Guidance for Industry 

 
Q4B Evaluation and Recommendation 

of Pharmacopoeial Texts for Use in the 

ICH Regions 

 
Annex 14 

Bacterial Endotoxins Test 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) 

 
October 2013 

ICH 

   
Guidance for Industry 

 
Q4B Evaluation and Recommendation of 

Pharmacopoeial Texts for Use in the 

ICH Regions
 
 
 
Annex 14 

Bacterial Endotoxins Test General 

Chapter 

 
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 http://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) 

 
October 2013 

ICH 

 
   
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.   European Union Consideration (4.3) ........................................................................................... 3 
 
D.   MHLW Consideration (4.4) .......................................................................................................... 3
  
E.   Health Canada Consideration (4.5) .............................................................................................. 3
  
REFERENCES USED FOR THE Q4B EVALUATION (5) .................................................... 3 
 
  Contains Nonbinding Recommendations  
 
1
 
Guidance for Industry  
Q4B Evaluation and Recommendation of Pharmacopoeial Texts  

for Use in the ICH Regions 

 
Annex 14 

Bacterial Endotoxins Test 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 Bacterial Endotoxins Test General Chapter. 
The proposed texts were submitted by the Pharmacopoeial Discussion Group (PDG). 
 
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 
                                                 
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, October  2012.  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,  October 2012. 
 
3We update guidance  documents periodically.  To make sure you have the most  recent version of a guidance, check 
the FDA Drugs guidance page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/  
Guidances/default.htm or the  FDA Biologics guidance page at  
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
1 
 Contains Nonbinding Recommendations  
 
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 analytical procedures described in the official pharmacopoeial 
texts, European Pharmacopoeia (Ph. Eur.): 2.6.14. Bacterial Endotoxins, Japanese 
Pharmacopoeia (JP): 4.01 Bacterial Endotoxins Test, and United States Pharmacopeia (USP) 
General Chapter <85> Bacterial Endotoxins Test, can be used as interchangeable in the ICH 
regions subject to the following conditions: 
 
1. (2.1.1)  Any of the three techniques can be used for the test.  In the event of doubt or 
dispute, the gel-clot limit test should be used to make the final decision on compliance for 
the product being tested. 
 
2. (2.1.2)  The USP, JP, and Ph. Eur. reference standards are considered interchangeable 
because they have been suitably calibrated against the WHO (World Health 
Organization) International Standard for Endotoxin. 
 
3. (2.1.3) In the section Photometric quantitative techniques, Preparatory testing, Test 
for interfering factors, the user should perform the test on solutions A, B, C, and D on at 
least two replicates using the optimal conditions as recommended by the lysate 
manufacturer.  
 
B.   Acceptance Criteria (2.2) 
 
The evaluated texts did not contain acceptance criteria.  Endotoxin limits should be specified in 
the application dossier unless otherwise specified in an individual monograph. 
 
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.  
2 
 Contains Nonbinding Recommendations  
 
 
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.  
 
C.  European Union Consideration (4.3) 
 
For the European Union, 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 2.6.14. on the basis of the declaration of interchangeability made above.  
 
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.  Health Canada Consideration (4.5) 
 
In Canada any of the pharmacopoeial texts cited in Section 2.1 of this annex and used in 
accordance with the conditions set out in this annex can be considered interchangeable. 
 
REFERENCES USED FOR THE Q4B EVALUATION (5) 
 
A. (5.1) 	The PDG Stage 5B sign-off document (Rev. 1  Correction 1):  Japanese 
Pharmacopoeial Forum, Volume 18, number 4 (December 2009). 
 
B. (5.2) 	The pharmacopoeial references for the Bacterial Endotoxins Test General 
Chapter for this annex are: 
 
1. (5.2.1) European Pharmacopoeia (Ph. Eur.):  Supplement 6.6 (official January 
1, 2010), Bacterial Endotoxins (reference 01/2010:20614). 
 
2. (5.2.2) Japanese Pharmacopoeia (JP): General Test 4.01 Bacterial Endotoxins 
Test as it appears in the JP Sixteenth Edition (March 24, 2011,  Th e Ministry of 
Health, Labour and Welfare Ministerial Notification No.65).  
 
3 
 Contains Nonbinding Recommendations  
 
3. (5.2.3) United States Pharmacopeia (USP):  Text for <85> Bacterial 
Endotoxins Test, USP 33 Reissue (published April 2010 and official October 1, 
2010). 
4