Guidance for Industry 

Q4B Evaluation and Recommendation 

of Pharmacopoeial Texts for Use in the 

ICH Regions 

Annex 4C 

Microbiological Examination of 

Nonsterile Products: Acceptance 

Criteria for Pharmaceutical 

Preparations and Substances for 

Pharmaceutical Use General Chapter 

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) 

April 2009 

ICH
 
 

Guidance for Industry 

Q4B Evaluation and Recommendation of 

Pharmacopoeial Texts for Use in the 

ICH Regions 

Annex 4C 

Microbiological Examination of Nonsterile 

Products: Acceptance Criteria for 

Pharmaceutical Preparations and Substances 

for Pharmaceutical Use General Chapter 

Additional copies are available from: 

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Center for Drug Evaluation and Research
 

Food and Drug Administration 

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Building 51, Room 2201
 

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(Tel) 301-796-3400

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

or 

Office of Communication, Outreach and 

Development, HFM-40 

Center for Biologics Evaluation and Research 

Food and Drug Administration 

1401 Rockville Pike, Rockville, MD 20852-1448 

 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) 

April 2009 

ICH 
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)..................................................................................................................2
 

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

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

i 
 

 

 

 

 

Contains Nonbinding Recommendations 

Guidance for Industry1 

Q4B Evaluation and Recommendation of Pharmacopoeial Texts 

for Use in the ICH Regions 

Annex 4C 

Microbiological Examination of Nonsterile Products: Acceptance 

Criteria for Pharmaceutical Preparations and Substances for 

Pharmaceutical Use 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 Microbiological Examination of Nonsterile 

Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for 

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, November 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, November 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. 

1 
Contains Nonbinding Recommendations 

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. 

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) 

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 Q4Bevaluated 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 

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

the method. 

C. EU Consideration (4.3) 

2 
 

 

 

Contains Nonbinding Recommendations 

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 (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. 

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