This poster was developed by the IPAC-RS Global Regulatory Review and Outreach China Subgroup (GRRO China). GRRO China proactively develops collaborative relationships with stakeholders in China, including the Chinese FDA (CFDA) and provincial FDAs, pharmacopeia, other standard-setting bodies, the pharmaceutical industry, suppliers and other trade groups. The Subgroup stays abreast of, and seeks to inform, as appropriate, regulatory developments for OINDPs in China. We summarize two major OINDP-related general chapters (Chapter <0111> and Chapter <0951>) in the 2015 edition of Chinese Pharmacopoeia. The 2015 edition of Chinese Pharmacopoeia went into effect on December 1, 2015. According to the CFDA, “the promulgation of the new edition of Chinese Pharmacopoeia marks the promotion of the level of China's drug use, production and supervision. It will drive the overall improvement of drug quality and play a significant role in ensuring drug safety and effectiveness for the public”.

(http://eng.sfda.gov.cn/WS03/CL0757/122060.html).

The 2015 edition of Chinese Pharmacopoeia has 4 volumes:

• Volume I: Traditional Chinese Medicine

• Volume II: Chemical Medicine

• Volume III: Biologics

• Volume IV: General Chapters, Guidances, and Excipients Monographs

B

1AstraZeneca; 2C & M Technical Consulting LLC; 3Merck; 4IPAC-RS Secretariat, Drinker Biddle & Reach LLP; †Corresponding Author (maggie.liu@dbr.com)

OINDP-Related General Chapters in 2015 Chinese Pharmacopoeia

Mark Hindle1, Cheryl Stults2, Zhenyu Wang3, Lee Nagao4, Maggie Liu4†

• Leak tests are required for inhalation aerosol products.

• The package insert for metered dose inhalers shall state (1) number of actuations per inhaler (2) amount of drug substance(s) delivered per actuation (3) number of actuations required to provide the minimum recommended dose (4) name of antibacterial agent if present.

• The package insert for capsule and blister inhalation powders shall state (1) amount of drug substance per capsule or individual blister (2) that the capsule should be placed in the inhalation device for inhalation - it should not be swallowed (3) product shelf life (4) product storage conditions.

The authors would like to thank Dr. Anny Shen at the Inhalation Drug Delivery Association in China (IDDA) for her general introduction of the 2015 Chinese Pharmacopoeia to the China subgroup. Drs. Sarah Lu, Ellen Wang and Lynn Yao of the China subgroup helped with translation of the OINDP-related chapters. The authors also thank other members of the China subgroup, the IPAC-RS Global Regulatory Review and Outreach group, as well as the IPAC-RS Board of Directors for their support for this work.

Acknowledgments

General chapter <0951> describes the test used to determine the fine particle characteristics of the aerosol clouds generated by preparations for inhalation. Three apparatuses are listed in <0951>:

The inhalation product attributes subject to testing in the Chinese Pharmacopoeia are similar to those listed in the European Pharmacopoeia and United States Pharmacopeia. The monographs describing the Chinese Pharmacopoeia tests for delivered dose uniformity (DDU) and aerodynamic particle size distribution provide content that is generally consistent with current scientific approaches. The detailed requirements for DDU are aligned with the European Pharmacopoeia and differ slightly from the United States Pharmacopeia. The aerodynamic size distribution methods are generally similar to the other two compendia although the fine particle dose (FPD) requirements are more specific than those in the other two compendia. As products are developed for use in China it will be useful to keep in mind these regional differences.

Summary

Introduction

Four of the general chapters in Volume IV are relevant to OINDPs: <0111>, <0112>, <0113> and <0951>. This poster summarizes the two major chapters: <0111> and <0951>.

Aerodynamic Size Distribution Assessment <0951>

Monographs Five respiratory drug product monographs are included in the 2015 Ch.P. The specific tests required by the monograph are listed in the table below.

Product Test Required Fine particle

dose Delivered dose

uniformity Leak rate

Beclometasone Dipropionate Inhalation Aerosol

Apparatus 1 No Yes

Beclometasone Dipropionate Powder for Inhalation

Apparatus 1

No N/A

Salbutamol Sulfate Inhalation Aerosol

Apparatus 1

Yes Yes

Salbutamol Sulfate Powder for Inhalation

Apparatus 1

No N/A

Terbutaline Sulphate Inhalation Aerosol

Apparatus 1 No Yes

Inhalation Aerosol (pMDI) Dry Powder Inhalers (DPIs)

Definition Drug containing solution, suspension or emulsion, packaged and sealed together with appropriate propellants in a pressurised container fitted with a fixed volume metering valve system. Co-solvents, solubilizing agents and stabilizers may also be present.

Defined as solid micronized drug substance alone or mixed with appropriate carriers and inhaled by patients into their lungs using a special powder inhaler. The powder is formulated as a capsule, blister or a multi-dose reservoir.

Delivered Dose Uniformity Use standard delivered dose testing equipment (Ph Eur).

Use standard delivered dose testing equipment (Ph Eur).

Individual inhaler: Determine 10 delivered doses in total: initial 3 doses, middle 4 doses, final 3 doses.

Different inhalers: Determine 1 dose from each of 10 individual inhalers as specified in product specification

Result assessment: Preparation complies if 9 out of 10 results lie between 75 and 125% of the average value and all lie between 65 and 135%.

If 2 or 3 values lie outside the 75 - 125% limits, repeat the test for 2 more inhalers. Not more than 3 of the 30 values lie outside the limits of 75 – 125% and no value lies outside the 65 – 135% limit.

Same as for pMDI

Number of Actuations Take 1 canister and perform successive actuations to waste. The interval between each actuation should be not less than 5 seconds. Total number of actuations should be not less than the labelled total actuations.

Actuate inhaler to empty using the prescribed air flow. The total number of deliveries should be not less than that stated on the label

Fine Particle Dose Performed according to the Determination of Aerodynamic Characteristics of the Fine Particles of Inhalation Products (General Chapter 0951) using the defined equipment and testing procedure for the specified inhalation aerosol product.

See also General Chapter 0951. Use defined equipment and testing procedure for the specified DPI.

Result assessment Calculated FPD should meet product specification requirement, and be not less than 15% of labelled delivered dose.

Calculated FPD should meet product specification requirement, and should be not less than 10% of labelled delivered dose.

Microbial Limits Performed using the microbial limit test for non-sterile products.

Same as for pMDI

Result assessment Results should comply with limits for microbial enumeration test, specified microorganisms and microbial limit test (General chapters 1105, 1106 and 1107).

Nebuliser Products Definition Solutions, suspensions or emulsions used to make inhaled aerosols using a continuous or metered

nebuliser. Nebuliser solutions should:

• Be diluted to the appropriate volume prior to use. Solutions can also be prepared from powders. • Have a pH between 3 and 8.5. • Have good dispersion properties (for suspensions and emulsions) • Unless the solution is sufficiently anti-microbial, suitable antibacterial agents should be added. If this is not

possible, the solution should be sterile. Delivery Rate and Total Delivered Dose

Performed using equipment and procedure as per Ph Eur

Result assessment Ph Eur Fine particle dose Performed and evaluated as described in General Chapter 0951 Efficacy of Antimicrobial Agent

If nebuliser product is antimicrobial, it should comply (General chapter 1121)

Sterility If the product is not antimicrobial, it should comply with the limit test for non-sterile products (General chapter 1101)

General requirements

• Any antibacterial agents should comply with the antibacterial potency test, liquid inhalation products should be sterile.

• Any additives to powder formulations should be non- irritating to the respiratory tract and all device components should be non-toxic and not react with the drug substance.

• An adequate fine particle dose should deposit in the lungs which should be suitably characterised. The drug substance particle size should be controlled at 10µm or less and most should be 5µm or less.

• For multi dose inhalers, delivered dose uniformity must be assessed both within an individual inhaler (intra) and between different inhalers (inter).

Chapter 0111 – Inhalation products

ChP <0951> Ph.Eur (8.0) General Chapter <2.9.18>

USP (38) General Chapter <601>

Procedure and Calculations

Apparatus 1: Glass Impinger

Apparatus A For nebulizers, pMDIs, and DPIs, same as Apparatus A in Ph.Eur. (8.0)

<0951> notes Apparatus 1 “Glass Impinger” as default apparatus when the product test procedure does not specify testing apparatus.

Apparatus 2: Andersen Cascade Impactor

Apparatus D Apparatus 1 (w/o pre-separator) Apparatus 3 (w/ pre-separator)

For pMDI and DPIs, same as apparatus D in Ph.Eur. (8.0)

Apparatus 3: Next Generation Impactor

Apparatus E Apparatus 5 (w/ pre-separator) For pMDI, same as apparatus E in Ph.Eur. (8.0)

For DPIs, similar to apparatus E in Ph.Eur. (8.0), except that <0951> does not specify the volume of air to be drawn during collection.

For nebulizers, <0951> requires NGI be cooled at 5°C for at least 90 mins prior to use. Test should be conducted at 15 L/min flow rate.

Test Compendia Chinese Pharmacopoeia Pharm. Euro. USP

DDU – Sampling #Inhalers used Beginning Middle End Total determinations

1(+2)

3 4 3

10 (+20)

1 (+2)

3 4 3

10 (+20)

10 (+20)

10 0

10 20

DDU – Acceptance criteria

9 of10 are 75-125% Avg and all 65-135% Avg;

If 7 or 8 of 10 are 75-125% Avg test 2

more inhalers and 27 of 30 are 75-125% Avg

and all 65-135% Avg

9 of10 are 80-120% Avg and all 65-135% Avg;

If 7 or 8 of 10 are 75-125% Avg,

test 2 more inhalers and 27 of 30 are 75-125% Avg

and all 65-135% Avg

9 of10 are 80-120% target and all 75-125% target;

If 7 or 8 of 10 are 80-120% target,

test 20 more inhalers and 27 of 30 are 80-120% target

and all 75-125% target

FPD – Acceptance criteria

not less than 15% (pMDI) or 10 % (DPI) of labelled delivered dose

Calculate FPD Calculate aerodynamic size distribution