Testing strategies for generic inhaled products

Mark Copley

The generic sector of the pharmaceutical industry is one of India’s most successful revenue generators and is growing fast, at an annual rate of 27 per cent (compared to a global average of 10 per cent)1. Supported by domestic law that sets tight restrictions on multiple patents for a drug, the sector also benefits from significant government investment. Current initiatives include a multi-billion dollar injection of government money to support public-private partnerships that capitalise on innovation, generous tax relief on R&D expenditure, and the introduction of 19 special economic zones to stimulate pharma sector investment. India’s generics are known for their quality and the industry not only provides inexpensive products to the fast-growing domestic market but also substantially boosts export income. Major Indian pharma manufacturers lead the way in competing in the US generics market with an established track record of success. Indeed, of the 255 Abbreviated New Drug Application (ANDA) approvals by the US FDA from January to July 2013, 103, over 40 per cent went to Indian companies1.

With the incidence and diagnosis of chronic obstructive pulmonary disease (COPD) and asthma rising across Asia, inhaled products are an increasingly important part of the country’s generic portfolio. However, the performance of metered dose and, in particular, dry powder inhalers (DPIs) can be very demanding to replicate. This article provides an introduction to two of the primary techniques used to characterise orally inhaled products (OIPs): delivered dose uniformity testing and aerodynamic particle size measurement. The role of these tests in generic product development and testing is outlined by focusing on how they support the demonstration of bioequivalence. New innovations that help to secure supportive in vitro data are also highlighted.

The regulatory framework for generic OIPs

Generics are prescribed interchangeably with the reference product setting a requirement for closely equivalent clinical efficacy. The regulatory framework designed to achieve this goal varies from country to country, but demonstrating bioequivalence is a unifying theme.

In Europe new regulatory guidance for inhaled generics for asthma and COPD was released in 20092. It sets out a stepwise approach to approval and indicates that bioequivalence can be demonstrated through in vitro testing alone, without any need for additional pharmacokinetic and pharmacodynamics (PK/PD) clinical studies. This approach has the potential to decrease the cost of development and reduce time to market but it requires the considered development of an appropriate in vitro testing strategy. The new EMA guidance is useful in providing quite specific criteria to demonstrate bioequivalence and highlights the need to confirm that3:

• the product contains the same active pharmaceutical ingredient (API), in the same solid state, as the reference product, and that any difference in crystallinity does not affect solubility
• any qualitative or quantitative change in excipient does not impact the performance of the product, aerosol particle behaviour, the inhalation behaviour of the patient or the safety profile of the product
• instructions for use of the product are identical to those of the reference product and that the inhaled volume needed to deliver a sufficient dose of the API is similar in each case (within +/- 15 per cent)
• the delivered dose of the product is the same as for the reference product (within +/- 15% of labelled claim)
• the inhalation device uses the same resistance to air flow as the reference device (within +/- 15%)

At the time of writing the FDA, in contrast, offers no directly equivalent guidance, instead appearing to prefer a ‘weight of evidence’ approach. Currently there are three distinct pathways to regulatory approval in the US with 505 (j), a streamlined process designed specifically for abbreviated new drug applications (ANDAs), the preferred route for generics.

Demonstrating bioequivalence in an OIP

By providing specific criteria for bioequivalence, the EMA guidance supports the identification of a more widely applicable in vitro testing strategy. A primary element of testing is analysis of the constituent ingredients, to verify the chemical assay of the API and/or its morphological form. This is an analytical requirement common to all generic products. However, beyond that the guidance raises some explicit issues relating to OIPs.

It is important to recognise that with an OIP drug delivery performance is dependent not on the formulation alone, but on interactions between the formulation and the delivery device. This is why it is essential that in vitro testing is applied to the complete inhaled product. Together formulation and device determine the amount of drug delivered and the particle size at which it enters the respiratory system; two defining characteristics for an OIP.

Delivered dose uniformity

Delivered dose uniformity (DDU) testing, which measures the amount of drug delivered by each actuation of the product, is an essential testing requirement for both generic and innovator OIPs. In terms of demonstrating bioequivalence DDU testing:

• confirms that the total dose of API delivered is comparable to the label claim of the reference product, to within the +/-15 per cent acceptable tolerance
• helps to show that the chosen excipient results in comparable product performance
• helps to demonstrate that the inhalation volume required to obtain the specified dose of API is the comparable for the generic and reference product

Figure 1: Image of DUSA testing apparatus set up for MDI testing

A typical dose uniformity sampling apparatus (DUSA), as used for DDU testing, is shown in (Figure 1). The test device is fired into the DUSA which contains a filter that catches the dose as the sample is drawn through the apparatus by a vacuum pump. Recovery of the dose and the application of gravimetric and chemical analysis, (usually High Pressure Liquid Chromatography (HLPC)), enables determination of the amount of API delivered.

To make DDU testing more representative of clinical performance the test conditions applied are tailored to match the way in which the product is used and operates. The majority of metered dose inhalers (MDIs) use a propellant to drive drug delivery making delivery performance independent of the inhalation profile of the patient. For MDIs the test flow rate is therefore set at a figure of 28.3 L/min (1scfm). This figure derives from historical calibration data for the Andersen Cascade Impactor (ACI) and has minimal clinical significance. For DPIs and nebulisers, in contrast, the efficiency of drug delivery is directly impacted by the inhalation characteristics of the patient. This is reflected in the test conditions applied.

For a DPI, the only motive energy for drug delivery comes from the patient’s inhalation manoeuvre and they are therefore considered as passive devices. As a result, the pharmacopoeias recommend that the test flow rate applied is determined for each individual product, based on an assumption that a typical patient will induce a pressure drop of 4 kPa across the device during inhalation. The internal flow resistance of the device determines the flow rate that this pressure drop induces, with lower resistance devices associated with high flows.

To prevent testing low resistance devices at excessively high flow rates, an upper flow rate limit for testing is set at 100 L/min. The duration of the test is fixed to reflect the total air volume of a single intake of breath with 4L specified by the pharmacopoeias and 2L by the FDA. Other volumes may also be used to demonstrate bioequivalence for the specific patient groups to which the marketed product would be targeted. Test volumes are converted into test durations on the basis of the flow rate determined for testing.

With nebulisers too the amount of drug delivered is a function of the patient’s breathing profile, as well as the duration of use, as these devices are used under tidal breathing conditions (i.e. at rest). New test methods 4, 5 have been introduced relatively recently that define standardised flow conditions for delivered dose testing for nebulisers by reflecting the breathing patterns of various different types of patient. For adults the specified breathing pattern is: 500 mL tidal volume; sinusoidal waveform; 15 cycles per minute; 1-to-1 inhalation/exhalation ratio. Alternative test conditions are specified for neonate, infant and child patients, for which nebulisers are a widely used drug delivery device, as no coordination is required. Similar test conditions also exist for MDIs when used with Spacers and Valved Holding Chambers (VHC), since these add-on devices are designed to improve drug delivery performance during both coordinated and uncoordinated use.

One final point to note on DDU testing is that for multi-dose inhalers it is essential to verify dose uniformity across the life of the product by testing, for example, the first three, middle four and final three doses, per device tested. This too is an essential element of bioequivalence demonstration.

Aerodynamic particle size distribution (APSD)

While DDU testing measures the amount of API delivered to the patient, APSD measurements are used to infer where that dose may deposit in vivo. For example, only particles less than five microns in size will tend to reach the peripheral airways of the lung. Particles greater than five microns are prevented from reaching the lungs as they deposit in the upper respiratory tract while those that are too small, less than one micron, risk being exhaled. In terms of bioequivalence testing APSD measurement can therefore be used to:

• verify that the inhalation volume needed to obtain a sufficient dose is equivalent to a reference product (in combination with DDU testing)
• thoroughly investigate the delivered particle size profile of the generic product to demonstrate the likelihood of closely similar in vivo deposition behaviour

Multistage cascade impaction is the technique used for APSD measurement for all OIPs, both innovator and generic products. The technique is valued because it comfortably spans the sub ten-micron fraction of interest and generates aerodynamic particle size data for the API alone, rather than for the whole formulation.

Figure 3: Schematic showing how a multistage cascade impactor works

Multistage cascade impactors divide a dose into size fractions on the basis of particle inertia, which is a function of velocity and aerodynamic particle size (Figure 3). The resulting fractions are analysed to determine the amount of API present and produce an APSD specifically for the API. Traditionally the Andersen Cascade Impactor (ACI) was used for this application but the Next Generation Impactor (NGI) is increasingly being chosen. This instrument was commercialised at the turn of the century and developed uniquely for pharmaceutical applications6.

As with DDU testing, the test conditions, and most specifically the air flow rate applied during APSD measurement is modified to reflect the way in which the OIP operates. Test flow rates closely similar to those applied during DDU testing are adopted. However, cascade impactors require a constant air flow rate, making it infeasible to apply the sinusoidal breathing pattern used for nebulisers. For nebulisers testing is therefore carried out at a constant 15 L/min, a flow rate representative of the mid-tidal flow rate of a typical adult user.

The use of APSD measurements to demonstrate bioequivalence is especially demanding, and the EMA guidance includes some quite specific recommendations to support this exercise. It recommends the stage-by-stage comparison of data or the comparison of a minimum of four groupings justified with reference to inferred deposition site within the lung. It is vital that the distribution is compared across its entirety – 10th and 90th percentile – as well as median values, to verify bioequivalence. Furthermore, the guidance recommends testing three batches of both the reference product and the generic with maximum allowable differences calculated to support a conclusion of bioequivalence 7. Such detailed comparisons are hampered by variability in cascade impaction data which can be considerable, especially on those impactor stages containing little mass of drug. Ref 8 provides useful guidance on how to improve the accuracy of this technique.

Measuring the cold Freon effect

Although delivered dose and APSD are widely recognised as critical, performance defining characteristics of OIPs, other in vitro methods are extremely helpful when it comes to conclusively demonstrating bioequivalence. Measurement of the cold Freon effect, for example, provides evidence that:

• any difference in excipients does not influence the inhalation behaviour of the patient

The cold Freon effect is the term given to the chilling sensation felt at the back of the throat following delivery of a dose with a propellant-driven MDI. It is caused by rapid evaporation of the propellant in combination with impaction of the delivered dose and can have a pronounced impact on patient experience. A marked cold Freon effect can cause a patient to abort or unsuccessfully complete inhalation, compromising the success of delivery. The EMA guidance points specifically to the cold Freon effect highlighting it as a potential source of variability between a reference and generic drug.

Figure 4: The Copley Spray Force Tester, SFT 1000, and Plume Temperature Tester, PTT 100, quantify the cold Freon effect helping to support the demonstration of bioequivalence

The reformulation of MDIs with propellants such as HFA 134a, as a result of the banning of CFCs in the Montreal Protocol, has provided a stimulus to the development of reliable measurement methods for this phenomenon. Alternative measurement methods remain in use but the commercialisation of dedicated instrumentation in this area is a welcome advance. One such solution is the Plume Temperature Tester Model PTT 1000 (Copley Scientific), which measures temperature as a function of distance from the mouthpiece. Used in combination with measurements of the impaction force of the plume, it eases the analytical challenge of quantifying the cold Freon effect to demonstrate bioequivalence.

Device resistance

As noted in the analysis of how to set conditions for DPI measurement internal device resistance has a direct impact on DPI performance. Device resistance influences the amount of air that can be drawn through the DPI by the patient, and therefore defines the success of drug delivery. Furthermore, DPIs with different internal resistance can feel very different to use so the issue has a direct impact on user experience. Measuring internal device resistance:

• confirms that the inhalation device presents the same resistance to air flow as the reference device (within +/- 15 per cent)

Figure 5: The apparatus used to determine an appropriate flow rate for DDU and APSD

(Figure 5) shows the test set-up used to determine the flow rate for DDU and APSD measurements which can be easily modified to demonstrate equivalent internal resistance. The resulting test simply involves applying a known flow rate through the device and measuring the pressure drop that develops across it. Measuring across a range of flow rates ensures complete characterisation of the device, as can be seen for a range of commercially available devices in (Figure 6).

Looking ahead

The development of successful generic OIPs undoubtedly presents a considerable challenge. The application of all relevant in vitro test methods is therefore vital when it comes to efficiently meeting regulatory requirements for the demonstration of bioequivalence. Identifying a productive in vitro strategy, based on the techniques outlined here, can eliminate the need for additional PK/PD trials, helping to bring new generics to market quickly and cost-efficiently.

Here, the focus has been on the in vitro methods indicated by the most recent regulatory guidance but with the evolution of inhaled product testing new techniques are becoming available to those looking to closely replicate the performance of an originator drug. For example, dissolution testing is an area of growing interest. Currently dissolution testing is not a routine test for inhaled drugs, however, as larger molecules are delivered via the pulmonary route solubility is of increasing concern, especially given the far from optimal dissolution conditions within the lung. There are now established methods for dissolution testing for inhaled drugs and these may prove valuable in the development of certain inhaled generics.

Furthermore, advances to make in vitro testing more representative of in vivo behaviour can also be helpful as exemplified by the growing use of breathing simulators. In DPI research breathing simulators enable investigation of the impact of inhalation characteristics on the performance of the device to ensure that it operates as required for all patient groups. Such testing therefore similarly supports the efficient development of a generic to match closely tailored performance. Developments such as these indicate that going forward the inhaled product testing kit for generic manufacturers will become both more sophisticated and more efficient.

References:

1. “World’s pharma innovation base moving to India, says IBEF” Manufacturing Chemist October 2013, pg. 34
2. European Medicines Agency “Guideline on the requirements for clinical documentation for orally inhaled products (OIP) including the requirements for demonstration of therapeutic equivalence between two inhaled products for use in the treatment of asthma and chronic obstructive pulmonary disease (COPD) in adults and for use in the treatment of asthma in children and adolescents” Issued Jan 2009
3. C. Hippchen “Pharmacopoeial requirements for dry powder inhalation systems” Presentation delivered at 2nd open forum on pharmaceutics and biopharmaceutics. Istanbul, Turkey, April 26/27 2012.
4. Ph. Eur 2.9.44
5. USP 1601
6. M. Copley “The NGI – 10 years on…” Manufacturing Chemist March 2007
7. A. Fuglsang “Regulatory issues and challenges relating to pulmonary products” Presentation delivered at 2nd open forum on pharmaceutics and biopharmaceutics. Istanbul, Turkey, April 26/27 2012.
8. M. Copley “Optimizing cascade impactor testing for characterizing orally inhaled and nasal spray drug products” Drug Delivery Technology July/August 2010