At the root of this challenge is a vertically integrated structure with ‘make’ functions separated from ‘test’ functions.
Formulation development under the current industry structure typically comprises the identification of formulation prototypes, which are then screened in preclinical species to select candidates for clinical assessment. Manufacturing processes for these candidates must then be scaled-up to generate the product to support extensive stability studies that drive regulatory submissions, with the remaining material packed, labelled and shipped to a clinical site for evaluation. This process can take 12–18 months to complete and requires significant investment before the product is known to meet the drug delivery need.
Translational Pharmaceutics has enabled a reconfiguration of conventional formulation development and optimisation processes, addressing gaps in observed human performance, by proceeding directly to clinic without conducting poorly predictive preclinical pharmacokinetic investigations. This data-driven, streamlined formulation development approach — termed RapidFACT — allows drug products to be screened iteratively in human subjects, dramatically increasing the accuracy of formulation evaluation and selection.
Make versus test
It is widely reported that up to 70% of new chemical entities (NCEs) entering drug development programmes possess insufficient aqueous solubility to allow adequate and consistent gastrointestinal (GI) absorption to ensure efficacy. In addition, industry’s desire for once-daily oral delivery to ensure a competitive position for new drugs, or to reposition existing products, is becoming ever more important. These challenges place a significant focus on formulation development and CMC teams to deliver the best possible drug product.
However, the development team is constrained by suboptimal industry configuration (Figure 1a). Two vertically integrated channels comprising ‘make’ functions, such as API production, formulation development and clinical trial manufacturing, and ‘test’ functions such as the use of preclinical laboratories, healthy volunteer clinics and patient centres were established by pharmaceutical companies during the blockbuster years.
Figure 1: Conventional industry structure (a) and horizontal integration using Translational Pharmaceutics (b)
This structure, which evolved when molecular chemistry was less challenging and marketing requirements were less stringent, is arguably unfit to address the drug development challenges faced by industry today. Development teams expend significant time and effort transitioning a product made in the make channel to the test channel. Fundamentally, this drives up the scope of the CMC data package, API consumption, overall cost and time, and runs the risk of not identifying a suitable drug product composition within the first development cycle.
Under this conventional structure, a formulation development programme is performed in the make channel to identify formulation prototypes, which are then screened in a preclinical species. Successful formulations can then be subjected to conventional CMC processes to generate data to support a regulatory assessment for a clinical study.
Significant emphasis is placed on lab and preclinical assessments. Formulation evaluations in preclinical species are quick and cheap compared with clinical studies under the conventional industry structure, but these are widely accepted as not being predictive of human performance. The net result is an increased risk of having to repeat this process, because the correct product is not identified within one cycle of development. The root of this problem is that supply chains are typically only vertically integrated.
Horizontal integration improves efficiency
In response to the need for horizontal integration, a Translational Pharmaceutics delivery platform has been developed, combining formulation development, GMP manufacturing and clinical testing functions and workflows (Figure 1b). This configuration allows batches of drug product to be manufactured, released for dosing and administered immediately to subjects within a few days. Such an approach enables a real-time adaptive manufacturing strategy to be applied to development processes, in which clinical data drives decision making. The inefficiencies of the conventional industry structure during these early development activities can therefore be removed.
Using the Translational Pharmaceutics approach, development programmes can progress to clinical dosing with a shorter product shelf-life, and therefore reduced CMC data packages. Typically, data to support 7 days of shelf-life is included in the regulatory submission, allowing ICH stability studies to be removed from the critical path and run in parallel with dosing. In addition, as manufacturing is on a small-scale, the development of pilot-scale manufacturing processes can be removed from the critical path to obtaining clinical data.
Finally, because cycle times between production and dosing are so short, a product can be rapidly made and tested before reviewing interim pharmacokinetic (PK), safety or pharmacodynamic (PD) data and using those data to determine the purpose of the next period of the clinical study. This means that the data on a drug product dose can influence the drug product composition selected and manufactured in any subsequent dosing period on a 7–14-day cycle.
Conventional versus RapidFACT formulation development processes
The conventional approach to the development of improved drug product formulations to enhance performance in humans is shown in Figure 2, illustrating the aforementioned acceptance of risk by relying on (poorly predictive) preclinical PK data to determine which systems to take forward into a human study.
Figure 2 Conventional industry structures
By contrast, a more streamlined approach is presented by a novel approach termed RapidFACT (Figure 3), which uses human clinical data to drive decision making, dramatically increasing the accuracy of formulation evaluation. Successful products from the Pharmaceutical Development programme are identified, and regulatory approval sought on batch analysis and short-term stability data on demonstration batches of candidate formulations. These batches are fully representative of potential clinical formulations, demonstrating to the regulators that a batch can be manufactured, a specification achieved and a stable product maintained until dosing is completed.
Figure 3 RapidFACT
Once regulatory approval is achieved, the first product to be tested can be manufactured and administered to subjects. The resultant clinical data then informs the selection of the product to be tested in the next dosing period.
Driving drug exposure
Initial clinical studies on poorly soluble drugs, performed using conventional powder-in-bottle or drug-in-capsule formulations, typically display significant variability in the fasted state, non-linear PK and a pronounced positive food effect. RapidFACT programmes can accelerate the process of switching to an enabled formulation. In one such case, the development team was challenged to identify an oral formulation, ideally a solid dosage form, which could overcome the observed PK variability in the fasted state and gave comparable bioavailability to that seen in the presence of food.
The formulation strategy selected was to mimic the food effect seen with the existing formulation by delivering the drug using a lipid-based, liquid-filled capsule formulation. In the development programme, excipients and prototype formulations were studied to evaluate physical and chemical compatibility, and stability. The resulting prototypes were screened through a discriminatory dissolution test using neat API, and the existing immediate release (IR) formulation as references. Finally, a series of demonstration batches of candidate formulations were manufactured under GMP to provide CMC data for submission to the UK regulatory authority. Approval to commence recruitment for the clinical study was received in 14 days.
The candidate formulations were then dosed to 10 healthy volunteers in the fasted state, versus the existing IR formulation dosed in the fed state. The three lipid-based formulations demonstrated relative bioavailabilities (Frel) of 133–160% when compared with the IR formulation. When the lead formulation was studied in the fed state in a fifth dosing period, it was confirmed that the food effect of the original formulation was overcome.
In this study, the first subject was dosed with the first prototype formulation just 16 weeks after formulation development. The total project duration from initiation to completion of the clinical phase was 26 weeks, minimising the impact of the formulation programme on the development plan, and thereby delivering both time and cost benefits.
Formulation design space
The case study above is an example of how fixed formulation compositions may be screened. However, development teams may also be interested in optimising formulation compositions to provide a desired clinical outcome, in which case a formulation design space (Figure 4) can be established using the RapidFACT platform. This approach builds upon established ICH Q8 principles, and allows products from any point with in a continuous composition space to be studied without having to submit multiple amendments to a regulatory authority.
Figure 4 Formulation design space
Modified release product development
RapidFACT and formulation design space can be applied to accelerate the development of modified release (MR) formulations. Conventionally, development teams faced with this challenge would identify MR dosage forms with three difference release rates for clinical evaluation. As there is no in vitro in vivo correlation confirmed, the team must make an assumption that one of these three release rates will meet their target product profile. As described previously, these prototypes are likely to have been selected based on preclinical PK data, using animal species with a very different GI anatomy and physiology.
In one RapidFACT case study, a once-daily MR tablet formulation was required to support the lifecycle management of a marketed product as quickly as possible. A single dimensional formulation design space with a flexible release rate was established to allow the iterative screening and optimisation of formulation composition within this range during clinical conduct.
Demonstration batches of product at either extreme of the design space were manufactured. These compositions were tested against a typical Phase I drug product specification, and then retested at 7 days to provide stability data to support a 1-week shelf-life. A clinical trial application was submitted to allow the manufacture and dosing of any product between those two points. Once regulatory and ethical approval was received, recruitment of a panel of 12 subjects took part in a five period crossover investigation. All subjects received the IR reference formulation to provide a bridge back to historical PK, before being dosed with a mid-range release rate MR formulation (FP1).
Collection and review of the PK on FP1 determined where to move in the design space for the next dosing period. Repeated make and test cycles were then executed until the desired PK was achieved before completing a food effect assessment on that selected product.
In this programme, all MR tablets provided good exposure indicating no significant loss in absorption throughout the GI tract, and an optimal once-daily formulation was identified that provided the required plasma concentration at 24 hours. This programme took less than 6 months from start of technical transfer experiments to identification of the preferred tablet formulation. As the programme studied multiple release rates compared with an immediate-release product, an additional benefit was realised in that in vitro in vivo correlation assessment could be performed using observed dissolution and PK data; in this case, a level A correlation was achieved.
Summary
Significant benefits can be derived from adopting the Translational Pharmaceutics approach of horizontal GMP manufacturing and clinical testing integration. Efficiency in early development shortens timelines, reduces costs and improves flexibility by being able to manufacture drug products in real-time, allowing the development team to evaluate and optimise new formulations in the clinic.
Reductions in development time are enabled, with the formulation team able to capitalise on clinical data emerging from as early as 4 months into the programme. An additional key benefit is greatly reduced API consumption, as only the drug products needed to support the immediate dosing period are manufactured (compared with the need for extensive stability studies to allow formulations to be assessed clinically, which require larger batches).
To date, more than 100 programmes have been completed across a wide range of applications. Solubility enhancement has been studied using all of the major techniques, including salt form and particle size changes, solubilisation strategies, lipidic formulations and spray-dried amorphous formulations. Modified release programmes have been conducted to optimise sustained release, delayed release and gastroretentive technologies, as both tablet and multiparticulate systems. In addition, non-oral drug delivery has been studied, including inhaled, transdermal and ocular drug products.
Combined, the benefits of a Translational Pharmaceutics approach is allowing industry to reconfigure development programmes and improve R&D efficiency and productivity.
