Revised version: June 2010
Harmonization may be carried out retrospectively for existing monographs or chapters or prospectively for new monographs or chapters.
The three pharmacopeias have a commitment to respecting the agreed working procedures and the associated time deadlines as an essential part of the Harmonization procedure. Harmonization of pharmacopeial documents in the PDG occurs based on decisions of the expert bodies of each pharmacopeia.
The PDG works transparently in many ways, including, principally, the public notice and comment procedures of each pharmacopeia. Where necessary, meetings of experts are held to identify potential solutions to resolve difficult problems.
The specific stages of the PDG Procedure (Process) involved in Harmonization are:
Based on inquiry among its users, the PDG identifies subjects to be harmonized among PDG pharmacopeias and nominates a coordinating pharmacopeia for each subject.
The PDG distributes the work by consensus amongst the three pharmacopeias. The PDG strives for a balance in the distribution of coordinating pharmacopeia assignments.
The coordinating pharmacopeia for a subject to be harmonized retrospectively collects the information on the existing specifications in the three pharmacopeias, on the grades of products marketed and on the potential analytical methods.
The coordinating pharmacopeia prepares a draft monograph or chapter, accompanied by a report giving the rationale for the proposal with validation data.
Stage 2 ends with the proposal draft, which is mentioned in this procedure as “stage 3 draft”.The Stage 3 draft, accompanied by supporting comments or data that explain the reasons for each test method or limit proposed, is sent by the coordinating pharmacopeia to the secretariats of the other two PDG pharmacopeias.
The three pharmacopeias forward the Stage 3 draft to their expert committee (meeting or consultation by correspondence).
Comments by the experts resulting from this preliminary survey are sent to their respective pharmacopeial secretariat, preferably within 2 months. The comment period should, however, not exceed 4 months. Within 2 months of receipt of the comments, the Pharmacopeial Secretariat should consolidate them and forward them to the coordinating pharmacopeia.
The coordinating pharmacopeia reviews the comments received and prepares a harmonized document (Stage 4 draft) accompanied by a commentary discussing comments received regarding the previous text and providing reasons for action taken in response to those comments.
The Stage 4 draft, as far as possible in “global style,” together with the commentary 1 is sent to the secretariats of the other pharmacopeias (end of Stage 3).
The Stage 4 draft and the commentary are published in the forum of each pharmacopeia in a section entitled International Harmonization. The draft is published in its entirety. The corresponding secretariats may have to add information needed for the understanding of implementation of the texts, e.g., the addition of the description of an analytical procedure or of reagents that do not exist in the pharmacopeia and a translation is added by the European and Japanese Pharmacopeias. The style may be adapted to that of the pharmacopeia concerned or the “global style” may be used. The three pharmacopeias endeavor to publish the drafts simultaneously or as closely as possible.
Comments regarding this draft are sent by readers of the forum to their respective Pharmacopeial secretariat, preferably within 4 months and at most within 6 months of publication in the forum.
Each pharmacopeia analyses the comments received and submits its consolidated comments to the coordinating pharmacopeia within 2 months of the end of the review/comment period.
The coordinating pharmacopeia reviews the comments received and prepares a draft harmonized document (Stage 5A draft) accompanied by a commentary discussing comments received regarding the previous text and providing reasons for action taken in response to those comments. When residual differences are anticipated for sign-off, the stage 5A draft may include a draft of the sign-off cover sheet.
The Stage 5A draft together with the commentary is sent to the secretariats of the other two PDG pharmacopeias.
The stage 5A draft is reviewed and commented on by the other two PDG pharmacopeias within 4 months of receipt. The three pharmacopeias shall do their utmost to reach full agreement already at this stage with a view to reaching a final consensus document.
If a consensus has not been reached, the coordinating pharmacopeia prepares a revised version (Stage 5A/2), taking relevant substantiated comments on the Stage 5A document from the two other pharmacopeias into consideration. The revised document (Stage 5A/2) together with the commentary is sent to the secretariats of the other two PDG pharmacopeias. The revised document is reviewed and commented by the other two PDG pharmacopeias preferably within 2 months of receipt. This review/comment and revision process of the 5A document is repeated (Stage 5A/n) until the three PDG pharmacopeias reach a consensus or until the coordinating pharmacopeia considers that Harmonization by attribute/provision should be applied.
If the coordinating pharmacopeia considers that certain attributes in the monograph or certain provisions in a general chapter (especially for retroactive Harmonization) are such that it will not be possible to harmonize within a reasonable time period, then Harmonization by attributes/provisions will be applied. If Harmonization by attributes/provisions is applied, a special sign-off cover sheet (see Appendixes 1 and 2) indicating Harmonization is included with the draft. The text contains only harmonized attributes/provisions; non-harmonized attributes/provisions and local requirements are not included. The table is prepared as follows:
- 3 pharmacopeias agree on the attribute/provision: ‘+’ in all columns
- 2 pharmacopeias agree that the attribute/provision should be included and have agreed on the method and limit: ‘+’ in the column for those two pharmacopeias, ‘–’ in the column for the pharmacopeia that will not stipulate the test
- 3 pharmacopeias agree that the attribute/provision should be included but have not come to an agreement on the method and/or limit: state attribute/provision under ‘Non-harmonized attributes/provisions’
- 1 pharmacopeia only will include an attribute/provision: state under ‘local requirement’.
The coordinating pharmacopeia collects information about needs for amendments (local requirements) corresponding to a general policy in the national or regional (European) area. Local requirements, if needed, will be listed on the sign-off cover sheet.
If the stage 5A draft is substantially different from the stage 4 draft, the PDG may decide that it should be published again in the forums; the draft then reverts technically to stage 4 revised.
B. Draft sign-off
When full agreement is reached, the 5B draft is sent by the coordinating pharmacopeia to the other pharmacopeias not later than 4 weeks before a PDG meeting for final confirmation. The document is then presented for sign-off at the PDG meeting.
Stage 6 takes place individually according to the procedures established by each pharmacopeial organization.
A. Adoption and publication
The document is submitted for adoption to the organization responsible for each pharmacopeia. Each pharmacopeia incorporates the harmonized draft according to its own procedure.
Adopted texts are published by the three pharmacopeias in the Supplements or, where applicable, in a new edition.
If a pharmacopeia includes a local requirement after the sign-off of a text, it will submit the PDG with a proposed revision of the sign-off cover sheet.
The pharmacopeias will inform each other of the date of implementation in the particular region.
The date of implementation of a harmonized document varies in the three PDG regions depending on their legal requirements, need of translation, and publication schedules. Each pharmacopeia generally allows some period of time after publication for implementation, to allow manufacturers and other users to achieve conformity.
C. Indication of Harmonization
Each pharmacopeia will introduce a statement indicating the Harmonization status. EP and USP reference the corresponding text of the other PDG pharmacopeias. JP references the harmonized text. In case of residual differences, these are indicated by specific symbols (black diamonds indicate non-harmonized attributes/provisions, white diamonds indicate local requirements). The residual differences all correspond to differences that have been agreed upon by PDG, via the sign-off cover sheet.
Harmonization is achieved when all pharmacopeias have highlighted Harmonization and any residual differences, based on a general policy in the national or regional area.
Concurrent to Stages 6A, B and C, a dialogue is opened between PDG and ICH Q4B Expert Working Group for the purpose of obtaining regulatory acceptance of the harmonized text. The coordinating pharmacopeia provides documents to ICH Q4B EWG as defined in the ICH Q4B Guideline.
Following Q4B evaluation process, a formal notification of regulatory acceptance is posted by ICH.
A topic-specific annex to Q4B guideline for each monograph or chapter concerned is processed for publishing and implementation by each regional authority.
Procedure for the revision of harmonized monographs and chapters
The Pharmacopeias participating in PDG have agreed not to revise unilaterally any harmonized document (monograph or chapter) after sign-off or after publication.
A pharmacopeia requesting the revision of a monograph or chapter shall apply the following criteria for justification of revision:
- Public health and safety reasons.
- Insufficient supply of pharmacopeial quality product on the market.
- Specified analytical reagents or equipment are not available.
- New methods of preparation of product/reagent are not covered by the current monograph.
- Analytical methods can be replaced by more appropriate/accurate/precise methods.
A pharmacopeia requesting the revision of a monograph or chapter shall provide PDG with a formal request including a rationale for revision and appropriate supportive data.
The PDG as a whole has to agree to initiate the revision. A coordinating pharmacopeia will be nominated.
The coordinating pharmacopeia, on the basis of data provided by the pharmacopeia requesting the revision, will prepare a Stage 3 draft (tracked-changed and clean versions).
The Working Procedure of the PDG will then be followed. The revisions of a sign-off document prepared for this or other reasons are indicated as revision 1, 2, 3, etc.
Whenever agreed by the PDG, an expedited procedure may be applied. In certain circumstances where appropriately justified, the expedited procedure would result in a revision reverting to Stage 5A as opposed to Stage 3. In these instances, a pharmacopeia requesting the revision of a monograph or chapter using the expedited procedure will submit a formal request for revision, including, in addition to the information supplied in the normal revision process, a justification for recommending the expedited procedure. Agreement by PDG to the expedited procedure will be handled on a case-by-case basis. After agreement by PDG to proceed with the revision, the coordinating pharmacopeia may proceed directly with the elaboration of a stage 5A draft.
PDG as a whole instead of a pharmacopeia may also request a revision.
Any pharmacopeia which has identified an error in a sign-off text may submit a request for correction to PDG together with appropriate justification. A cover sheet (see Appendix 3) is prepared by the pharmacopeia requesting the correction, together with appropriate justification. The cover sheet includes the name and code of the general chapter or monograph, the date of the sign-off and the description of the correction. After confirmation by PDG, the cover sheet is signed-off at the PDG meeting. When needed for clarity purposes, a full text including the correction is to be signed-off together with the cover sheet.
Addition or Revision of a Local Requirement
Any pharmacopeia which has identified a need for addition of a new local requirement or a revision of a local requirement already included in a previously signed-off cover sheet will inform PDG accordingly, together with appropriate justification. When needed for clarity purposes, the pharmacopeia provides PDG with a full text including the new/revised local requirements or with the published local text, if available. A revised cover sheet (see Appendix 4) is prepared by the pharmacopeia requesting the revision. The cover sheet includes the name and code of the general chapter or monograph, the date of the sign-off and the description of the new/revised local requirement. After agreement by PDG that this is a local requirement, only the revised cover sheet is signed-off at the PDG meeting.