á1196ñPHARMACOPEIAL HARMONIZATION
This general information chapter provides information about the concept of harmonization by the Pharmacopeial Discussion Group (PDG).The chapter provides:(1)the PDG Policy Statement;(2)the PDG Working Procedures;(3)a discussion;(4)a status report;and (5)a glossary.
HARMONIZATION POLICY
The following policy statement was approved by the PDGat its September 2002meeting.
General Information
In 1989,the PDGwas formed with representatives from the European Directorate for the Quality of Medicines in the Council of Europe,the United States Pharmacopeial Convention,Inc.,and the Japanese Pharmacopoeia in the Ministry of Health and Welfare—now the Ministry of Health,Labor,and Welfare (MHLW).Since that time,the PDGgenerally meets twice a year to work on pharmacopeial harmonization topics.In May 2001,the PDGwelcomed the World Health Organization as an observer.While not part of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH),the PDGusually meets in conjunction with the ICHand provides the ICH Steering Committee with reports of its progress.To facilitate harmonization of some ICH Quality guidelines and the Quality section of the Common Technical Document,the PDGrepresentatives sometimes attend ICHexpert working group discussions as observers.
Purpose
Apharmacopeial monograph for an active ingredient or excipient,preparation,or other substance used in the manufacture or compounding of a medicinal product generally provides a name,definition,description,and sometimes packaging,labeling,and storage statements.Thereafter,the monograph provides tests,procedures,and acceptance criteria that constitute the specification.For frequently cited procedures,a monograph may refer to a general chapter for editorial convenience.The PDGworks to harmonize excipient monographs and general chapters.This will reduce manufacturers'burden of performing analytical procedures in different ways,using different acceptance criteria.At all times,the PDGworks to maintain an optimal level of science consistent with protection of the public health.
Definition of Harmonization
The PDGhas defined harmonization of a pharmacopeial monograph or general chapter as follows:
“Apharmacopeial general chapter or other pharmacopeial document is harmonized when a pharmaceutical substance or product tested by the document's harmonized procedure yields the same results and the same accept/reject decision is reached.”
When using a fully harmonized pharmacopeial monograph or general chapter,an analyst will perform the same procedures and reach the same accept/reject decisions irrespective of which PDGpharmacopeia is referenced.This approach is called interchangeability,and each pharmacopeia will identify,in an appropriate manner,such a monograph or general chapter.
When full harmonization of a pharmacopeial monograph or general chapter is not possible,the PDGworks to harmonize it using an approach termed harmonization by attribute.In this approach,some elements of a monograph or general chapter may be harmonized,but others may not.When a monograph is harmonized by attribute,a combination of approaches is needed.For nonharmonized elements,reliance on the individual PDGpharmacopeia is necessary.
Process
Harmonization of pharmacopeial documents in the PDGis based upon decisions of the expert bodies of each pharmacopeia.The PDGworks transparently in many ways,principally through the public notice and comment procedures of each pharmacopeia.The details are described below under PDG Working Procedures.
Implementation
The implementation of a harmonized document varies in the three PDGregions,depending upon their legal requirements,need for translation,and publication schedules.Each pharmacopeia generally allows some period of time after publication to implement official harmonized texts to allow manufacturers and other users to achieve conformity.Harmonization is not achieved until the text becomes official in all three pharmacopeias.
Revision of Harmonized Monographs
The pharmacopeias participating in the PDGhave agreed not to revise unilaterally any harmonized document after publication.Should revisions be necessary for any appropriate reasons,the initiating pharmacopeia notifies the PDG,and revision proceeds according to the PDG Working Procedures.
Change to read:
PDG WORKING PROCEDURES
General
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 respect the agreed working procedures and the associated time deadlines as an essential part of the harmonization procedure.
Harmonization of pharmacopeial documents in the PDGis performed on the basis of decisions of the expert bodies of each pharmacopeia.The PDGworks transparently in many ways,but principally through the public notice and comment procedures of each pharmacopeia.
Where necessary,meetings of experts are held to identify potential solutions to difficult problems.
The specific stages of the PDGprocess involved in harmonization are described below.
Stage 1:Identification
On the basis of an inquiry among its users,the PDGidentifies subjects to be harmonized among PDGpharmacopeias and nominates a coordinating pharmacopeia for each subject.
The PDGdistributes the work by consensus among the three pharmacopeias and strives for a balance in the distribution of assignments to coordinating pharmacopeias.
Stage 2:Investigation
For a subject to be harmonized retrospectively,the coordinating pharmacopeia collects the information on the existing specifications in the three pharmacopeias,on the grades of products marketed,and on the potential analytical procedures.
The coordinating pharmacopeia prepares a draft monograph or chapter,accompanied by a report giving the rationale for the proposal with validation data.
Stage 2ends with the proposal draft,which is mentioned in this procedure as a Stage 3draft.The Stage 3draft,accompanied by supporting comments or data that explain the reasons for each test procedure or limit proposed,is sent by the coordinating pharmacopeia to the secretariats of the other two PDGpharmacopeias.
Stage 3:Proposal for Expert Committee Review
The three pharmacopeias forward the Stage 3draft to their expert committee (through meetings or consultation by correspondence).
Comments by the experts resulting from this preliminary survey are sent to their respective pharmacopeial secretariat,preferably within 2months.However,the comment period should not exceed 4months.Within 2months of receipt of the comments,the pharmacopeial secretariat should consolidate the comments and forward them to the coordinating pharmacopeia.
The coordinating pharmacopeia reviews the comments received and prepares a harmonized document (Stage 4draft)accompanied by a commentary discussing comments received about the previous text and providing reasons for action taken in response to those comments.
The Stage 4draft,as far as possible written in global style—a style easily understood by a variety of readers—together with the commentary,are sent to the secretariats of the other pharmacopeias (end of Stage 3).
Stage 4:Official Inquiry
The Stage 4draft and the commentary are published in the revision document of each pharmacopeia in a section entitled International Harmonization.The draft is published in its entirety.
The corresponding secretariats may have to add information essential to the understanding of the implementation of the texts (e.g.,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 Pharmacopoeias.The style may be adapted to that of the pharmacopeia concerned,or global style may be used.
Apharmacopeia can add text,either to amplify some of the requirements with additional information or because national requirements and compendial policy dictate that the addition is necessary.However,there must be a clear indication that this additional information is not part of the harmonized document.This will avoid additional text being included after the harmonization process is completed,but will allow interested parties to review a complete text.USP28The three pharmacopeias endeavor to publish the drafts simultaneously or as close together as possible.
Apharmacopeia can add text,either to amplify some of the requirements with additional information or because national requirements and compendial policy dictate that the addition is necessary.However,there must be a clear indication that this additional information is not part of the harmonized document.This will avoid additional text being included after the harmonization process is completed,but will allow interested parties to review a complete text.USP28The three pharmacopeias endeavor to publish the drafts simultaneously or as close together as possible.Comments regarding this draft are sent by readers of the revision document to their respective pharmacopeial secretariat,preferably within 4months and at most within 6months of its publication.
Each pharmacopeia analyzes the comments received and submits its consolidated comments to the coordinating pharmacopeia within 2months of the end of the review or comment period.
The coordinating pharmacopeia reviews the comments received and prepares a draft harmonized document (Stage 5Adraft),accompanied by a commentary discussing comments received regarding the previous text and providing reasons for action taken in response to those comments.
The Stage 5Adraft,together with the commentary,is sent to the secretariats of the other two PDGpharmacopeias.
Stage 5.Consensus
5A.PROVISIONAL
The Stage 5Adraft is reviewed and commented on by the other two PDGpharmacopeias within 4months of receipt.The three pharmacopeias shall do their utmost to reach full agreement at this stage to obtain a final consensus document.
If a consensus has not been reached,the coordinating pharmacopeia prepares a revised version (Stage 5A/2),taking into consideration relevant,substantiated comments on the Stage 5Adocument from the two other pharmacopeias.The revised document (Stage 5A/2),together with the commentary,is sent to the secretariats of the other two PDGpharmacopeias.The revised document is reviewed and commented on by the other two PDGpharmacopeias,preferably within 2months of receipt.This review or comment and revision process of the 5Adocument is repeated (Stage 5A/n)until the three PDGpharmacopeias reach a consensus or until the coordinating pharmacopeia considers that harmonization by attribute should be applied.
If the coordinating pharmacopeia considers certain attributes in the monograph or provisions in a general chapter (especially for retroactive harmonization)are such that it will not be possible to harmonize within a reasonable time period,harmonization by attribute will be applied.If harmonization by attribute is applied,a special cover page (see the table in the Appendix)indicating harmonization is included with the draft.The text contains harmonized attributes and provisions,andUSP28nonharmonized and local attributes are not included.The nonharmonized attributes are clearly indicated in the text as such.USP28The table is prepared as follows:if three pharmacopeias agree on the attribute,there will be a (+)in all columns;if two pharmacopeias agree that the attribute should be included and have agreed on the method and limit,there will be a (+)in the column for those two pharmacopeias,and a (–)in the column for the pharmacopeia that will not stipulate the test.
harmonized attributes and provisions,andUSP28nonharmonized and local attributes are not included.The nonharmonized attributes are clearly indicated in the text as such.USP28The table is prepared as follows:if three pharmacopeias agree on the attribute,there will be a (+)in all columns;if two pharmacopeias agree that the attribute should be included and have agreed on the method and limit,there will be a (+)in the column for those two pharmacopeias,and a (–)in the column for the pharmacopeia that will not stipulate the test.For nonharmonized or local requirements,if three pharmacopeias agree that the attribute should be included,but have not come to agreement on the method or limit:state attribute under “nonharmonized attributes.”If only one pharmacopeia will include an attribute:state under “local requirement.”
If the Stage 5Adraft is substantially different from the Stage 4draft,the PDGmay decide that it should be published again in the revision documents;the draft then reverts technically to Stage 4,revised.
5B.DRAFT SIGN-OFF
When USP28agreement is reached,the 5Bdraft is sent by the coordinating pharmacopeia to the other pharmacopeias no later than 4weeks before a PDGmeeting for final confirmation.The document is then presented for sign-off at the PDGmeeting.This document includes nonharmonized attributes clearly marked as such.USP28
USP28agreement is reached,the 5Bdraft is sent by the coordinating pharmacopeia to the other pharmacopeias no later than 4weeks before a PDGmeeting for final confirmation.The document is then presented for sign-off at the PDGmeeting.This document includes nonharmonized attributes clearly marked as such.USP28
Stage 6:Regional Adoption and Implementation
Regional Adoption and Implementation
NOTE—The last two stages of the implementation of the “harmonized”chapters and monographs take place independently according to the procedures established by each pharmacopeial organization.
6A.Regional AdoptionUSP28
USP28
The document is submitted for adoption to the organization responsible for each pharmacopeia.Each pharmacopeia incorporates the harmonized draft according to its own procedures.Stylistic and editorial differences may occur.USP28
Stylistic and editorial differences may occur.USP28
Adopted texts are published by the three pharmacopeias in their supplements,or where applicable,in a new edition.
If necessary,the Stage 5Bdraft may be adopted with some amendments (local requirements)corresponding to a general policy in the national or regional (European)area.If a pharmacopeia includes a local attribute after the sign-off of a text,it will inform the PDG.It is,however,preferred to include the nonharmonized text in Stage 5Bas an alert to the other pharmacopeias that there will be some differences in text in the final document.USP28
It is,however,preferred to include the nonharmonized text in Stage 5Bas an alert to the other pharmacopeias that there will be some differences in text in the final document.USP28
Users of the pharmacopeias are appropriately informed of the harmonization status of monographs and general chapters.In the European Pharmacopoeia (EP)and USP–NF,for general chapters,this is done via a preliminary paragraph.For the Japanese Pharmacopoeia (JP),a notification is made by the MHLW,and information is given in a general chapter.
6B.ImplementationUSP28
The pharmacopeias will inform each other of the date of implementation in their particular region.
The date of implementation of a harmonized document varies in the three PDGregions 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.Harmonization is not achieved until the text becomes official in all three pharmacopeias.
Stage 7:Inter-Regional Implementation
Inter-Regional Implementation
When a harmonized text has become official in all three pharmacopeias,EPand USPpublish a statement indicating the harmonization status of the text;JPpublishes a statement to the same effect at Stage 6B.These statements are intended to promote regulatory acceptance of interchangeability of harmonized monographs and general chapters.USP28
USP28
Revision
The procedure for the revision of harmonized monographs and chapters is as follows.
The pharmacopeias participating in the PDGhave agreed not to revise unilaterally any harmonized document (monograph or chapter)after sign-off or after publication.
Apharmacopeia requesting the revision of a monograph or chapter shall apply the following criteria for justification of the revision:
- Public health and safety reasons.
- Insufficient supply of pharmacopeial-quality product on the market.
- Specified analytical reagents or equipment unavailable.
- New methods of preparation of products or reagents not covered by the current monograph.
- Analytical procedures capable of being replaced by more appropriate,accurate,or precise procedures.
The PDGas a whole has to agree to initiate the revision.Acoordinating pharmacopeia will be nominated.The coordinating pharmacopeia will prepare a Stage 3draft,based on the validation of data provided by the pharmacopeia requesting the revision.
The PDG Working Procedureswill then be followed.The revisions of a sign-off document prepared for this or other reasons are indicated as revision 1,2,3,etc.
In case of health and safety issues,and whenever agreed to by the PDG,an accelerated procedure shall be applied (shortening or eliminating stages).
Discussion
Harmonization of general chapters and monographs benefits manufacturers of pharmaceutical products intended for human use,regulatory agencies,and ultimately,practitioners and patients.Benefits are derived from (1)reduced development effort;(2)simplification of regulatory filings;and (3)reduced release testing.
Pharmacopeial harmonization amplifies the work of the ICH,particularly for Quality topics.While the PDGis not part of the ICH,the PDGperiodically provides updates to the ICH Steering Committee,and in the past participated in a joint task force.This task force focused on harmonization of general chapters considered important to the ICHharmonized document Specifications:Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products:Chemical Substances (Q6A).USPalso participates in the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Products (VICH).As with the ICH,some of the quality guidelines developed in VICHdepend upon harmonization of pharmacopeial general chapters.Amajor difference between the PDGand ICH/VICHs is that the ICH/VICHguidelines generally are applicable only to ingredients and drug products not previously registered in an ICH/VICHregion or nation,whereas the PDGharmonization applies to all marketed products in the applicable region or nation.
In the case of harmonization by attribute,nonharmonization or divergence will be indicated in USP–NFand EPby the symbol 
.For these nonharmonized attributes,reliance upon the individual pharmacopeia is required.Amonograph or general chapter in one PDGpharmacopeia may unilaterally include additional local or national attributes that are not included in the corresponding text of the other pharmacopeias.Such text is not considered by the PDGto be a divergence from the PDGharmonized text.
.For these nonharmonized attributes,reliance upon the individual pharmacopeia is required.Amonograph or general chapter in one PDGpharmacopeia may unilaterally include additional local or national attributes that are not included in the corresponding text of the other pharmacopeias.Such text is not considered by the PDGto be a divergence from the PDGharmonized text.As with other USP–NFrevisions,draft harmonization texts are published for comment in Pharmacopeial Forum.Final harmonized official text in USP–NFis presented in the latest edition,Supplement,or Interim Revision Announcement.The current status of all harmonization projects appears in Table 1and Table 2.These status tables will be updated in subsequent editions of USP–NFand its Supplements.
In the U.S.,cases of noncompliance or dispute are resolved through performance of the official procedure in USPor NF.If the procedure and its acceptance criteria are harmonized in the PDG,then a manufacturer may follow the relevant compendial instructions in USP–NF,EP,or JP.
Table 1.Status of Harmonization—Excipient
Monographs
Monographs
| Excipient Name | Coordinating Pharmacopeia |
Harmonization Stage |
| Alcohol | EP | 6 |
| Benzyl Alcohol | EP | 6 |
| Dehydrated Alcohol | EP | 6 |
| Butylparaben | EP | 6USP28 |
| Calcium Carbonate | USP | 2 |
| Calcium Disodium Edetate | JP | 5A2 |
| Calcium Phosphate Dibasic (and anhydrous) |
JP | 5BUSP28 |
| Carboxymethylcellulose Calcium |
USP | 6 |
| Carboxymethylcellulose Sodium |
USP | 4 |
| Carmellose | JP | 2 |
| Cellulose Acetate | USP | 6 |
| Cellulose Acetate Phthalate | USP | 6 |
| Microcrystalline Cellulose | USP | 6USP28 |
| Cellulose,Powdered | USP | 6USP28 |
| Citric Acid,Anhydrous | EP | 6 |
| Citric Acid,Monohydrate | EP | 6 |
| Copovidone | JP | 2 |
| Croscarmellulose Sodium | USP | 6 |
| Crospovidone | EP | 4 |
| Ethylcellulose | EP | 6 |
| Ethylparaben | EP | 6USP28 |
| Gelatin | EP | 2 |
| Glucose | EP | 2 |
| Glycerin | USP | 3 |
| Glyceryl Monostearate | USP | 2 |
| Hydroxyethyl Cellulose | EP | 4 |
| Hydroxypropyl Cellulose | USP | 4 |
| Hydroxypropyl Cellulose, Low Substituted |
USP | 4 |
| Hydroxypropylmethyl Cellulose |
JP | 6USP28 |
| Hydroxypropylmethyl Cellulose Phthalate |
USP | 5AUSP28 |
| Lactose,Anhydrous | USP | 6 |
| Lactose,Monohydrate | USP | 6 |
| Magnesium Stearate | USP | 4USP28 |
| Mannitol | EP | 2 |
| Methylcellulose | JP | 6USP28 |
| Methylparaben | EP | 6USP28 |
| Petrolatum,White | USP | 4 |
| Polyethylene Glycol | USP | 4 |
| Polysorbate 80 | EP | 3 |
| Povidone | JP | 5A |
| Propylene Glycol | EP | 3USP28 |
| Propylparaben | EP | 6USP28 |
| Saccharin | USP | 6 |
| Saccharin,Calcium | USP | 6 |
| Saccharin,Sodium | USP | 6 |
| Silicon Dioxide | JP | 4 |
| Silicon Dioxide,Colloidal | JP | 4 |
| Sodium Chloride | EP | 6 |
| Sodium Lauryl Sulfate | USP | 2 |
| Sodium Starch Glycolate | USP | 6USP28 |
| Starch,Corn | USP | 6 |
| Starch,Potato | EP | 6 |
| Starch,Pregelatinized | JP | 2 |
| Starch,Rice | EP | 4RevisedUSP28 |
| Starch,Wheat | EP | 6 |
| Stearic Acid | EP | 4 |
| Sucrose | EP | 3 |
| Talc | EP | 6USP28 |
| Titanium Dioxide | JP | 5A2 |
Table 2.Status of Harmonization—General Chapters
| Chapter Title | Coordinating Pharmacopeia |
Harmonization Stage |
| Amino Acid Determination | USP | 6 |
| Bacterial Endotoxins | JP | 7 |
| Bulk Density and Tapped Density |
EP | 3 |
| Conductivity |
EP | 2USP28 |
| Degree of Color of Liquids; Clarity and Degree of Opalescence of Liquids |
EP | 3 |
| Density of Solids | EP | 3 |
| Disintegration | USP | 4 |
| Dissolution | USP | 4 |
| Capillary Electrophoresis | EP | 6 |
| Polyacrylamide Gel Electrophoresis |
EP | 6 |
| Extractable Volume of Parenterals |
EP | 6 |
| Flowability (Powder Flow) | USP | 4 |
| Heavy Metals | USP | 3 |
| Inhalation | EP | 3 |
| Isoelectric Focusing | EP | 6 |
| Light Diffraction Measure of Particle Size |
EP | 3 |
| Microbial Contamination | ||
| Tests for specified microor ganisms |
EP | 4 |
| Microbial Enumeration | EP | 4 |
| Microbial Attributes | EP | 4USP28 |
| Optical Microscopy | USP | 5AUSP28 |
| Particle Size Distribution Estimation by Analytical Sieving |
USP | 5AUSP28 |
| Peptide Mapping | USP | 6 |
| Porosimetry by Mercury Intrusion |
EP | 3 |
| Powder Fineness | USP | 5AUSP28 |
| Protein Determination | USP | 6 |
| Residue on Ignition (Revision 1)USP28 |
JP | 6 |
| Specific Surface Area | EP | 6USP28 |
| Sterility Tests | EP | 6 |
| Tablet Friability | USP | 3 |
| Thermal Behavior of Powders |
EP | 2USP28 |
| Uniformity of Content/Mass | USP | 5A2USP28 |
| X-Ray Diffraction—Solids | EP | 3 |
Harmonized Monographs and Chapters
HARMONIZED CHAPTERS
á85ñBacterial Endotoxins Test—
This chapter has been harmonized by PDGand published in the European Pharmacopoeia and in the Japanese Pharmacopoeia.Portions of the chapter that are not harmonized with the other two pharmacopeias are marked by the symbol .Footnotes 1,2,and 4are in the USPbut are not in the EPor JP.These footnotes give additional information,such as the calculation of endotoxin limits for different classes of products (Footnote 4)or reference USPchapters (Footnote 2).
.Footnotes 1,2,and 4are in the USPbut are not in the EPor JP.These footnotes give additional information,such as the calculation of endotoxin limits for different classes of products (Footnote 4)or reference USPchapters (Footnote 2).
The USP Endotoxin Reference Standard is harmonized with the International Reference Standard for Endotoxin and the EP Endotoxin Reference Standard and indirectly harmonized with the JP Endotoxin Reference Standard that is indexed to the International Reference Standard.The result is that 1USP Endotoxin Unit =1International Endotoxin Unit =1EP Endotoxin Unit.
GLOSSARY
Harmonized monograph or general chapter—
Text that has reached Stage 5Band that has been countersigned by the three PDGpharmacopeias.
Total harmonization—
Amonograph or a general chapter that is identical in the three PDGpharmacopeias in terms of identical tests,test procedures,and acceptance criteria.
Harmonization by attributes—
Amonograph or a general chapter that contains a combination of harmonized and nonharmonized tests or sections.
Interchangeability—
Atest or a section of a monograph or a general chapter that is not the same among the PDGpharmacopeias,but the accept/reject decision is the same regardless of which one of the tests or sections of the PDGpharmacopeia is used.
Local or national divergence—
Amonograph or a general chapter in one of the PDGpharmacopeias contains specific attributes of local or national origin in addition to the PDGharmonized/nonharmonized attributes.
Nonharmonized attributes—
Attributes that could not be agreed upon by the three PDGpharmacopeias because of regional differences,regulatory differences,nonavailability of reagents,etc.
Appendix
Example
Pharmacopeial Discussion Group
Sign-Off Document
Name:__________
| Attributes | EP | JP | USP |
| 1 | + | + | + |
| 2 | + | + | – |
| 3 | + | + | + |
| 4 | + | + | + |
| 5 | + | + | + |
| 6 | + | + | + |
| 7 | + | – | + |
| 8 | + | + | + |
| 9 | + | + | + |
| 10 | + | – | + |
| 11 | + | + | + |
Legend
+will adopt and implement;–will not stipulate
Nonharmonized attributes
Reagents and reference materials
Each pharmacopeia will adapt the text to take account of local reference materials and reagent specifications.
Date:
Signatures:
European Pharmacopoeia Japanese Pharmacopoeia United States Pharmacopeia