topics for pharmaceutical excipients update in ipec japan · pharmaceutical excipients...

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September 18, 2012 Dr. Keiji Kijima, Secretary General, IPEC Japan

Topics for Pharmaceutical Excipients Update in IPEC Japan

Agenda

JPE (Japanese Pharmaceutical Excipients)

JP (Japanese Pharmacopoeia),JP16,JP16-I

MF (Master File System)

GMP Software (Partial Amendment of the List of JP

Articles for Exception to the Application of GMP Software)

GAB (GMP Auditing Board)

Pharmaceutical Excipients

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)

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JPE

Public consultation

Study Committee

IPEC Japan (Council)

Notification

Proposal

Japanese Pharmaceutical Excipient (JPE)

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.


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 Excipients 1993→ 206 monographs

Japanese Pharmaceutical Excipients/Supplement 1994→

92 monographs supplied and

1 monograph deleted

---Total 297 monographs


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TOTAL MONOGRPHS

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

FOR THE REVISED JAPANESE PHARMACEUTICAL EXCIPIENTS (JPE) 2012

MHLW started the committee for the

revision of JPE in 2010.

The committee has been held 9 times till

Dec. 2011.

[Expected: Revised---approx. 43 monographs;

New---approx. 12 monographs]


The public comment was collected in March of 2012.

→ A notification will be given by a

chief of the bureau in charge for the

enforcement during this fiscal year.

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(ACCORDING TO THE ANNOUNCEMENT IN THE PUBLIC COMMENT)

1.Aceslfame potassium 2.Ammonioalkyl Methacrylate Copolymer Dispersion 3. Isomalt 4. Liquefied Petroleum Gas 5. Gellan Gum 6. Dimethyl Ether 7. Hydrophobically modified hydroxyl propyl methylcellulose 8. Polyoxyl 35 Caster Oil 9. Polyvinyl alcohol-Acrylic acid Methyl methacrylate copolymer 10.Polyvinyl alcohol-polyethylene glycol graft copolymer 11.D-Manmitol. Xylitol. Microcrystalline cellulose. Crospovidon.

Anhydrous Dibasic Calcium phosphate mixture 12. D-Mannitol. Xylitol. Microcrystalline cellulose. Crospovidon.

Anhydrous Dibasic Calcium phosphate mixture. Magnesium aluminometa silicate mixture

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).

Judgment of advisability

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.

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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.


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.


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.

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)

JP16 The Ministry of Health, Labour and walfare

Ministerial Notification No.65

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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.

JP16 General Notices

JP Edition Publication Outline Monographs

JP１ 1886

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.

JP16 The Ministry of Health, Labour and walfare

Ministerial Notification No.65 JP

Public consultation

JP Committee

PMDA (Expert Committee)

Ministerial Notification based on Pharmaceutical Affairs Law

Final Draft

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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

JP The Ministry of Health, Labour and walfare

Ministerial Notification No.65 JP16 Supplement I

2012.10.1 enforcement (Schedule)

Revision of monograph

Newly added 77 (Chemical 62, Antibiotic 1, biotechnological/biological products 7)

Excipients 2 (Crospovidon, Hypromellose Acetate Succinate)

Crude Drug 5

Revised 176, Deleted 4

Master File System for Drug Substances

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.

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

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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).

Items for registration

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


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


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.

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Exception to the Application of GMP Software

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.

Partial Amendment of the List of JP Articles for the Exception to the Application of GMP Software (January 17, 2012)

There is a list of JP articles (which are exclusively used for the production of drugs) to which the manufacturing control and quality control rule (GMP Software) specified in the MHLW Notice No. 42 of 2004 does not apply. This list has been amended this time. There are some changes in the title names and new inclusion of Trehalose Hydrate, and total number becomes 108 articles.


1 Acacia 20 Light Anhydrous Silicic Acid

2 Powdered Acacia 21 Hydrogenated Oil 3 Sodium Bisulfite 22 Sesame Oil 4 Ethylenediamine 23 Wheat Starch

5 Ether 24 Rice Starch

6 Olive Oil 25 Cholesterol 7 Orange Oil 26 Saccharin Sodium Hydrate

8 Kaolin 27 Calcium Oxide

9 Cacao Butter 28 Titanium Oxide

10 Capsules 29 Water 11 Carnauba Wax 30 Hydrophilic Ointment 12 Carmellose 31 Stearyl Alcohol 13 Carmellose Calcium 32 Stearic Acid

14 Carmellose Sodium 33 Calcium Stearate

15 Agar 34 Polyoxyl 40 Stearate

16 Powdered Agar 35 Magnesium Stearate

17 Beef Tollow 36 Purified Water 18 Absorptive Ointment 37 Purified water in containers 19 Croscarmellose Sodium 38 Petroleum Benzin


39 Cetanol 58 Tragacanth

40 Exsiccated Gypsum 59 Powdered Tragacanth

41 Cellacefate 60 Lard

42 Gelatin 61 Trehalose Hydrate

43 Purified Gelatin 62 Rape Seed Oil 44 Purified Shellac 63 Anhydrous Lactose

45 White Shellac 64 Lactose Hydrate

46 Microcrystalline Cellulose 65 White Ointment 47 Powdered Cellulose 66 White Soft Suger 48 Sorbitan Sesquioleate 67 Sucrose

49 Soybean Oil 68 Honey 50 Talc 69 Mentha Water 51 Simple Syrup 70 Ethyl Parahydroxy Benzoate

52 Simple Ointment 71 Butyl Parahydroxy Benzoate

53 Calmellia Oil 72 Propyl Parahydroxy Benzoate

54 Dextrin 73 Methyl Parahydroxy Benzoate

55 Sodium Starch Glycolate 74 Paraffin

56 Corn Starch 75 Potato Starch

57 Corn Oil 76 Hydroxy Propyl Cellulose


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77 Low Substituted Hydroxy Propylcellulose 96 Meglumine

78 Hypromellose 97 Methyl Cellulose

79 Hypromellose Phthalate 98 Aluminum Monosearate

80 Sodium Pyrosulfite 99 Glyceryl Monostearate

81 Pyroxylin 100 Coconut Oil 82 Wine 101 Lauromacrogol 83 Pullulan 102 Peanut Oil 84 Propylene Glycol 103 Hydrous Lanolin

85 Bentonite 104 Purified Lanolin

86 Povidone 105 Rosin

87 Polysorbate 80 106 Yellow Petrolatum

88 Macrogol 400 107 White Petrolatum

89 Macrogol 1500 108 Hydrophilic Petrolatum

90 Macrogol 4000

91 Macrogol 6000

92 Macrogol 20000

93 Macrogol Ointment

94 Yellow Bees Wax

95 White Bees Wax


☆ 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.”

GAB (GMP Auditing Board for

Pharmaceutical Excipients)

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



☆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.



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☆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 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.



☆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.



Outline of GMP Auditing Board for Pharmaceutical Excipients

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Advantage 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.

Comparison of ICH GMP Guide for Active Pharmaceutical Ingredients (ICH Q7a), The Joint IPEC-PQG GMP Guide (Joint GMP) and Self-imposed of GMP for Pharmaceutical Excipients (IPEC Japan GMP Guide). Comparative study of GMP guide is now under making among those of the Joint IPEC-PQG (excipient), ICH Q7A (API) and IPEC Japan (excipient). It is the purpose of this study secondarily to investigate the difference between the certification systems of Excipact etc. and our system of GAB (GMP Auditing Board for Pharmaceutical Excipents), where dependent GMP guide is different respectively, to make clear whether there is actual difference, and to make adjustment if necessary.



IPEC Japan GMP Standard for Pharmaceutical Excipients Intended to provide guidance on self-imposed controls required for assuring the quality of pharmaceutical excipients, and to make a contribution to the development of pharmaceutical drug products of a higher quality. The content of the quality control system is reflected by the intention of the regulatory authority as a whole. Joint IPEC-PQG GMP for Pharmaceutical Excipients Covers the quality management system and the extent of GMP necessary throughout manufacturing of pharmaceutical excipients. The quality management system standard is constructed on the basis of ISO 9001. ICH Q7A GMP Guide for API Intended to help ensure that APIs meet the quality and purity characteristics that they purport to possess by manufacturing under an appropriate system for managing quality.



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