preparations and Substances 
for Pharmaceutical Use General Chapter 
Guidance for Industry 
 
Additional copies are available from: 
 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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 Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
or 
 
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Phone: 800-835-4709 or 240-402-8010 
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 
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 
E.  Canada Consideration (4.5) .......................................................................................................... 3 
V.  REFERENCES USED FOR THE Q4B EVALUATION (5) ........................................ 3 
  Contains Nonbinding Recommendations 
 
 
Q4B Evaluation and Recommendation of Pharmacopoeial Texts  
for Use in the ICH Regions 
 
Annex 4C(R1) 
Microbiological Examination of Nonsterile Products: Acceptance 
Criteria for Pharmaceutical Preparations and Substances for 
Pharmaceutical Use General Chapter 
1
Guidance for Industry  
 
 
 
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 
                                                 
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.  
 
1  Contains Nonbinding Recommendations 
 
 
This annex is the result of the Q4B process for Microbiological Examination of Nonsterile 
Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for 
Pharmaceutical Use.  The proposed texts were submitted by the Pharmacopoeial Discussion 
Group (PDG).  For each regulatory region, the pharmacopoeial text is nonmandatory and is 
provided for informational purposes only.  This revision, Q4B Annex 4C(R1), adds the Health 
Canada interchangeability statement in section IV.E (4.5). 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys 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) 
 
The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group 
(EWG), recommends that the official pharmacopoeial texts, Ph. Eur. 5.1.4. Microbiological 
Quality of Non-Sterile Pharmaceutical Preparations and Substances for Pharmaceutical Use, JP 
General Information 12. Microbial Attributes of Non-sterile Pharmaceutical Products, and USP 
<1111> Microbiological Attributes of Nonsterile Pharmaceutical Products, can be used as 
interchangeable in the ICH regions. 
 
 
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 (2) 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) 
 
Based on the recommendation above, and with reference to the conditions set forth in this annex, 
the pharmacopoeial texts referenced in section II (2) of this annex can be considered 
interchangeable.  However, FDA might request that a company demonstrate that the chosen 
2  Contains Nonbinding Recommendations 
 
method is acceptable and suitable for a specific material or product, irrespective of the origin of 
the method.  
 
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 (2), in accordance with the conditions set out in this annex, as fulfilling 
the requirements for compliance with the Ph. Eur. Chapter 5.1.4. on the basis of the declaration 
of interchangeability made above. 
 
D.  MHLW Consideration (4.4) 
 
The pharmacopoeial texts referenced in section II (2) 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 (2) 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 14, Number 4 (December 2005).   
 
B. (5.2)  The pharmacopoeial references for Microbiological Examination of Nonsterile 
Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for 
Pharmaceutical Use for this annex are: 
 
1. (5.2.1)  European Pharmacopoeia (Ph. Eur.):  6.3 Edition (official on January 
2009) Microbiological Quality of Non-Sterile Pharmaceutical Preparations and 
Substances for Pharmaceutical Use  (reference 01/2009: 50104). 
 
2. (5.2.2)  Japanese Pharmacopoeia (JP): JP General Information 12. Microbial 
Attributes of Non-sterile Pharmaceutical Products as it appears in Supplement I to 
the Japanese Pharmacopoeia Fifteenth Edition (September 28, 2007, Notification 
PFSB No. 0928001).  The English version was published on January 9, 2008. 
 
3. (5.2.3)  United States Pharmacopeia (USP):  <1111> Microbiological Attributes 
of Nonsterile Pharmaceutical Products official in USP 30, January 2007. 
 
3