Inhaler Testing

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Delivered Dose Uniformity

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The Delivered or Emitted Dose is the total amount of drug emitted from the inhaler device and hence available to the user.

Its uniformity is a Critical Quality Attribute (CQA) in determining the safety, quality and efficacy of an orally inhaled and nasal drug product (OINDP).

Based on an original design by Charles Thiel in 3M’s laboratories in Minneapolis, USA, the Dosage Unit Sampling Apparatus (DUSA) for MDIs has been designed specifically for the sampling and testing of Metered Dose Inhalers (MDIs).

It is used to perform those tests specified in the Pharmacopoeias relating to “delivered” or “emitted” dose, namely “Delivered Dose Uniformity” and “Delivered Dose Uniformity over the Entire Contents”.

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The Dosage Unit Sampling Apparatus (DUSA) for MDIs consists of one collection tube, two rinsing caps, one filter support cap, one flow meter adapter and a starter pack of filters supplied in a handy carrying case.

The standard collection tube itself and associated caps are manufactured from TecaPro MT, an FDA approved inert polypropylene specifically formulated for medical and pharmaceutical applications.

Alternative materials are available on request e.g. aluminium or 316 stainless steel. All tubes and caps are laser numbered to assist in traceability.

The sample collection tube is fitted with a 25 mm glass fibre filter having a typical aerosol retention of 0.3 microns. It has a volume of approx. 50 mL which equates to that of the human oropharynx.

The standard unit comes with silicone rubber seals. LDPE seals are available as an option, where extractables may be an issue.

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A second and larger version of the Sampling Apparatus for MDIs, capable of sampling at a variety of flow rates up to 100 L/min, is available for use with Dry Powder Inhalers (DPIs).

In the case of the system for DPIs however, an electrically operated, timer controlled, two-way solenoid valve (Critical Flow Controller) is positioned in the line between the collection tube and the vacuum pump to control the air flow supply to the inhaler and to ensure that critical (sonic) flow conditions are maintained during testing.

This allows the time that the test flow is applied to the inhaler to be adjusted to a specific volume, for example 4 litres, thus equating to human inspiration.

This is necessary because unlike MDIs, the majority of DPIs are passive breath-actuated devices which rely on the patient’s inspiration rather than a propellant for dose emission.

The Dose Unit Sampling Apparatus (DUSA) for DPIs utilises the same materials and is of similar construction to that of its MDI counterpart.

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Both European and US Pharmacopoeia state that tests should be carried out on a minimum of 10 containers and that in the case of multiple-dose devices tests should be carried out throughout the life of the inhaler i.e. Dose Uniformity over the Entire Contents.

For an inhaler having a label claim of 200 doses, this could mean firing each unit 200 times with no less than 190 shots being fired to waste for each individual container.

Traditionally, this firing to waste is carried out in a fume cupboard or into some specially built evacuation system which removes the drug particles from the atmosphere, or to a large filtering system which traps the drug. Such facilities may not always be available or suitable for this application.

The Waste Shot Collector WSC2 is a compact vacuum filtration system suitable for use with both MDI and DPI applications.

The user simply places the inhaler in the mouthpiece of the Waste Shot Collector and fires a shot in the normal manner. The waste dose is captured in a disposable cartridge containing a HEPA filter capable of retaining 99.97% of particles over 0.3 microns.

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Nebulisers convert liquids into a cloud of droplets suitable for respiration. Conventional nebulisers are widely used in both hospital and home. Their main advantage is that unlike other devices, they require little or no coordination on the part of the patient in order to use them.

The breathing pattern employed in the testing of nebulisers is particularly important since in vivo this determines the amount of active available to the user.

For this reason, the two tests specified in the Pharmacopoeias to characterise delivered dose, Active Substance Delivery Rate and Total Active Substance Delivered are based on tidal flow conditions generated by a breath simulator, as opposed to fixed flow rates.

The Delivered Dose Sampling Apparatus for Nebulisers consists of a Breath Simulator to generate the specified breathing profile, a filter holder containing the filter to capture the drug and a suitable mouthpiece adapter to connect the filter holder to the nebuliser under test.

Various patterns are available for neonatal, infant, child and adult applications.

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The coordination required by the patient to synchronise the actuation of the inhaler with inhalation can be a problem when using pressurised metered dose inhalers (pMDIs) particularly in the young, old or chronically ill. Add-on devices, such as spacers and valved holding chambers (VHCs), eliminate this problem by providing a reservoir of aerosolised particles that during treatment, the patient inhales from via a mouthpiece or facemask.

Two “delivered dose” tests are described in the Pharmacopoeia to determine the total mass of drug delivered from the spacer or VHC dependent on whether the device is intended for use with a mouthpiece (Part 2) or a facemask (Part 3).

Both of the apparatuses supplied by Copley to meet these tests comprise a breath simulator to generate the specified breath profile, a filter holder containing the filter to capture the active drug and a suitable mouthpiece adapter to connect the filter holder to the mouthpiece of the spacer/VHC concerned.

In the case of the facemask apparatus, the unit is supplied in addition with a choice of face model (infant, child or adult) together with a securing device designed to hold the facemask in contact with the face model in a manner representative of conditions in vivo.

Aerodynamic Particle Size

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Together with delivered dose uniformity, the Aerodynamic Particle Size Distribution (APSD) is widely recognised as a Critical Quality Attribute (CGA) in the in vitro characterisation of inhaled and nasal products since it is the APSD of an aerosol cloud that defines where the particles in that cloud are deposited following inhalation.

It is generally accepted that to be therapeutically effective, the particles should be in the range of 1 to 5 microns since particles > 5 microns will generally impact in the oropharynx and be swallowed whereas those < 1 micron may remain entrained in the airstream and be exhaled during the next breathing cycle.

The preferred instrument of choice for measuring the APSD of inhaled and nasal products is the cascade impactor because:

• Cascade impactors measure aerodynamic particle size
• Cascade impactors allow measurement of the active pharmaceutical ingredient (drug)
• Cascade impactors measure the entire dose

Between them, the US and European Pharmacopoeias list no less than five different cascade impactors/impingers suitable for the aerodynamic assessment of fine particles.

However, only the Andersen Cascade Impactor (ACI), the Next Generation Impactor (NGI) and the Multi-Stage Liquid Impinger (MSLI) appear in both Pharmacopoeias.

When selecting an impactor, much will depend on the product to be tested, the data that is required, the geographical location where the product is to be marketed and whether the unit is to be used for product development or quality control.

In research applications, in vitro – in vivo correlation and bioequivalence may be important and so detailed particle size data may be required. In routine quality control, where the concern is batch-to-batch variation, a coarser test may be acceptable.

To see an animation of how a cascade impactor works, please click on the following link: How Does a Cascade Impactor Work?

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Cascade impactors operate on the principle of inertial impaction. Each stage of the impactor comprises a series of nozzles or jets through which the sample laden air is drawn, directing any airborne towards the surface of the collection plate for that particular stage.

Whether a particular particle impacts on that stage is dependent on its aerodynamic diameter. Particles having sufficient inertia will impact on that particular stage collection plate, whilst smaller particles will remain entrained in the air stream and pass to the next stage where the process is repeated.

The stages are normally assembled in a stack or row in order of decreasing particle size. As the jets get smaller, the air velocity increases such that smaller particles are collected. At the end of the test, the particle mass relating to each stage is recovered using a suitable solvent and then analysed usually using HPLC to determine the amount of drug actually present.

To see an animation of how a cascade impactor works, please click on the following link: How Does a Cascade Impactor Work?

The Andersen Cascade Impactor (ACI) is arguably the most commonly used impactor within the pharmaceutical industry for the testing of inhaled products. The ACI is an 8-stage cascade impactor suitable for measuring the aerodynamic particle size distribution (APSD) of both MDIs and DPIs.

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In 1997, a group of prominent pharmaceutical companies came together in the form of a consortium with the express intent of developing a new impactor specifically for inhaled and nasal products.

The result, the Next Generation Impactor (NGI), was launched in 2000 and subsequently accepted into the Pharmacopoeias in 2005. The NGI has seven stages, five of which are in the range 0.5 to 5 microns plus a micro-orifice collector which acts as a final filter and a horizontal planar layout adopted for ease of operation and automation.

The air flow passes through the impactor in a saw tooth pattern. Particle sizing is achieved by successively increasing the velocity of the air stream by forcing it though a series of nozzles containing progressively reducing jet diameters.

The resultant samples from each stage are collected in a series of collection cups. A removable tray holds all the sample collection cups such that all the cups can be removed and/or replaced in one single operation.

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The Multi-Stage Liquid Impinger (MSLI) is a versatile five-stage liquid impinger which can be used for determining the particle size (aerodynamic size distribution) of DPIs in the case of USP Chapter <601> and for MDIs, DPIs and nebulisers in the case of Ph.Eur. Chapter 2.9.18.

The MSLI is available in a range of materials: aluminium, 316 stainless steel or titanium. This choice allows flexibility in terms of corrosion resistance, weight and cost. It is fitted with PTFE seals as standard.

The design is such that at a flow rate of 60 L/min, the cut-off diameters of Stages 1, 2, 3 and 4 are 13, 6.8, 3.1 and 1.7 microns. Stage 5 comprises an integral paper filter to capture the remaining fraction of particles less than 1.7 microns.

The MSLI has, by definition, no inter-stage losses and is suitable for use throughout the range 30 – 100 L/min. Unlike the ACI, NGI and MMI, the collection stages of the MSLI are kept moist which helps to reduce the problem of re-entrainment sometimes experienced when using more conventional impactors. It employs the same induction port as other impactors.

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The Marple-Miller Cascade Impactor Model 160 is specified as Apparatus 2 in the USP and is a five-stage cascade impactor which has been designed for determining the particle size (aerodynamic size distribution) of Dry Powder Inhalers (DPIs).

The Model 160 has five impaction stages and is calibrated for operation between 60 and 90 L/min. Each stage has a removable collection cup to assist in the quick and simple recovery of the drug particles with low inter-stage losses. A paper filter is incorporated after Stage 5 to ensure total mass balance.

Two other versions of the impactor are available, such that between the three impactors, a flow rate range of 4.9 to 90 L/min is covered.

In this impactor, particles are deposited directly onto the bottom of the stage collection cups which can then be easily removed after each test without dismantling the impactor.

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The value of the Glass Twin Impinger, particularly with respect to routine quality control, is recognised by its retention as Apparatus A in Ph.Eur. 2.9.18.

Its usage is restricted to the assessment of nebulisers, MDIs and such DPIs where it can be demonstrated that a flow rate of 60 (+/-5) L/min is suitable.

Developed at GSK’s laboratories in Ware, UK, the Glass Twin Impinger is relatively easy to use and assemble. It operates on the principle of liquid impingement to divide the dose emitted from the inhaler into respirable and non-respirable fractions.

The non-respirable dose impacts on the oropharynx and is subsequently swallowed. This is considered as the back of the glass throat and the upper impingement chamber (collectively described as Stage 1). The remaining respirable dose penetrating the lungs is collected in the lower impingement chamber (Stage 2).

The upper impingement chamber is designed such that at a flow rate of 60 L/min through the impinger, the particle cut-off is 6.4 microns. Particles smaller than 6.4 microns pass into the lower impingement chamber.

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The coordination required by the patient to synchronise the actuation of the inhaler with inhalation can be a problem when using pressurised metered dose inhalers (pMDIs) particularly in the young, old or chronically ill. Add-on devices, such as spacers and valved holding chambers (VHCs), eliminate this problem by providing a reservoir of aerosolised particles that during treatment, the patient inhales from via a mouthpiece or facemask.

The new USP draft chapter <1602> for testing “Spacers and Valved Holding Chambers used with Inhalation Aerosols” specifies two tests relating to the Aerodynamic Particle Size Distribution (APSD) of the accessories concerned.

Test Part 1A is designed to measure the APSD from the accessory when used in optimal conditions, that is to say, with no delay following the actuation of the inhaler. Test Part 1B is used in worst case conditions with a delay of 2 or more seconds between inhaler actuation and sampling onset.

A minimum of Cascade Impactor (ACI, NGI or MMI), Breath Actuation Controller, Vacuum Pump and Flow Meter are necessary if the requirements of both tests are to be satisfied.

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Nasal sprays typically produce droplets in the range 20-200 microns which is outside the effective range of inertial impactors. For this reason, the droplet size distribution of nasal sprays and aerosols is normally determined by means of laser diffraction.

At the same time, however, most sprays deliver a proportion (typically <5%) of fine droplets in the <10 micron range.

It is important to quantify this “fine particle dose” since it can penetrate beyond the nasal tract and into the lower respiratory tract or lungs, which may prove undesirable.

For this reason, the FDA recommends the use of a cascade impactor in conjunction with a high volume expansion chamber to measure the amount of drug in small particles or droplets in respect of nasal sprays and the particle/droplet size distribution in the case of nasal aerosols.

In accordance with the draft guidance, Copley Scientific now offer a range of glass expansion chambers to be used with either the Andersen Cascade Impactor or Next Generation Impactor to meet these requirements.

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In 2006, the European Medicines Agency (EMA) issued a new “Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products” in which they included regulatory guidance on the drug aspects of nebulisers on the grounds that the safety and efficacy of nebulisers was dependent on the nebuliser/drug combination and not just on the nebuliser alone.

As a result of the EMA initiative and recognising the lack of suitable test methods for nebulisers, the Pharmacopoeias have in turn introduced a new Chapter on “Preparations for Nebulisation: Characterisation” (see Ph.Eur. Chapter 2.9.44 and USP Chapter <1601>).

The method concerned is based on the Next Generation Impactor (NGI) described on Page 36 of our Inhaler Testing Brochure (see right). The recommended flow rate of 15 L/min employed in the APSD testing of nebulisers is lower than that of other OINDPs in order to better simulate the normal tidal breathing conditions employed in their in vivo use.

For this reason, the archival calibration of the Next Generation Impactor was extended from 30 L/min down to 15 L/min in 2004.

Introduction to Abbreviated Impactor Measurement

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The concept of Abbreviated Impactor Measurement (AIM) as typified by the two stage Glass Impinger is not new. However initiatives in recent years have centered around abbreviated versions of the Andersen Cascade Impactor.

AIM is founded on the basis that once the full Aerodynamic Particle Size Distribution (APSD) profile of the product has been established in development using a full-resolution cascade impactor (and the process validated) then for product batch release testing and QC applications, it is possible to use simpler but highly sensitive metrics, solely to determine of the product is fit for purpose. This is known as Efficient Data Analysis (EDA).

Although EDA can be applied to full-resolution impactor testing, its true value comes from combining it with an Abbreviated Impactor since only a reduced number of stages are required, speeding up throughput and reducing operator error.

Abbreviated Impactor Measurement has also been suggested as a possible useful tool in R&D for the fast screening of new formulations in product development.

Fast Screening Andersen (FSA)

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The Fast Screening Andersen (FSA) is an AIM version of the standard full-resolution Andersen Cascade Impactor (ACI) suitably modified to provide a reduced stack plus filter (F) suitable for either:

  • Quality Control (FSA-QC) or
  • Product Development (FSA-HRT)

In the FSA-QC, Stages 0 (or -1, or 2A) and F are used in conjunction with a Stage X, having a cut-off diameter as close as possible to the Mass Median Aerodynamic Diameter (MMAD) of the aerosol, as determined during full-resolution cascade impactor testing.

In the FSA-HRT, stages with cut-off diameters are available at 5.0 and 1.0 microns for MDI applications at 28.3 L/min. Stages having more traditional cut-off points of 4.7 and 1.1 microns are also available for varying flow rates, primarily for DPI applications.

Reduced Next Generation Impactor (rNGI)

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The drive for greater efficiency continues to stimulate debate as to whether full-resolution, multiple-stage cascade impaction still needs to be applied to the extent that it is currently.

The Reduced Next Generation Impactor (rNGI) is an abbreviated method for utilising the NGI in both AIM-QC and AIM-HRT applications.

In the same way as with the Fast Screening Andersen (FSA), depending on the flow rate to be used, a stage of the NGI can be selected having a cut-off diameter close to the product MMAD (in the case of an rNGI-QC application) or close to 5 microns (in the case of a rNGI-HRT application).

A paper filter held in place with a special rNGI Filter Holder Assembly is now placed in the top of the stage immediately after that of the one selected.

On operating the rNGI, particles smaller than the cut-off diameter of the stage preceding the filter will be captured on the filter, whilst particles larger than that stage will impact as normal in the collection cups of those stages upstream.

Fast Screening Impactor (FSI)

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Based on proven NGI Preseparator technology, the Fast Screening Impactor (FSI) represents a purpose-made approach to AIM that segregates the dose into Coarse Particle Mass (CPM) and Fine Particle Mass (FPM) making it suitable for AIM-HRT applications (i.e. FSI-HRT) for MDIs, DPIs and nasal sprays.

A range of inserts is available, generating a 5 micron cut-off diameter within the flow rate range of 30-100 L/min at 5L/min intervals, making it ideal for DPIs tested at a flow rate that equates to a 4 kPa pressure drop over the inhaler.

The FSI uses the same Induction Port as the NGI. It employs a two-stage separation process in which first large non-inhalable boluses are captured in a liquid trap followed by a fine-cut impaction stage at 5 microns.

Bespoke inserts are available on request with a range of cut-off diameter/flow rate combinations allowing for a FSI-QC version.

Introduction to Improved IVIVC

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Better In Vitro – In Vivo Correlation (IVIVC) has long been an industry aim. This is particularly difficult in the case of inhaled and nasal products because of the complications involved in precisely correlating drug deposition behaviour with clinical efficacy, the impact of patient-to-patient variability and the complex interaction between formulation and device.

One strategy for improving the significance of cascade impaction data is to modify the test set-up in order to mimic the in vivo drug delivery process more closely.

Two factors that have been identified as critical to this process are:

  • 1. Replacing the existing Ph.Eur./USP Induction Port with a mouth/throat model having a more realistic human-like geometry.
  • 2. Replacing the existing constant flow rate conditions employed in testing with breathing profiles more representative of conditions in vivo.

The Alberta Idealised Throat (AIT) and the Mixing Inlet are two devices designed to address these particular problems.

Alberta Idealised Throat (AIT)

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For more than a decade, researchers at the Aerosol Research Laboratory, University of Alberta, Canada have been working to develop a more suitable representation of the mouth-throat for routine cascade impactor testing, aiming to produce an interface that is both easy to manufacture and reflective of in vivo behaviour, a solution that lies part way between the human throat cast and the pharmacopoeial induction port.

The Alberta Idealised Throat (AIT) was developed as a result of extensive research into typical patient populations including information provided by CT and MRI scans, direct visual observation of living subjects and data in the archival literature.

The throat has a standardised, highly reproducible, human like geometry offering robust performance independent of flow rate.

Its smooth, more uniform internal geometry has been specifically designed to make drug recovery quick and simple in comparison with a human throat cast. Quick release clips make for easy internal access.

The Alberta Idealised Throat (AIT) is based on adult geometry, but child and infant geometries are available on request.

Mixing Inlet

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The cut-off diameters generated by each stage of any cascade impactor are dependent on a steady, fixed flow of air passing through it.

In contrast, the in vivo inhalation profiles of breathing cycles generated by patients produce a continually varying flow rate far removed from the fixed, steady-state flow rates employed in in vitro testing.

For this reason, there have been various attempts to link cascade impactors directly to breath simulators in order to reproduce actual clinical conditions more closely. Any such system must be capable of varying the flow rate through the inhaler whilst ensuring that the aerosol generated is sampled at a fixed rate through the impactor.

The Mixing Inlet fits between the USP Induction Port (or Alberta Idealised Throat) and the inlet of the impactor used to carry out the test.

It is designed to permit the cascade impactor to be operated at a constant flow rate (e.g. 100 L/min), whilst allowing a lower fixed or variable rate, such as a breathing pattern generated by a breath simulator, to pass through the inhaler itself.

Ancillaries

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This section describes the Ancillaries required in addition to the Dosage Unit Sampling Apparatus (DUSA) and Cascade Impactor to make up a fully operating test system for determining the Delivered Dose Uniformity and Aerodynamic Particle Size Distribution of orally inhaled and nasal drug products (OINDPs).

The following equipment is described in detail:

  • Breath Simulators
  • Critical (Sonic) Flow Controllers
  • Data Analysis – CITDAS (Copley Inhaler Testing Data Analysis Software)
  • Flow Meters
  • Mouthpiece Adapters
  • Tubing and Quick Release Connectors
  • Vacuum Pumps

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Breath Simulators are increasingly used in testing orally inhaled and nasal drug products (OINDPs) to replace existing constant flow conditions with breathing profiles more representative of conditions in vivo.

Copley Scientific offer a choice of three Breath Simulators (Models BRS 1100, BRS 2000 and BRS 3000) covering a range of breathing patterns from neonate through to infant, child and adult. The simplest, microproessor controlled version covers the volume range 0 – 800 mL, whilst the largest unit is an embedded computer controlled 5 Litre system capable of testing MDIs, DPIs, Nebulisers, Spacers and Holding Chambers. The latter can be used for improved IVIVC applications, with real breath profiles generated in clinic.

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Ph.Eur. Chapter 2.9.18 and USP Chapter <601> both specify various types of multi-stage cascade impactor that can be used for measuring the particle size distribution of inhalers together with instructions as to how the resulting data should be analysed. Hitherto, this data analysis has largely been performed using a variety of techniques with little attention being paid to standardisation and validation.

Copley Inhaler Testing Data Analysis Software (CITDAS) Version 3.10 is a proven third generation software programme designed specifically for the simple and rapid processing of impactor drug deposition data according to pharmacopoeial requirements. It has an existing database of over 300 users.

Based on over 12 years of experience, CITDAS can be installed and up and running in minutes – it requires no specialist IT knowledge to install and does not require 21 CFR 11 because the data output is in hard copy format. It will accept data from the Andersen Cascade Impactor, the Multi-Stage Liquid Impinger, the Marple-Miller Impactor or the Next Generation Impactor.

Provision is made to customise the data options to individual needs.

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The Delivered Dose Uniformity (DDU) and Aerodynamic Particle Size Distribution (APSD) are two of the main Critical Quality Attributes (CQAs) in measuring the therapeutic efficacy of orally inhaled and nasal products.

The data produced by both of these tests can be severely compromised if the flow rate used during testing is inaccurate and/or inconsistent.

Indeed, Stokes’ Law which describes the relationship between stage cut-off diameter, nozzle diameter and air flow rate, demonstrates that a 5% deviation in flow rate changes the stage cut-off diameter by approximately 2.5%.

At a flow rate of 60 L/min for example, Stage 1 of an Andersen Cascade Impactor should give a theoretical cut-off of 4.7 microns – reduce that rate to 57 L/min and cut-off is effectively reduced to 4.58 microns.

Copley Scientific offers two Flow Meters with the required range and accuracy to measure the flow in inhaler testing systems, one based on differential pressure and the other on thermal mass measurement methods.

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The mouthpiece adapters supplied by Copley Scientific are specially moulded from high quality silicone rubber in order to guarantee an airtight seal between the inhaler under test and the test apparatus.

There is no standard mouthpiece adapter as each inhaler design is different. Adapters are available however for the more common devices on the market (see ordering information).

For other unlisted inhalers, we require a sample of the inhaler to be tested, so that we can make a “cast” of the mouthpiece and produce an appropriate moulding tool.

This moulding tool is then used to mould the mouthpiece adapter(s) to that particular inhaler design.

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Copley Scientific offers a range of tubing and quick release connectors in both polypropylene and stainless steel to connect up the various components of your inhaler testing system.

This section also covers a range of silicone rubber and 316 stainless steel rinsing caps suitable for capping off the open ends of ACI and NGI induction ports and the NGI preseparator during manual drug recovery.

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At the heart of every inhaler testing system is the Pump. The Pharmacopoeias are careful to point out that “a vacuum pump with excess capacity must be selected in order to draw air at the designated volumetric flow rate” through the system and in the case of Dry Powder Inhalers, to generate sonic flow.

Copley Scientific offers a choice of three pumps dependent on the set-up concerned and the capacity required.

Foremost in the design specification were those features that you, the user, identified as being essential to inhaler testing, namely that the pump should:

  • be equipped with the correct fittings to link to the test system concerned
  • have sufficient capacity to provide the required test flow and in the case of DPIs to ensure critical (sonic) flow
  • have low noise levels, suitable for a laboratory environment
  • be low maintenance

Introduction to Critical (Sonic) Flow Control

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The vast majority of Dry Powder Inhalers (DPIs) are classified as “passive” breath activated devices, that is to say, they rely solely on the patient’s inspiration to operate.

There is no necessity to co-ordinate breathing with the activation – the patient simply inhales deeply to access the drug.

It follows that both the delivered dose and fine particle dose of DPIs are dependent on the strength and duration of the patient’s inspiration, a critical quality attribute (CQA) which must be simulated during in vitro testing.

The testing of DPIs is further complicated by the fact that different inhalers provide varying degrees of resistance to flow i.e. some require more effort to inhale than others.

The Critical Flow Controller Series TPK allows the setting of specific flow rates and simulated inspiration volumes whilst at the same time maintaining the critical (sonic) flow conditions and hence stable flow control critical to good measurement practice.

Two versions are available, the TPK and TPK 2000.

Critical Flow Controller Model TPK

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A number of factors can have a significant effect on the testing of Dry Powder Inhalers:

  • The resistance to flow posed by the inhaler under test
  • The appropriate flow rate, Q, required to generate a 4 kPa pressure drop over the inhaler concerned
  • The duration of the inspiration required to give the specified test volume
  • The stability of the flow rate in terms of critical (sonic) flow

The “Apparatus suitable for measuring the uniformity of delivered dose for powder inhalers” and the “Experimental set-up for testing powder inhalers” described in Ph.Eur. in Chapters 0671 and 2.9.18 respectively and “Apparatus B: Sampling Apparatus for dry powder inhalers” and the “Apparatus 2, 3, 4 or 5: General control equipment” described in USP Chapter 601 take all of these factors into account.

These specifications form the basis of the Critical Flow Controller Model TPK which incorporates all of the equipment required into a single integrated system.

Critical Flow Controller Model TPK 2000

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The new improved Critical Flow Controller Model TPK 2000 is designed to control and document all the critical parameters associated with the delivered dose testing and aerodynamic particle size distribution measurement of Dry Powder Inhalers (DPIs).

Its predecessor, the Critical Flow Controller Model TPK has already become an international standard in the field of DPI testing.

The new improved Critical Flow Controller Model TPK 2000 retains the same critical specifications laid down in Ph.Eur. and USP as the earlier model but incorporates a number of additional features.

Breath Actuation Controller Model BAC 2000

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A cut-down version of the Critical Flow Controller Model TPK 2000, the Breath Actuation Controller Model BAC 2000 is an electrically operated, timer controlled two-way solenoid valve.

The BAC 2000 is a microprocessor controlled instrument specifically designed for use in three test applications:

1) Breath Actuated (or Breath Operated) Metered Dose Inhalers

2) Spacers and Valved Holding Chambers (VHCs) used with MDIs

3) Nebulisers according to USP <1601> and Ph.Eur. 2.9.44

In practice, it is positioned in the line between the DUSA collection tube/cascade impactor and the vacuum pump in order to control the air flow supply to the inhaler under test.

The solenoid valve employed provides near instantaneous starting and stopping of the air flow during testing and has both delay and inhaled time functions.

Special Applications

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At present, there are no official dissolution test methods described that are applicable to inhaled products. One of the main problems facing the developers of such methods is the identification and segregation of that part of the total emitted dose actually reaching the target site (as opposed to the whole dose) in a form readily adaptable to conventional dissolution testing techniques.

The NGI Dissolution Cup and Membrane Holder is a modification of the standard NGI collection cup which allows size-fractionated particles from an aerosol cloud to be collected and then tested in a conventional dissolution tester in a manner similar to the Paddle over DiscMethod described in USP Method 5 and Ph.Eur. 2.9.4.

A similar technique can be employed using the Andersen Cascade Impactor, in this case, by applying a 76 mm polycarbonate filter to the appropriate collection plates prior to analysis, such that the drug is captured directly on the membrane, and then sandwiching the inverted membrane between the glass and PTFE surfaces of the Watchglass/PTFE Assembly normally used for transdermal patches.

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In recent years, there has been increased interest in the development of generic OIPs as the patents on the original formulations expire.

This generic drug development has led to the reintroduction into the Pharmacopoeia of some of the test methods employed in the development of the original drugs.

This section describes three such methods, and the test equipment required to perform them, now embedded in USP and relating to fluticasone propionate (aerosol and powder), salmeterol(powder) and fluticasone propionate/salmeterol combinations (aerosol and powder) respectively.

The test equipment concerned comprises two Glass Sample Collection Apparatuses for the DDU testing of aerosols (MDIs) and powders (DPIs) and a modified Andersen Cascade Impactor (ACI) for APSD studies.

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Spray pattern and plume geometry are common techniques employed in the pharmaceutical industry to characterise and quantify the shape of the emitted spray from Metered Dose Inhalers (MDIs) and Nasal Sprays.

However, possibly of as much concern as either of these two parameters is the reaction of the user to the impaction force of the MDI or spray on the throat or nasal passages.

The “cold Freon®” effect (the initial reaction to the cold blast of MDI propellant on the back of the throat) can often result in the patient aborting the inhalation process and hence receiving inconsistent delivery to the lungs. Similar reactions can be generated by nasal sprays.

The “cold Freon®” effect is a function of aerosol spray force and plume temperature.

The Spray Force Tester Model SFT 1000 and Plume Temperature Tester Model PTT 1000 are two simple instruments designed to quantify these two essential parameters.

Automation

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The requirements of the regulators responsible for the safety, quality and efficacy of orally inhaled and nasal drug products (OINDPs) place a heavy burden on those companies involved in the development and manufacture of those products in terms of testing.

Fully automated test systems have been developed to address these problems, however they do tend to be expensive, complex to operate and resource intensive to develop, validate and maintain.

In this instance, semi-automated systems available at a fraction of the cost of their fully-automated counterparts can provide a viable solution.

Copley Scientific supplies a broad range of labour saving devices and semi-automated systems for both Delivered Dose Uniformity and Aerodynamic Particle Size testing.

DUSA Shaker

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All of the tests involved in Delivered Dose Uniformity require the collection and drug recovery of individual doses into the collection tube of a Dosage Unit Sampling Apparatus (DUSA) appropriate to its type (MDI or DPI) prior to assay.

To maximise throughput, most users utilise a number of collection tubes to collect the required samples. Once the samples have been collected, solvent is added to each of the tubes and the tubes shaken manually to facilitate drug recovery.

This manual shaking process is time consuming, variable (both inter- and intra- analyst) due to inconsistent and incomplete wetting of the internal surfaces and can lead to repetitive strain injury (RSI).

The DUSA Shaker uses a combination of lateral (side-to-side) shaking whilst simultaneously rolling the tubes to automate the internal rinsing of the DUSA collection tubes whilst freeing up analysts to perform other tasks and reducing analyst exposure to RSI.

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Sample Preparation Unit (Induction Ports & Preseparators)

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A significant number of the procedures performed during inhaler testing are highly repetitive but not technically complex and do not therefore justify full automation.

Relatively simple and inexpensive sample preparation tools can help reduce the unwanted effects of repetitive strain injury (RSI), alleviate bottlenecks and ensure that testing is carried out in a consistent, reproducible and controlled manner.

The Sample Preparation Unit Model SPU 2000 is one such tool.

It has been designed to provide an inexpensive means of recovering active drug from the induction ports employed on the Andersen Cascade Impactor (ACI) , the Next Generation Impactor (NGI) and the Multi-Stage Liquid Impinger (MSLI) and the preseparator of the Next Generation Impactor (NGI).

Sample Preparation (NGI Gentle Rocker)

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A significant number of procedures performed during inhaler testing are highly repetitive and their performance can lead to bottlenecks which compromise overall laboratory operations and efficiency.

Relatively simple and inexpensive sample recovery tools have been designed to alleviate such problems and to ensure testing is carried out in a consistent, reproducible and controlled fashion.

The NGI Gentle Rocker, for example, is a simple economical device for gently agitating the contents of the NGI collection cups in order to dissolve the active drug in the solvent prior to analysis.

The unit comprises a pivoting platform specifically designed to accept the NGI cup collection tray linked to a synchronous motor drive unit and controller.

In operation, the Gentle Rocker rocks back and forth about a central longitudinal axis. The resulting constant motion helps to dissolve the drug in a controlled manner freeing up analyst time for other tasks.

Cup Coating (NGI)

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Particle bounce and re-entrainment can be a particular problem when using cascade impactors to measure the aerodynamic particle size distribution (APSD) of orally inhaled and nasal drug products.

Particle bounce is a phenomenon whereby the particle impacts against the collection surface appropriate to its size but rather than adhering to that surface “bounces” back into the air stream whereupon it is re-entrained and passes to a lower stage than that intended.

The normal method of addressing this problem is to coat the collection surfaces with a tacky viscous material such as, for example, glycerol or silicone oil.

The amount, uniformity and method of application are critical parameters within the coating process.

The NGI Cup Coater has been designed as a standardised approach to this problem and eliminates many of the variables inherent in this process.

Impactor Cleaning System (ACI and NGI)

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Cascade Impactors are precision instruments and should be treated with care. Regular cleaning and drying is an essential element of good impactor practice in ensuring that the instrument is free of debris prior to testing and that the unit remains in optimum condition throughout its life.

The importance of proper, consistent, reproducible and controlled cleaning and drying procedures should not be overlooked.

The Copley Impactor Cleaning System is designed to provide exactly that. The system comprises five key elements, the Impactor Carrying Rack which accepts the various parts of the Cascade Impactor (ACI or NGI), the Impactor Ultrasonic Bath which provides the first step in the cleaning process, the Impactor Rinsing Bath, the Impactor Suction Aspirator and the Impactor Drying Oven.

NGI Induction Port and Preseparator Rinsers

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The Induction Port and Preseparator Rinsers are two similar devices designed to automate the process of rinsing the NGI Induction Port and Preseparator prior to analysis.

Both units are bench standing and can accommodate three induction ports or preseparators respectively.

The actual rinsing action takes the form of a tumbling end-over-end motion, combined in the case of the preseparator rinser with an axial turning motion such that the preseparator rotates simultaneously about two axes.

NGI Assistant

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The NGI Assistant is a labour saving device that places a known quantity of solvent in each cup of three NGI cup trays, gently agitates the contents in order to dissolve the active drug in solvent and then places a representative sample of solution from each of the cups into HPLC vials for subsequent analysis.

It takes approx. 45-60 minutes to process three trays.

Qualification

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Hitherto, the scientific community has used the terms “validation” and “qualification” on an interchangeable basis thus creating a degree of ambiguity as to their use.

For this reason, USP have suggested that:

a) the term “qualification” be applied to instrumentation and
b) the term “validation” to processes and software

Hence the term “Analytical Instrument Qualification (AIQ)” is used for ensuring that an instrument is suitable for its intended application, and the term “Analytical Method Validation” is used for ensuring that the analytical and software procedures employed are suitable for their intended application.

The USP Chapter <1058> Analytical Instrument Qualification describes in detail a four phase approach to qualification based on design (DQ), installation (IQ), operational (OQ) and performance (PQ) qualification.

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Both European and US Pharmacopoeias lay down certain criteria which the cascade impaction system and test criteria selected for the inhaler must fulfil prior to and during use.

The performance and reproducibility of a cascade impactor are dependent on a number of factors, the most critical being the nozzle dimensions (and their spatial arrangement) on each stage together with the air flow rate passing through it.

Providing these critical dimensions are within the quoted specification, then the impactors concerned can be expected to give comparable results.

The process of measuring the nozzle diameters and other critical dimensions of cascade impactors is called stage mensuration.

Both Ph.Eur. and USP recommend stage mensuration of impactors prior to use and periodically thereafter.

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If stage mensuration results in an Effective Diameter in excess of an upper limit, then the stage must be replaced. This is a sign that the nozzles have worn, either as a result of corrosion from the solvents used to dissolve the active drug or erosion from the constant rapid passage of particles through the nozzles concerned. In this case, there is no further option available as it is not practical to reapply metal to impactor nozzles.

The majority of failed stages however relate to cases where the Effective Diameter decreases below the lower limit for the stage. This is usually caused by a build-up of hardened particulates or, more likely, because the corrosion process products metal salts that occlude the nozzle.

In this instance, a combination of ultrasonic cleaning and “stage pinning” is often sufficient to remove deposits and restore performance.

Impactor Stage Pinning involves pushing stainless steel “go” pins with a diameter between the nominal diameter and the lower tolerance limit for the stage through each nozzle in order to clear accumulated debris.

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According to USP Chapter <1058>, Analytical Instrument Qualification is “the collection of documented evidence that an instrument performs suitably for its intended purpose”.

Whilst mensuration or calibration is an important part of the qualification process, it does not in itself qualify the whole inhaler testing system for use.

The Installation Qualification/Operation Qualification Documentation (IQ/OQ) provided by Copley Scientific guides the user through this important process and confirms that the system is fully qualified for use.

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All inhaler testing systems should be tested on a regular basis as to their suitability for use.

The Qualification Kit includes all of the tools required to perform your Inhaler Testing IQ/OQ Qualification procedures.

It includes a vacuum regulation test rig, digital and absolute pressure meters, stop watch, temperature/humidity meter and all the associated tubing and fittings to qualify your inhaler testing system in-house, supplied in a handy carrying case complete with the required calibration certificates.

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The seals on cascade impactors can deteriorate with repeated use and exposure to solvent. Leaks then occur which because the system operates under vacuum allows air into the system causing erroneous results due to incorrect flow rates and poor aerodynamic performance.

For this reason, all cascade impactors should be tested on a regular basis to check the integrity of the sealing system. The most common method is to use a Leak Test Kit to block the entry to the impactor inlet, generate a vacuum within the impactor using a vacuum source and then monitor any rise in pressure using a pressure meter located within the enclosed system.

This method is sensitive, accurate, straightforward and fast. It is ideal for verification checks during the life of the impactor or, indeed, as a fast system suitability test before an impactor is used.

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The Pharmacopoeias recommend stage mensuration at regular intervals to ensure that only impactors within specification are used for testing inhaler output.

Unfortunately, because of the instrumentation, skill and time required to conduct a test, it is not practical to use stage mensuration on, for example, a daily basis. Currently, therefore, there is no practical means of checking the system suitability of an impactor on a daily or individual test basis.

Nozzle dimensional performance can however be indirectly monitored by measuring the pressure drop (Delta-P) across each stage of the impactor at a particular flow rate by using a suitable “Delta-P” Apparatus linked to a Flow Resistance Monitor.

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The build-up of static electricity on plastic, non-conductive surfaces such as those found in inhaler actuators and/or spacers can present specific problems with inhalers, particularly dry powder devices.

Generally speaking, metal objects such as impactors, particularly those manufactured from stainless steel do not present a problem.

Indeed, most problems of this nature emanate from the movement of the analyst around the laboratory prior to handling static sensitive equipment.

Irrespective of the source, it is preferable to take action to reduce static to a minimum on the grounds that it is one less variable capable of affecting the results.

Copley Scientific offers a range of equipment to monitor and minimise electrostatic effects in inhaler devices during the testing process.

The DIS 6000 has been designed as a direct response to this problem. With a footprint of just 650 x 450 x 640 mm (w x d x h), the DIS 6000 is one of the most compact dissolution testers available on the market today.

The Dissolution Tester DIS 8000 represents the very latest in tablet testing technology. CNC production techniques combined with modern microprocessor design guarantees the highest standards of performance and reliability.

The Testers have been specifically designed for use in the quality and production control of normal, plain coated and delayed release coated tablets and gelatin capsules in accordance with the specifications as laid down in European, United States and associated Pharmacopoeias.

Based on an original design by Roche, the friability tester has now become an accepted standard throughout the pharmaceutical industry for determining the resistance of uncoated tablets to the abrasion and shock experienced in manufacturing, packing and shipping operations.

Together with friability testing, the testing of a tablet’s hardness (or more correctly breaking force) plays a vital role in both product development and subsequent quality control.

The Delivered or Emitted Dose is the total amount of drug emitted from the inhaler device and hence available to the user.

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