Webinar report: Presenting a modeling approach to overcoming bioequivalence hurdles
For generics companies developing orally inhaled drug products, bioequivalence is a both a simple aim and an incredibly complex undertaking.
At a webinar hosted by Business Trade Media International on April 28, Nanopharm’s Gemma Budd and Nuria Manzano provided attendees with live insights into how advanced in vitro and in silico models are answering some of today’s key challenges in this area, supported by an evolving regulatory environment.
The US Food & Drug Administration (FDA), via updated Product Specific Guidances (PSGs), has opened the door to a new pathway for approval of inhaled generics. These changes provide a clear signal of endorsement for the use of more sophisticated in vitro tests and in silico computational modeling methods for demonstrating bioequivalence.
This contrasts with the traditional pathway, which relied on a ‘weight of evidence’ approach, where four pillars of proof must be met: formulation and device similarity; in vitro test equivalence; systemic exposure equivalence; and pharmacodynamic (PD) or comparative clinical endpoint (CCEP) studies. Crucially, when it comes to this last point, significant patient-to-patient variability in areas such as physiology and device-related behaviors have made it very difficult for generics companies to meet the required criteria, slowing patient access to much needed medications at affordable prices.
While the new pathway relieves some of this pressure – primarily through removing the requirement for challenging and costly CCEP studies – it places greater emphasis on building out the required supporting evidence from, for example, computational modeling studies, even if they might be framed as an option in the technical guidance.
“The use of the word ‘optional’ has led to a lot of confusion in the industry, and the temptation has been to interpret that as meaning you don’t need to do it,” said Gemma. “Our experience suggests that passing the new in vitro studies isn’t as easy as it first seems and so, maybe, it’s an expectation from the regulators that this kind of approach [modeling] might be needed to help explain some of the data that comes out of the pivotal studies.”
Greater regulatory scrutiny increases the complexity of testing and demands greater validation of test methods, as Nuria explained: “Regulatory expectation is that the data that we generate needs to be more clinically relevant than was required before.” Among the new in vitro studies referenced within the updated FDA pathway for establishing bioequivalence is Realistic Aerodynamic Particle Size Distribution (rAPSD). rAPSD employs anatomical mouth-throat models and realistic breathing profiles to more accurately reflect patient usage conditions and, therefore, provides higher in vitro in vivo correlation (IVIVC) compared with compendial APSD.
Nuria presented a case study to highlight the value of rAPSD for a customer selecting product batches for a PK study for a Dry Powder Inhaler (DPI). Initial in vitro APSD tests employed compendial Next Generation Impactor (NGI) evaluation with the USP induction port and a fixed-flow inhalation rate, with good correlation between the test and reference products. However, in vivo analysis revealed poor correlation between Cmax and total drug exposure. This highlighted the complex variability apparent in both patient-device and formulation-device interactions. It also pointed to the IVIVC limitations of a standard measurement technique such as compendial APSD. In contrast, when using a medium Oropharyngeal Consortium (OPC) model and breathing profiles from healthy volunteers, both batches delivered desirable results in vitro and in vivo, demonstrating the importance of using realistic methods to de-risk studies.
In a second case study, Nuria explored rAPSD method development for a generic suspension pMDI using breathing profiles from real asthmatic patients. Two mouth-throat models were selected for testing. For model A, measurements for mass balance were found to meet USP acceptance criteria but the T/R ratio was found to be unacceptably high at around 150%, likely due to the Impactor Sized Mass (ISM) as a percentage of the delivered dose being very low at under 10%. Repeat testing with mouth-throat model B found inconsistencies in mass balances but a higher ISM, which triggered an improved T/R ratio. Neither cases were acceptable. Further optimization of the actuation delay in the method with Model B achieved acceptable mass balance and ISM figures and, crucially, a T/R ratio of around 95%. This highlights the importance of fine-tuning patient-specific parameters such as actuation maneuver in the lab to demonstrate bioequivalence when deploying these more sensitive methods, without overdiscriminating.
Webinar attendees were given an overview of innovative Nanopharm technologies designed to minimize in vitro testing variability, including the Realistic Automated Actuator Profiler (RAP), which supports consistent, predictable device control over pMDI actuation during rAPSD testing to mitigate study risk – an instrument developed specifically by Nanopharm for this purpose. There was also an overview of in silico tools that can be used to accelerate the development of test methods by pinpointing critical variables that have influence over factors such as deposition.
Case studies were presented to illuminate the benefits of such tools as part of an ‘alternative’ in vitro in silico development pathway for inhaled generics. The first focused on understanding rAPSD sensitivity through the use of Computational Fluid Dynamics (CFD), which is based on three-dimensional lung modelling from high-resolution CT scans. In testing, variations in plume angle, actuation point and inhaler-throat alignment were assessed for their impact on deposition. In some cases, the simulations deviated sufficiently from the baseline to represent a T/R fail despite testing being carried out with the same product. This data can be helpful to explain marginal population bioequivalence (PBE) failures driven by sensitivities in method parameters. As a result, such sensitivities can either be controlled in the lab or, if control measures cannot be implemented, generics companies have a framework for explanation when in dialogue with regulators.
A further case study highlighted weaknesses in rAPSD testing’s separate treatment of population extremes. Nanopharm highlighted through the use of rapid deposition analysis (RDA) how an exclusive focus on modeling data for patients with small throats can show non-bioequivalence but, when pooled with broader data to provide patient population heterogeneity and account for other patient-to-patient variability such as lung physiology, BE was evidenced, suggesting that inherent patient-to-patient variability is more impactful than minor differences between batches. This sends a powerful message to regulators about how to interpret data coming from the in vitro studies’ focus on isolated groups, potentially supporting a justification of widening acceptance criteria to more biorelevant limits.
A final case study looked at the use of in silico tools to analyze the impact of variable deposition. Here, Physiologically Based Pharmacokinetic (PBPK) modelling via Nanopharm’s Simhalation™ tool was employed to predict exposure and transport in the body for albuterol, with a range of profiles featuring modified ratios of central/peripheral deposition (while total dose delivered remained constant). The findings highlighted a significant change in Cmax, with higher peripheral deposition leading to faster absorption but exposure (AUC) largely unchanged overall.
The evidence presented by Nanopharm in this webinar underlined how demonstrating bioequivalence remains a complex task, even in light of the new FDA-approved pathway unlocked by the updated Product Specific Guidances. Furthermore, it highlighted how advanced in silico tools complement in vitro studies to deliver essential, additional layers to the robust evidence base required by regulators.
Gemma concluded: “Both in vitro and in silico studies can help you build a more comprehensive picture about how your product is performing in the context of bioequivalence. If you do it in a holistic, joined-up manner, it’s going to be much more credible and confidence-building when talking to the regulators.”
To watch the on-demand webinar in full, click here. For more information about Nanopharm’s advanced approach to demonstrating bioequivalence, including SmartTrack™, our proprietary integrated in vitro in silico modeling platform, contact our team today.
