History of PDG

Fumi YamamotoDirector,Pharmaceutical Evaluation Division,Pharmaceutical Safety and Environmental Health Bureau,Ministry of Health, Labour and Welfare

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History of PDG

October 3, 2019The PDG 30th Anniversary Symposium

• What is PDG

• History of PDG

• Working Procedures of PDG

• Publication of Harmonization Status

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Today’s Topic

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Why do we need “Harmonization”?

If each country/region has own pharmaceutical regulation without harmonization….

→ When pharmaceutical products that approved in one country/region

are sold in other countries/regions, the products must meet the quality

specification of that countries/regions

- Must conduct tests based on each country/region requirement on the

product even though existence of test data

Pharmacopoeias Standardization

→ can make the test methods and the quality standards which

are valid throughout the world

Waste of resources!!

What is “PDG”?

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【Purpose of Activities】

• Standardize the test procedures and acceptance criteria that differ among pharmacopoeias

→ Standardize general chapters and excipient monographs

→ Reduce manufacturers’ burden of performing analytical procedures • Maintain an optimal level of science

PDG (Pharmacopoeial

Discussion Group）

Ph. Eur. (European Pharmacopoeia)

JP (Japanese Pharmacopoeia)

USP (United States Pharmacopeia)

Establishment :1989Observer :WHO（Since May, 2001)

Meetings :Twice every year(F2F and Video conference, hosted in turn)

Status of each Pharmacopoeia

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Ph. Eur. USP JP

Issued by • European Directorate for the Quality of Medicines and HealthCare （EDQM）

• Founded in1964• Strasbourg, France• Pharmaceutical

medical quality department within the European Council

• USP Convention • Founded in 1820• Maryland, USA• the incorporated non-

profit organization independent of regulatory authorities

the Ministry of Health, Labour and Welfare (MHLW)

Status prepared under the treaty of Council of Europe and is referenced under the order of EU

Food, Drug, and Cosmetic Act

Act on Securing Quality, Efficacy and Safety Products Including Pharmaceuticals and Medical Devices

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30 years of PDG Activities

Establishment of PDG

First sign-off(SDS-PAGE)

Participation of WHO observer

Enactment of Policy and Working Procedure

1995

ICH Q6A agreement – Specifications for new drugs

1999

Establishment of ICH Q4B –Evaluate for inter-regional regulatory acceptance

2003

Revision of Policy and Working Procedure –Change in definition of harmonization and adoption of harmonization by attribute

2003

2010Discontinue

Major activities up till September 2019General Chapters (Physico-chemical, Drug formulation, Physical methods, Microbial, Biological)

→28 out of 31 general studies (PDG work program) have been harmonizedExcipients monographs

→46 out of 60 monographs (PDG work program) have been harmonized

PDG

ICH

Singing-off of last ICH Q4B Annex

Re-examination of system

2017

Maintenance procedure of ICH Q4B Annex

Establishment of PDG

1989 May - USP Spring Conference (Virginia, USA)

Jun. - EP 25th anniversary Open Conference (Strasbourg, France)

Sep. - International conference (Tokyo, Japan)

Dr. Lee T. Grady (USP)Dr. Peter J. Schorn (EP)Dr. Mitsuru Uchiyama (JP)

1990 1st PDG Face to Face meeting

1991 Excipient International conference (Orlando, USA)→ IPEC was formed

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PDG activities in 1990 to 2000PDG Statement of Harmonization Policy

established in 1995

PDG harmonization policy in the early stages was prerequisites of reaching full harmonization of general chapters or monographs, based on objective comparability.→First sign-off in 1999 (SDS-PAGE）

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No achievement of harmonization for several years

Trial and error period

PDG activities since 2002

→ Evaluate interchangeability of harmonized pharmacopoeial text by ICH→ Establishment of ICH Q4B

Main Discussion point：

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Difference in interpretation of “Objective equivalency”

→ may cause problems in regulatory interchangeability by other regulatory authority

→ modify the definition of harmonization and adopt harmonization by attribute

Differentiate between “pharmacopoeial harmonization” that mainly PDG works for, and “regulatory interchangeability” of harmonized text that regulatory

authority guarantees as a result of pharmacopoeial harmonization.

Policy of Pharmacopoeial Harmonization

Purpose

To avoid redundant testing for different acceptance criteria in each pharmacopoeia

To contribute pubic health by maintaining an optimal level of science

Definition of harmonization

The tests should not result in disparity in the accept/reject decision of pharmaceuticals

→ Explicit description of definition in consideration of interchangeability

When full harmonization is not achievable, the approach of “harmonization by attribute” is applied. For non-harmonized attribute, using of other approaches such as “alternative method” is relied on the individual pharmacopoeia.

→ Introduction of partial harmonization10


PDG Statement of Harmonization PolicyRevision November 2003

Procedure of Pharmacopoeial Harmonization

Working Procedure

Harmonization occurs based on decisions of expert bodies of each pharmacopoeia

PDG works transparently in many ways principally including public notice and comment procedures of each pharmacopoeia.

Implementation

Implementation of harmonized document varies among pharmacopoeias (due to legal requirements, need for translation, publication schedules, etc.)

Each pharmacopoeia generally sets a period of time for transition before implementation.

Revision

Each pharmacopoeia does not revise unilaterally after publication. When necessary, revision should be conducted according to the PDG Working Procedures. 11


Working Procedure of PDGRevision version June 2010

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2010 version 2017 version

Stage 1 Identification Pre- PDG IdentificationInvestigationDevelopment of clear conceptStage 2 Investigation

Stage 3 Proposal for Expert Committee Review

Stage 1 Preparation of first draft

Stage 4 Official inquiry Stage 2 Official inquiry

Stage 5 Consensus Stage 3 Consensus

Stage 6 Regional adoption and

implementation

Stage 4 Regional adoption and

implementation

Stage 7 Inter-regional acceptance Stage 5 Inter-regional acceptance

Procedure was simplified→ harmonize more effectively in a shorter period of time

Procedure of Pharmacopoeial HarmonizationWorking Procedure of PDGRevision version September 2017

PDG Working Procedures (1)

Pre-PDG

Stage 1: Preparation of first draft

Stage 2: Official Inquiry

Stage 3: Consensus

Stage 4: Regional adoption and implementation

Stage 5: Inter-regional acceptance (for chapters previouslyevaluated by ICH Q4B for Regulatory

Interchangeability)


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Revision

Correction of a sign-off text

Correction of a sign-off cover sheet

PDG Working Procedures (2)

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PDG Work Program – General ChaptersGeneral Chapters:G-01 Analytical Sieving G-02 Bulk Density and Tapped DensityG-03 ConductivityG-04 Gas Pycnometric Density of Solids G-05 Powder FlowG-06 Tablet FriabilityG-07 Elemental Impurities*1

G-08 Inhalation*2

G-09 Optical MicroscopyG-10 Powder FinenessG-11 Specific Surface AreaG-12 Porosimetry by Mercury Intrusion*2

G-13 Laser Diffraction Measurement of Particle SizeG-14 X-Ray Powder DiffractionG-15 Water-solid InteractionG-16 Thermal AnalysisG-17 Uniformity of Delivered Dose of Inhalations*2

G-18 Microcalorimetry*2

G-19 Density of Solids*2

G-20 Chromatography*1

G-21 Dynamic Light Scattering*1

*１：First harmonization*2：Suppressed in 2017

General Methods Relevant to Q6A）:Q-01 DissolutionQ-02 DisintegrationQ-03/04 Uniformity of Content/MassQ-05a Tests for Specified MicroorganismQ-05b Microbial EnumerationQ-05c Limits for Non-sterile ProductsQ-06 Bacterial EndotoxinQ-07 Color (Instrumental Method)Q-08 Extractable VolumeQ-09 Particulate ContaminationQ-10 Residue on IgnitionQ-11 Sterility TestMethods for Biotechnology Products:B-01 Amino Acid DeterminationB-02 Capillary ElectrophoresisB-03 Isoelectric FocusingB-04 Protein Determination*2

B-05 Peptide MappingB-06 Polyacrylamide Gel Electrophoresis

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PDG Work Program – Excipient MonographsE-01 AlcoholsE-02 Dehydrated AlcoholE-03 Benzyl AlcoholE-04 Calcium Disodium EdetateE-05 Calcium Phosphate DibasicE-06 Calcium Phosphate Dibasic

AnhydrousE-07 Carmellose CalciumE-08 Carmellose Sodium*1

E-09 Croscarmellose SodiumE-10 Microcrystalline CelluloseE-11 Cellulose, PowderedE-12 Cellulose Acetate (2017)*2

E-13 Cellulose Acetate Phthalate E-14 Citric Acid, AnhydrousE-15 Citric Acid, MonohydrateE-16 CrospovidoneE-17 EthylcelluloseE-18 HydroxyethylcelluloseE-19 HydroxypropylcelluloseE-20 Hydroxypropylcellulose,

Low SubstitutedE-21 HypromelloseE-22 Hypromellose Phthalate

E-23 Lactose, AnhydrousE-24 Lactose, Monohydrate E-25 Magnesium Stearate E-26 MethylcelluloseE-27 Methyl ParabenE-28 Petrolatum*1

E-29 Petrolatum, White*1

E-30 Polyethylene Glycol*1

E-31 Polysorbate 80E-32 PovidoneE-33 Saccharin (2017）*2

E-34 Saccharin, Sodium（2017）*2

E-35 Saccharin, Calcium（2017）*2

E-36 Silicon Dioxide*1

E-37 Silicon Dioxide, Colloidal*1

E-38 Sodium ChlorideE-39 Sodium Starch GlycolateE-40 Starch, CornE-41 Starch, PotatoE-42 Starch, RiceE-43 Starch, WheatE-44 Stearic AcidE-45 SucroseE-46 Talc

E-47 Titanium Dioxide（2010）*2

E-48 Ethyl ParabenE-49 Propyl ParabenE-50 Butyl ParabenE-51 Glycerin*1

E-52 CarmelloseE-53 Calcium Carbonate（2017）*2

E-54 CopovidoneE-55a Gelatin, gelling typeE-55b Gelatin, non-gelling gradeE-56 SucroseE-57 Glyceryl Monostearate（2011）*2

E-58 MannitolE-59 Propylene Glycol*1

E-60 Sodium LaurylsulfateE-61 Starch, Pregelatinized*1

E-62 Sterile Water for Injection*1

E-63 Lactose for Inhalation（2018）*2

E-64 IsomaltE-65 Isostearyl Alcohol*1

E-66 Myristyl Myristate*1

E-67 Sodium Cetyl Sulfate（2018）*2

E-68 Polysorbate 65*1

E-69 Calcium Silicate*1

*１：First harmonization, *2：Suppressed (Year)

Publication of Harmonization Status

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EP：https://www.edqm.eu/en/international-harmonisation-614.html

JP：https://www.pmda.go.jp/rs-std-jp/standards-development/jp/0005.html

USP：https://www.usp.org/harmonized-standards/pdg

https://www.edqm.eu/en/international-harmonisation-614.html

https://www.pmda.go.jp/rs-std-jp/standards-development/jp/0005.html

https://www.usp.org/harmonized-standards/pdg

Thank you for your attention‼

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Documents

History of PDG