equipment options for aim and beyond - ipac-rs · pdf fileequipment options for aim and beyond...

IPAC-RS 2011 Conference

Equipment Options for

AIM and Beyond

Jolyon P. Mitchell Ph.D., FRSC(UK), C.Chem., C.Sci.

Scientific Director, Trudell Medical International,

and

Adviser to IPAC-RS

1


SUMMARY

1. Background to the AIM Concept

2. AIM Equipment derived from the Andersen Cascade

Impactor (ACI)

3. AIM Equipment derived from the Next Generation

Pharmaceutical Impactor (NGI)

• Fast Screening Impactor (FSI)

• Modifications to the NGI itself

4. Other possibilities

5. Future needs

6. Approach to introducing AIM into the compendia

2


1: BACKGROUND

• AIM: Abbreviated Impactor Measurement(measurement techniques are the focus of this talk)

• EDA: Efficient Data Analysis(already covered in previous presentations)

3

The two concepts are closely linked with the

focus of AIM being on the measurement

equipment, and EDA on data handling


UNDERLYING PRINCIPLE OF AIM

• The cascade impactor is NOT a lung simulator

• However, it DOES determine APSD from which pertinent size sub-fractions may be obtained.

• The handling of these sub-fractions is at the heart of EDA

4

ICRP-66 lung deposition sub-fractions

compared with stage collection efficiency

curves for the Andersen 8-stage CI:

Mitchell & Dunbar JAM 2005;18(4):439-51.

IPAC-RS 2011 Conference5

A REMINDER: AIM-EDA GOALS

1. Investigate alternative methods that are better able to detect changes in APSD for Quality Control (QC) purposes

2. Develop standardized, robust methodologies that can be incorporated into the pharmacopeias in a fully harmonized way:

• Offer more than one alternative, as different inhaler classes are likely to need different AIM-based approaches


AIM HAS 2 DISTINCT PATHWAYS

6

AIM

MEASUREMENTS

FULL RESOLUTION CI

MEASUREMENTS

MMAD, SPM, LPM

REFERENCE

TECHNIQUE

PRODUCT

QC

SPM, LPM

EDA METRICS

Better decision making

tool than grouped CI stages

HRT-RELEVANT

APPLICATIONS

EPM, FPM, CPM

HRT METRICS

Appropriate in

support of IVIVRs:

Likely use

anatomically correct

inletFocus of today’s talk will be on AIM-QC systems


2: AIM EQUIPMENT FROM THE

ANDERSEN CASCADE IMPACTOR (ACI)

• Two campaigns at Trudell Medical International:

1. 2008: Assess viability of approach with two abbreviated ACI designs

• Copley FSA (C-FSA)

• In-house FSA with inactive stage ‘0’ (T-FSA)

2. 2009: Undertake a designed experiment on behalf of IPAC-RS to assess precision and accuracy of two ACI designs

• ‘QC’ impactor

• ‘HRT’ impactor

7


CAMPAIGN 1: C-FSA

• C-FSA is two-stage stack

that divides the incoming

dose into coarse, fine and

extra fine fractions (CPF,

FPF and EPF, respectively)

• The C-FSA was operated

with stage cut-off diameters

of 4.7 and 1.0 microns at

28.3 L/min

• Other cut-off combinations

are possible

8


CAMPAIGN 1: T-FSA

• T-FSA was developed at TMI, and has stage cut-off diameters of 4.7 and 1.1 microns at 28.3 L/min, for direct comparison with stages 2 and 5 of the full resolution ACI

• It also includes a non-operable (collection surface removed) ACI stage 0 to provide functional dead space before the first size separating stage

9


CAMPAIGN 1: Methods

• STUDY 1 – 125 μg/actuation pMDI delivering ‘dry’

fluticasone propionate particles in HFA- 134

propellant:

• Mitchell, JP et al. AAPS PharmSciTechnol., 2009, 10(1),

243-251.

• STUDY 2 – 100 μg/actuation pMDI delivering

beclomethasone dipropionate particles with ethanol

co-solvent (8% v/v) in HFA- 134 propellant:

• Mitchell et al. AAPS PharmSciTechnol., 2009, 10(1), 252-

257.

10


CAMPAIGN 1 STUDY 1: - LEARNINGS

1. It was essential to coat

collection surfaces with an

agent to prevent particle

bounce and re-

entrainment biasing FPF to

larger values

2. Brij-35 polyoxyethylene 23

lauryl ether surfactant was

used, but alternatives are

likely to be equally as good

11

uncoated surfaces

Brij-35 coated surfaces


CAMPAIGN 1 STUDY 2: LEARNINGS

3. The additional functional

space afforded by the

inactive stage ‘0’ was

needed to match ethanol

evaporation with full

resolution ACI

12

Closer agreement between FPF

from full resolution ACI when

Inactive stage ‘0’ was present

Liquid ethanol-sensitive paper showing

presence of liquid phase on upper stage

when inactive stage ‘0’ was NOT present


CAMPAIGN 2: IPAC-RS EXPERIMENT

• To be covered in

the following

presentation

• The experiment

was a success,

demonstrating

consistent

variability

between the

abbreviated and

full systems

13


FOLLOW-ON STUDY:

PARTICLE BOUNCE IN AIM-pHRT

Learnings:

• Brij-35 surfactant layer on

collection plate of lower

stage displaced radially by

flow from upper stage

• Saturating glass fiber filter

created a soft surface

resisting lateral

displacement of surfactant

14


STATISTICS COMPARING MODIFIED WITH

UN-MODIFIED AIM-pHRT

15

LEARNING: Bias eliminated by use of surfactant-saturated filter


3: AIM EQUIPMENT RELATED TO THE NGI

• Almost all other work has been undertaken with

either the FSI or modified versions of the NGI itself

• Although initial data were on the FSI were presented

by Russell-Graham et al. at DDL20 in December

2009, the EPAG-sponsored Workshop on AIM at

DDL21 last December contained an update

• 6 presentations represent the current state-of-the-

art with respect to these systems

• Copies are available in the public area of the EPAG website

at www.epag.co.uk

16


Background

• On December 8th, 2010, EPAG organized a half-day

workshop focusing on experimental aspects relating

to the AIM concept in relation to the more efficient

testing of oral inhaled products (OIPs)

• About 70 participants heard seven presentations

(see Table)

• The complete transcript of the Workshop, together

with each presentation are available on the EPAG

website at www.epag.co.uk


FSI = Fast Screening Impactor (MSP Corp., St. Paul, MN, USA);

NGI = Next Generation Pharmaceutical Impactor (MSP Corp.)

Presentation OIP Type(s) Equipment

Russell-Graham et al. DPI FSI

Tservistas et al. Nebulizer FSI

Svensson and Berg pMDI, DPI Modified NGI configurations (2)

Després-Gnis DPI FSI

Sheng and Watanabe pMDI, nebulizer FSI

Rogueda et al. DPI, nebulizer FSI

AIM WORKSHOP PRESENTATIONS

• Snap-shot summaries of key points from these presentations follow


FSI ANATOMY

• Use of modified pre-separator with

a single cut-point at 5 µm

aerodynamic diameter

• Filter collects particles < 5µm (Fine

Particle Fraction)

• Reduced number of stages should

greatly improve experiment time

• LEARNING: Coating the base of the

coarse particle collector in the FSI

with silicone oil was needed to

mitigate particle bounce

(5 µm)

(0.2 µm)

Courtesy: Russell-Graham, D et al.

Insert with

5 µm* cut-

off

Filter

holder


RESULTS

DPI Product 1:two dosage strengths

DPI Product 2:combination

product

DPI Product 4:higher flow rate

dependency DPI

• FSI slightly, but detectably over-estimated FPF



TWO POSSIBLE CAUSES

• Differences in internal dead-space

between the FSI and NGI :

• FSI @ 960mL

• NGI @ 2000mL

• Pressure drop profiles at start-up

differ for the abbreviated and full

resolution systems

• LEARNING: The DPI test method,

involving start-up of the impactor

from zero flow rate, is a more

stringent test to achieve replication in

performance between abbreviated

and full resolution systems

(a) at start-up

(b) completemeasurement

Flow-time profiles



MORE DPI-BASED EXPERIENCES WITH FSI

• FSI-measured total emitted

mass compared well with

that obtained by DUSA

apparatus

22

AptarDPI

LEARNING:Internal losses within the FSIare very small

Courtesy: Desprez-Gnis, F. et al.


FSI FOR NEBULIZER TESTING: 1

23

PARI e-Flow® nebulizer

Courtesy: Tservistas, M. et al.

LEARNINGS:1.Cooling the FSI had little

effect on FPF2.Agreement between FPF

for FSI and NGI was good3.These meaurements were made

at constant flow rate (15 L/min)


FSI FOR NEBULIZER TESTING: 2

• Aeroneb Go® vibrating

mesh nebulizer

• Higher flow rates (28.3 and

30 L/min)

• Screening of 8 different

formulations

24

LEARNING:

• Excellent agreement between FSI and NGI operated at constant flow rate for these aqueous systems

Courtesy: Sheng,G. et al.


REDUCED NGI CONFIGURATIONS

25

Flow to

vacuum

pump

Configuration 1: Particles collected on internal filter

= fine particle mass on filter MOC nozzle

NGI

body

Flow direct to

vacuum pump

MOC nozzle

Configuration 2: Particles collected on external filter

= fine particle mass on filter or return

flow via NGI

NGI

body

air flow

pathway

Courtesy Svensson, M. et al.


REDUCED NGI: RESULTS

26

Configuration 1 Configuration 2

Configuration 2 Configuration 2

Courtesy Svensson, M. et al.

LEARNING:• Excellent agreement for both pMDI and DPI formats with either configuration


4: OTHER POSSIBILITIES: THE TWIN IMPINGER

• The Twin Impinger could be

developed as an AIM

apparatus.

• It has a single cut-point size

(6.4 μm at 60 L/min), and

eliminates bounce and re-

entrainment by collecting

the particles under a fluid.

• Recovery of active

pharmaceutical ingredient

from this fluid can in some

cases be achieved without

further analytical work-up.

Twin Impinger


TWIN IMPINGER

• Unfortunately, validation data are not available

• The cut-point size also needs to be reduced closer to

5 μm at flow rates appropriate for the various OIP

classes:

• This would be a relatively easy change to make

• The use of more robust materials than glass may also be

worthwhile considering

28


COMBINED AIM-DUSA

• There are benefits to be

gained in terms of the

decision-making power by the

elimination of confounding

variables intrinsic to separate

measurements

• IPAC-RS intends to make the

detailed design of the

apparatus available once it

has been optimised, so that

the community involved in

OIP in vitro testing can

evaluate its usefulness

29


5: FUTURE NEEDS

1. Confirmation that the FSI performance can be

matched with that of the NGI for DPI testing

2. Evaluation of the Twin Impinger as a potential AIM-

based apparatus avoiding bias from particle bounce

3. Published calibration data for archival versions of

each short-runner AIM apparatus:

a. FSI with cut-point at 5 μm

b. C-FSA and variants with cut-points at 4.7 and 5 μm

(reduced NGI variants already have NGI archival data)

4. More published data demonstrating robustness of

AIM approach, especially when linked to EDA30


6: AIM INTO THE COMPENDIA

• Evidence:

• Are AIM techniques sufficiently robust?

• Can they be applied across all classes of OINDP?

• One common cut-point (5 μm) or more than one?

• Is a ‘Quality’ benefit available beyond that currently

available from existing apparatuses and data analysis?

• Does AIM-EDA have the discriminating ability to identify

‘good’ from ‘OOS’ batches at least as good as at present?

• Are there published AIM calibration data, preferably with

‘archival’ apparatuses?

• Performance at different flow rates – especially important

for DPI testing

31THE WHOLE PROCESS WILL LIKELY TAKE SEVERAL YEARS


Acknowledgements

• I wish to acknowledge the support of my colleagues

in the Cascade Impactor Working Group of IPAC-RS

as well as participants in the EPAG-sponsored

Workshop on AIM methods

• I also wish to acknowledge the support of the

Aerosol Laboratory team at Trudell Medical

International in the execution and interpretation of

the data from measurements undertaken there

32

equipment options for aim and beyond - ipac-rs · pdf fileequipment options for aim and beyond...

Documents