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Dr. Keiji Kijima, Secretary General, IPEC Japan April 26, 2012

The current state of Pharmaceutical Excipients in Japan

-JPE, JP, DMF, GAB (GMP Auditing Board)- JPE (Japanese Pharmaceutical Excipients)

JP (Japanese Pharmacopoeia)

MF (Master File System)

GAB (GMP Auditing Board)

others

Agenda

Pharmaceutical Excipients are substances(s) other than drug substance(s) contained in preparations which are used to increase the utility of the preparation, to enable manufacturing of drug products easy, to keep product’s integrity, to improve the appearance of a formulation and so forth.

Pharmaceutical Excipients

For these purposes, suitable excipients may be added in the drug manufacturing. The excipients used, however, must be non-toxic, harmless and pharmacologically inactive in the amount administered and must not interfere with the therapeutic efficacy or the quality test of the preparations. (JP16)

Pharmaceutical Excipients

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JPE

Public consultation

Study Committee

IPEC Japan (Council)

Notification

Proposal

As preparation technologies are advanced and preparation designs are diversified, the role of pharmaceutical excipients is increasing in the characteristics such as dissolution, stability, solubility, etc.

Japanese Pharmaceutical Excipient (JPE)

Ministry of Health, Labor and Welfare (MHLW) announced the standards of the pharmaceutical excipients not included in Japanese Pharmacopoeia by the publication of ‘Japanese Pharmaceutical Excipients’ .

Japanese Pharmaceutical Excipient (JPE)

Japanese Pharmaceutical Excipients 1993→ 206 monographs

Japanese Pharmaceutical Excipients/Supplement 1994→

92 monographs supplied and

1 monograph deleted

---Total 297 monographs

Total Monogrphs

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JPE 1996 → 99 monographs supplied

→ Total monographs 396

Japanese Pharmaceutical Excipients 1998 → 42 monographs supplied and

2 monographs deleted

---Total 436 monographs

Total Monogrphs

Japanese Pharmaceutical Excipients 2003 → 44 monographs added

and 1 monographs deleted

---Total 479

Total Monogrphs

MHLW started the committee for the

revision of JPE in 2010.

The committee has been held 9 times till

Dec. 2011.

[Expected: Revised---approx. 40 monographs;

New---approx. 12 monographs]

For the Revised Japanese Pharmaceutical Excipients (JPE) 2012

The public comment will be collected in spring of 2012.

→ A notification will be given by a

chief of the bureau in charge in

summer.

For the Revised Japanese Pharmaceutical Excipients (JPE) 2012

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JPE consists of pharmaceutical excipients not included in Japanese Pharmacopoeia as well as those having precedent use and often used for the marketable pharmaceutical preparations.

There are also pharmaceutical excipients specified in attachment in the application of approval of medicines

→ Therefore, it is useful for pharmaceutical

companies to apply for the approval of medicines.

Situation of Japanese Pharmaceutical Excipients (JPE)

The pharmaceutical excipients,

not applied to GMP, are applicable to SELF-IMPOSED STANDARDS FOR MANUFACTURING CONTROL OF PHARMACEUTICAL EXCIPIENTS (SELF-IMPOSED GMP).

Situation of Japanese Pharmaceutical Excipients (JPE)

JPE is provided to determine the standards concerning General Notices, Preparations, Descriptions, Storages, etc. The pharmaceutical excipients are to be tested according to the provisions given in General Notice, General Tests and the pertinent monographs.

Judgment of advisability

The items of the Description in the monographs are given for the information, and should not be taken as indicating standards for conformity.

Judgment of advisability

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Unless otherwise specified in General Notices, General Tests and the pertinent monographs, the provisions given in General Notice, General Tests in JP 16 shall be applied.

Situation of Japanese Pharmaceutical Excipients (JPE)

For pharmaceutical excipients specified in JPE Monographs which are manufactured as source materials derived from animals, the relevant animals must be healthy in principle, unless otherwise specified.

Situation of Japanese Pharmaceutical Excipients (JPE)

Pursuant to Paragraph 1, Article 41 of the Pharmaceutical Affairs Law (Law No.145, 1960), the Japanese Pharmacopoeia (hereinafter referred to as “new Pharmacopoeia”), which has been established as follows*, shall be applied on April 1, 2011. *The term “as follows” here indicates the contents of the Japanese Pharmacopoeia Sixteenth Edition from General Notices to Ultraviolet-visible Reference Spectra (pp.1-2131)

The official name of this pharmacopoeia is 第十六改正日本薬局方, and may be abbreviated as 日局十六,日局16, JP XVI or JP 16.

The English name of the pharmacopoeia is The Japanese Pharmacopoeia, Sixteenth Edition.

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JP Edition Publication Outline Monographs

JP１ 1886年

272

JP15 2006. 3. 31 1483

Supplement I 2007. 9. 28 1567

partial revision 2008. 2. 21 Glycerin (DEG) 1567

partial revision 2008. 7. 31 Heparin Sodium (OSCS) 1567

partial revision 2009. 3. 31 1568

Supplement II 2009. 9. 30 1673

partial revision 2010. 7. 30 1673

JP16 2011. 3. 24 1764

JP 16th Edition carries 1764 articles, owing to the addition of 106 articles and the deletion of 15 articles.

JP

Public consultation

JP Committee

PMDA (Expert Committee)

Ministerial Notification based on Pharmaceutical Affairs Law

Final Draft

The following items in General Tests, Processed and Apparatus were revised:

2.01 Liquid Chromatography

2.46 Residual Solvents Test

2.51 Conductivity Measurement

2.54 pH Determination

2.58 X-Ray Powder Diffraction Method

3.01 Determination of Bulk and Tapped Densities

and so on. Total 15 items

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The harmonized General Tests and Monographs among the Japanese Pharmacopoeia, the European Pharmacopoeia and the United States Pharmacopeia are preceded by the statement as such.

The parts of the test, being not harmonized, are surrounded by the symbols(◆ ◆).

Based on the Revised Pharmaceutical Affairs Law which was enforced on April 1, 2005, Master File Systems (MF) had been implemented ever since in Japan.

Master File System for Drug Substances

However, concerning existing pharmaceutical excipients, it is considered appropriate to refrain from submitting application of MF in Japan at present based on the PFSB/ELD Notification No.0210004 issued by Ministry of Health, Labor and Welfare on February 10, 2005.

Master File System for Drug Substances

Scope of MF Utilization

Applications of MF registrations and changes to registered contents and notifications of minor changes to the registered contents shall be submitted to the Pharmaceuticals and Medical Devices Agency (hereinafter referred to as “PMDA”), pursuant to the procedures and forms specified in the Enforcement Regulations of the Pharmaceutical Affairs Law (MHW Ministerial Ordinance No.1, 1961).

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Items for registration

The following raw materials to be used for the manufacture of pharmaceuticals and medical devices can be registered in MF.

Items for registration

1. Drug substances, intermediates and pharmaceutical product materials (materials of pharmaceutical products with special dosage form, etc.)

2. New excipients and pre-mix excipients with a different composition ratio from existing ones

3. Materials for medical devices

4. Containers / packaging materials

Items for registration

Drug substances, intermediates and pharmaceutical product materials (materials of pharmaceutical products with special dosage form, etc.) used for OTC drugs (excluding OTC with new active ingredients or those with their active ingredients still in the reexamination period) are not appropriate for registration in MF, as it is considered that their quality and safety are already established even with existing specification and test methods.

As the pharmaceutical excipients in JP 16 are generally classified as ‘Medicine’, they should follow the GMP standard. Among them, 108 monographs receive the application of the GMP HARDWARE, but avoid the application of GMP SOFTWARE.

IPEC Japan started the work to edit ‘SELF-IMPOSED GMP’ since 1995. The process is as follows:

SELF-IMPOSED STANDARDS FOR MANUFACTURING CONTROL OF PHARMACEUTICAL EXCIPIENTS

(SELF-IMPOSED GMP)

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Established

The 1st revised version

April 1, 1996

October 1, 2006

SELF-IMPOSED GMP 〔GMP SOFTWARE〕

Established

The 1st revised version

The 2nd revised version

April 1, 1998

October 1, 2006

December 7, 2006

SELF-IMPOSED GMP 〔GMP HARDWARE〕

SELF-IMPOSED GMP 〔VALIDATION STANDARDS〕

Established

October 1, 2006

Change of management, Deviation of management and Addition of Q & A about the validation standards

SELF-IMPOSED GMP 〔COLLECTION OF Q & A〕

Established April 1, 2008

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SELF-IMPOSED GMP GUIDANCE BOOK FOR PLACTICE

＜Revision＞

Established December 1, 2010

In order not to interfere with enforcing the self-imposed GMP, explanatory information, matters to be checked or attended, and Q&A are supplemented to each articles.

English version of ‘SELF-IMPOSED GMP AND ITS EXPLANATION’ was completed on December 1, 2011 to inform our GMP to foreign countries. In addition, the GMP Committee of IPEC Japan is making a comparison of ‘SELF-IMPOSED GMP’ with ICH Q7 or IPEC Joint GMP to understand GMP at the level of the international standard.

English Version

☆ According to MHLW Ministerial Ordinance about GQP;

“The manufacturers of APIs shall ensure that the production duties at the factory concerned are conducted properly and efficiently with manufacturing control and quality control.”

GMP Auditing Board for Pharmaceutical Excipients

☆ However, As for pharmaceutical excipients, the production duties are not established as legal requirements.

GMP Auditing Board for Pharmaceutical Excipients

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☆Pharmaceutical excipients are often used in common at plural pharmaceutical companies. In that case, It is a good policy for the pharmaceutical companies to reduce an audit burden by using audit result of the 3rd party.

GMP Auditing Board for Pharmaceutical Excipients

☆The manufactures of pharmaceutical excipients can reduce a burden to accept an audit from every company that is using the same product, too.

GMP Auditing Board for Pharmaceutical Excipients

☆GMP Auditing Board for Pharmaceutical Excipients is established in 2005 to secure the quality of pharmaceutical excipients of our country and to raise the reliability of the manufacturers of pharmaceutical excipients.

GMP Auditing Board for Pharmaceutical Excipients

☆The Board evaluates the GMP situation enforced by the manufactures based on SELF-IMPOSED GMP STANDARDS, edited by IPEC Japan, and then performs appropriate authorization.

GMP Auditing Board for Pharmaceutical Excipients

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Outline of GMP Auditing Board for Pharmaceutical Excipients

The board audits the pharmaceutical excipients company whether the company conducts production duties at the manufacturing site concerned properly and efficiently with manufacturing control and quality control.

→Therefore, the pharmaceutical company might secure the good quality and reliability

of the pharmaceutical excipient product effectively if passed the audition.

Advantage of GMP Auditing Board for Pharmaceutical Excipients

The number of Pharmaceutical excipients, which have been used so far, is 1228 monographs according to ‘Japanese Pharmaceutical Excipients Directory 2007’. But among them, about 200 monographs are listed in JP 16.

Japanese Pharmaceutical Excipients Directory by IPEC Japan

Pharmaceutical excipients which are generally used in the process of dosage form formulation play an important role in securing the quality, efficacy and safety through maintaining the dosage form and stabilizing the drug. In association with higher levels of pharmaceutical technology and diversified dosage forms in recent years, the role of pharmaceutical excipients has been increasing.

For the purpose of appropriate use of pharmaceutical excipients, the Japanese edition of “Japanese Pharmaceutical Excipients Directory (JPED)” was published on the basis of collective investigations of the available information on definitions, properties, specifications, uses, maximum dose and so forth related to approval drugs.

Japanese Pharmaceutical Excipients Directory by IPEC Japan