Guidance for Industry 
 
 
Q4B Evaluation and 
Recommendation of 
Pharmacopoeial Texts for Use 
in the ICH Regions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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) 
 
February 2008 
ICH 
 
 
 
   
Guidance for Industry 
 
Q4B Evaluation and 
Recommendation of 
Pharmacopoeial Texts for Use 
in the ICH Regions 
 
 
 
Additional copies are available from: 
 
Office of Training and Communication 
Division of Drug Information, HFD-240 
Center for Drug Evaluation and Research 
Food and Drug Administration 
5600 Fishers Lane 
Rockville, MD  20857 
(Tel) 301-827-4573 
 http://www.fda.gov/cder/guidance/index.htm 
 
Office of Communication, Training and  
Manufacturers Assistance, 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) 
 
February 2008 
ICH 
  
  TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION (1, 1.1, 1.3).........................................................................................1 
II.  BACKGROUND (1.2).......................................................................................................2 
A.  The Pharmacopoeial Discussion Group (PDG) (1.2.1)...............................................................2 
B.  The Q4B Expert Working Group (EWG) (1.2.2)........................................................................2 
III.  GENERAL PRINCIPLES (1.4).......................................................................................2 
IV.  GUIDANCE (2).................................................................................................................3 
A.  Q4B Evaluation Process (2.1)........................................................................................................3 
1. Step 1 (2.1.1)....................................................................................................................................3 
2. Step 2 (2.1.2)....................................................................................................................................3 
3. Step 3 (2.1.3)....................................................................................................................................4 
4. Step 4 (2.1.4)....................................................................................................................................4 
5. Step 5 (2.1.5 )...................................................................................................................................4 
B.  Annex Contents (2.2).....................................................................................................................4 
C.  Use of the Pharmacopoeial Text (2.3)...........................................................................................4 
GLOSSARY (3).............................................................................................................................6 
ATTACHMENT I.........................................................................................................................7 
ATTACHMENT II.......................................................................................................................8 
i  Contains Nonbinding Recommendations 
 
1
Guidance for Industry  
Q4B Evaluation and Recommendation of Pharmacopoeial Texts  
for Use in the ICH Regions 
 
 
 
 
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, 1.1, 1.3)2 
 
This document describes a process for the evaluation and recommendation 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. Following favorable 
evaluations, ICH will issue topic-specific annexes with information about these texts and their 
implementation (the Q4B Outcomes).  Implementation of the Q4B annexes is intended to avoid 
redundant testing by industry. 
 
Initially, the Q4B process will focus on evaluating the 11 General Test Chapters discussed 
during the development of ICH Q6A (refer to Attachment I).  Many other pharmacopoeial 
harmonization proposals are being developed and could also be considered for Q4B evaluation. 
 
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. 
                                                 
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 2007.  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 2007. 
 
  1 Contains Nonbinding Recommendations 
 
 
 II.  BACKGROUND (1.2) 
 
When issuing Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug 
Substances and New Drug Products: Chemical Substances, and Q6B: Specifications: Test 
Procedures and Acceptance Criteria for Biotechnological/Biological Products, ICH recognized 
that full use and value of both ICH guidances would depend on the successful harmonization of 
pharmacopoeial procedures and encouraged the work of the Pharmacopoeial Discussion Group 
(PDG). 
 
  A.  The Pharmacopoeial Discussion Group (PDG) (1.2.1) 
 
The PDG, founded in 1990, consists of representatives from the European Directorate for the 
Quality of Medicines (EDQM) in the Council of Europe; the Ministry of Health, Labour and 
Welfare (MHLW) of Japan; and the United States Pharmacopeial Convention, Inc. (USP).  The 
PDG produces harmonized pharmacopoeial texts through independent public comment and 
consultation.  The PDG reports on the status of its harmonization efforts at ICH meetings as 
appropriate. 
 
  B.  The Q4B Expert Working Group (EWG) (1.2.2) 
 
In November 2003, ICH established the Q4B EWG to evaluate and recommend pharmacopoeial 
texts that are proposed for use in the three ICH regions.  The Q4B EWG anticipates that the PDG 
will be the principal source of pharmacopoeial text proposals.  There might be an occasion where 
not all three parties of the PDG participate in a harmonization effort for a specific 
pharmacopoeial text.  In such a case, the Q4B EWG can accept proposals from one or two PDG 
pharmacopoeias. 
 
 
III.  GENERAL PRINCIPLES (1.4) 
 
The EWG will evaluate pharmacopoeial text proposals and assess the regulatory impact of the 
proposals.  The Q4B EWG will continue its dialogue with the PDG as necessary during the Q4B 
process.  Following its evaluation, the Q4B EWG will reach a conclusion and make a 
recommendation on the use of the text in the ICH regions, which will be conveyed to the ICH 
Steering Committee.  For each proposal that is favorably evaluated, the Q4B EWG intends to 
develop a topic-specific annex to the Q4B guidance following the ICH step process.  The annex 
will provide information on how the pharmacopoeial texts can be used in the ICH regions.  Each 
annex will be issued as a stand-alone companion document to the Q4B guidance. 
 
To preserve transparency, the Q4B EWG should be notified of any revisions to a pharmacopoeial 
text that has been submitted to the Q4B evaluation process.  Any change to pharmacopoeial text 
that has been proposed to, or recommended through, the Q4B evaluation process will prompt a 
Q4B EWG review to assess both the merit of the change and the appropriateness of any 
subsequent Q4B activity related to that text.   
 
 
  2 Contains Nonbinding Recommendations 
 
IV.  GUIDANCE (2) 
 
A.  Q4B Evaluation Process (2.1) 
 
The process begins with a document submission to the Q4B EWG.  For PDG proposed 
pharmacopoeial text, the document submission should be provided as soon as possible after 
PDG Stage 5B sign-off (refer to Attachment II).  The document submission should outline 
any issues for resolution and should contain any appropriate supporting data.   
When the Q4B evaluation process results in a conclusion and recommendation that the 
pharmacopoeial text can be used as interchangeable in the ICH regions, a topic-specific Q4B 
annex will be issued following the steps in the ICH process as detailed below.   
 
1.  Step 1 (2.1.1) 
 
Each Q4B party independently evaluates the documents for regulatory impact.  
Additional discussion within the Q4B EWG, and/or communication/dialogue with the 
submitting party (e.g., the PDG), might be warranted to resolve any issues that surfaced 
during the evaluation (see example in the figure below).   
PDG  Q4B 
Submission  Evaluation 
(or Revision)  and feedback 
Preparation 
to Q4B  to PDG 
of Topic-
specific 
Annex 
Dialogue 
between PDG 
& Q4B 
           
When the Q4B evaluation process results in a recommendation that the pharmacopoeial 
text can be used as interchangeable in the ICH regions, the Q4B EWG prepares and signs 
off on a draft Q4B annex, which is submitted to the Steering Committee for adoption at 
Step 2. 
 
2.  Step 2 (2.1.2) 
 
The Steering Committee agrees, based on the report of the Q4B EWG, that there is 
sufficient scientific consensus on the technical issues for the draft annex to proceed to 
Step 3 regulatory consultation and discussion. 
 
  3 Contains Nonbinding Recommendations 
 
3.  Step 3 (2.1.3)   
 
The draft Q4B annex is made available for regulatory consultation in the three regions 
(generally for 3 months).  The regulatory consultation and discussion should focus on the 
Q4B Outcome in the annex.  The Q4B EWG can revise the annex based on comments 
received and submits a final draft of the annex to the ICH Steering Committee. 
 
 4.  Step 4 (2.1.4) 
 
The ICH Steering Committee adopts the annex and issues it as a stand-alone companion 
document to the ICH Q4B guidance. 
 
5.  Step 5 (2.1.5) 
 
The annex moves to the regional regulatory implementation step. 
 
B.  Annex Contents (2.2) 
 
The Q4B annexes will contain the following information at a minimum.  Other information 
might be incorporated on a case-by-case basis. 
 
  Topic title 
  Introduction  
  Q4B Outcome  
  As appropriate, statements that will assist in the use of the referenced pharmacopoeial 
text by stakeholders  
  Implementation timelines indicating regulators' advice on when stakeholders can 
begin using the pharmacopoeial text as interchangeable 
  References to methods and acceptance criteria, as appropriate 
 
C.  Use of the Pharmacopoeial Text (2.3) 
 
After a regulatory ICH region has implemented the Q4B annex, the official pharmacopoeial 
texts referenced in the annex can be used as interchangeable in that region.    Any general 
and/or specific implementation recommendations for a regulatory region will be provided in 
the Q4B topic specific annex as part of section IV (4) Considerations for Implementation. 
The basic information will be as provided below: 
  Considerations for Implementation (2.3.1) 
 
General consideration:  When sponsors or manufacturers change their existing methods to 
the implemented Q4B-evaluated pharmacopoeial texts that are referenced in section II (2) of 
the annex, any change notification, variation, and/or prior approval procedures should be 
  4 Contains Nonbinding Recommendations 
 
handled in accordance with established regional regulatory mechanisms pertaining to 
compendial changes. 
 
In addition to these general considerations, specific information for each regulatory region 
can assist the implementation in that region.  Each regulatory region will provide such 
notification to its stakeholders in conjunction with regional implementation of the annex. 
 
FDA consideration:  Based on the recommendation above, and in accordance with the 
conditions set forth in the annex, the pharmacopoeial texts as referenced in section II (2) of 
the 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. 
 
EU consideration:  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) of the annex, in accordance 
with the conditions set out in the annex, as fulfilling the requirements for compliance with 
the Ph. Eur. Chapter [chapter name and Ph. Eur. Reference], on the basis of the declaration 
of interchangeability made above. 
 
MHLW consideration:  The pharmacopoeial texts as referenced in section II (2) of the 
annex can be used as interchangeable in accordance with the conditions set out in the annex. 
Details of implementation requirements will be provided in the notification by MHLW when 
the specific annex is implemented. 
  5 Contains Nonbinding Recommendations 
 
 
GLOSSARY (3) 
 
Document Submission:  The working documents received from the PDG or one or more 
pharmacopoeial sources (USP, Ph. Eur., or JP) that contain the proposed pharmacopoeial text 
and any other support documents provided for Q4B evaluation. 
 
Interchangeable:  Where such status is indicated, any of the official texts from JP, EP, or 
USP can be substituted one for the other (appropriately referenced) in the ICH regions for 
purposes of the pharmaceutical registration/approval process.  Using any of the 
interchangeable methods, an analyst will reach the same accept or reject decisions 
irrespective of which PDG pharmacopeia is used. 
 
PDG:  The three-party Pharmacopoeial Discussion Group consisting of representatives from 
the European Directorate for the Quality of Medicines (EDQM) in the Council of Europe; the 
Ministry of Health, Labour and Welfare (MHLW) of Japan, and the United States 
Pharmacopeial Convention, Inc. (USP). 
 
Pharmacopoeial text:  The pharmacopoeial monographs, general test chapters, and 
analytical methods emanating from the three regional pharmacopoeias. 
 
Q4B Outcome  Produced by the Q4B evaluation process; information concerning how the 
evaluated pharmacopoeial text can be used.  The Q4B Outcome is included as part of the 
topic-specific Q4B annex developed as a result of each favorable evaluation. 
 
  6 Contains Nonbinding Recommendations 
 
ATTACHMENT I 
 
General Chapters Discussed During ICH Q6A Development 
     
Dissolution 
Disintegration 
Uniformity of Content   Harmonized to 
Uniformity of 
Uniformity of Mass 
Dosage Units 
Extractable Volume 
Particulate Matter 
Sterility 
Microbiological Quality 
Bacterial Endotoxins 
Residue on Ignition/Sulphated 
Ash 
Color 
  7 Contains Nonbinding Recommendations 
 
 
ATTACHMENT II 
 
PDG Document Submission Provided for ICH Q4B EWG Evaluation  
 
This is an example of a document submission from the PDG: 
  
The Coordinating Pharmacopoeia, on behalf of PDG, is asked to provide, as soon as possible 
after PDG Stage 5B sign-off and usually within six months, the following texts and information 
(termed the document submission as defined in the Q4B guidance) to the Q4B EWG, via the ICH 
secretariat, with a copy to the Q4B EWG Rapporteur (for awareness): 
 
1.  The PDG sign-off document containing the PDG-harmonized text (PDG Stage 5B).  
2.  A Briefing Note dealing in particular with:  
a.  Residual differences between one or more of the pharmacopoeias, to include a 
commentary on any difference from the point of view of harmonization; 
b.  Any specific issues relating to publication;  
c.  If any equivalency study was conducted, a summary of the outcome; 
d.  The projected publication and implementation schedule in each pharmacopoeia,   
and 
e.  Any additional information not covered above. 
3.  The texts as intended for adoption and publication in each pharmacopoeia together 
with a statement of any local differences with respect to the sign-off text.   
    4.  Additional clarifying information is incorporated by one or more of the PDG 
pharmacopoeias in their respective information chapters on pharmacopoeial 
harmonization.  Therefore, the revised information chapter on harmonization from 
each pharmacopoeia incorporating such information (in draft form where this is 
available) should accompany the provided documents. 
If any changes occur or additional differences are discovered after submission to Q4B for 
evaluation, the Q4B EWG should be informed promptly by the pharmacopoeia concerned. 
 
  8