Program 2017

• Patient centered integrated device implementation in early development
• Role of developability and pre-formulation development
• Analytical tools and workflows to assess device ability potential of therapeutic proteins.

Formulation development for biologics is constantly changing to reflect the emerging of new antibody scaffolds, the increasing use of subcutaneous injection and the growing constraints on development timelines particularly at the early clinical stages. The growth of self-injectable combination products has necessitated the holistic evaluation of several components at the same time in a fully integrated approach. The interactions between each component collectively drive the final product performance and quality in the hands of the patient. Multiple variables could interact between each other and then affect key quality attributes of the final product. The role of developability and deviceability to minimize the unexpected is critical as well as the use of proper workflows and analytical methods. Drug Device integrated development through a patient-centric Integrated System Design approach is a strategic imperative. This talk will present a summary of current challenges and opportunities for effective development of robust drug products.

• Study Design and Constraints
• Material Quality
• mAb Stability as a lyophile: A case study

Cycle time reduction to achieve faster throughput of medicines development can be achieved with strategies that include high throughput formulation screening. Innovative approaches using high throughput screens often have practical considerations and limitations that must be understood to achieve sound formulation selection decisions. Whilst some of these are similar to conventional formulation development considerations, additional concerns when using 96 well plate based formats must be taken into consideration during sample preparation, stability storage conditions, analytical testing and the statistical designs that underpin these studies. This presentation will cover some of the concerns and mitigating approaches to high throughput approaches using robotic liquid handlers, will describe a case study of a high throughput formulation approach for a mAb and will discuss some of the trade-offs made during final formulation selection decision.

• MD simulations reveal molecular interactions that may facilitate interpretation of experimental data
• Energy calculations enable estimates of amorphous miscibility
• Water uptake and the influence of water on drug-excipient interactions can be explored
• Water clustering leads to domains having enhanced mobility

Molecular dynamics (MD) computer simulations have shown promise in predicting various properties of amorphous excipients, amorphous drugs, and amorphous drug formulations. Structural, thermodynamic, and kinetic features that can be compared to experimental observations are of particular interest. MD simulations enable molecular level exploration of underlying molecular interactions of the excipients themselves, drug-excipient interactions, and the influence of water uptake. Thermodynamic properties such as the Flory-Huggins interaction parameter can be determined in order to predict amorphous drug miscibility with amorphous excipients and the solubility or dissolution rate enhancement potentially attainable through the use of amorphous systems. Dynamic properties related to molecular mobility are also of interest. Insights obtained from studies of various systems including polymer excipients (PVP, PVA, PLA, HPMC, and HPMCAS), several model drugs including indomethacin, felodipine, and carbamazepine, and their amorphous formulations at varying water contents will serve as examples in this presentation.

• Barriers to oral bioavailability
• Benefits of smaller crystalline particles
• SoluMatrix Fine Particle Technology™
• Case studies

• Pentarins are miniaturized drug conjugates that rapidly penetrate deep into solid tumors to drive efficacy
• Pentarins can contain components with diverse physiochemical properties, such as amphiphilic conjugates, requiring careful formulation optimization for physical (solubility, aggregation/ Self-assembly)
• Pentarins must be formulated with compatibile surfactants, complexing agents, and co-solvents
• When there is a cleavable linker the Pentarin must have sufficient chemical stability (pH effect, temperature) in the formulation to enable in vivo testing
• The high throughput optimization of Pentarins requires the in vivo evaluation of lead conjugates necessitating seamless interactions between medicinal chemistry, biology and formulation

Pentarins™ are miniaturized drug conjugates that possess complex molecular structure and provide rapid and deep penetration into solid tumors leading to improved efficacy. Tarveda’s lead Pentarin™, PEN-221 is currently in a Phase 1/2a clinical trial. PEN-221 is designed to treat patients with neuroendocrine cancers and small cell lung cancers that overexpress somatostatin receptor 2. Early-stage pharmaceutical pre-formulation is a critical component in the rapid development of stable, safe, and effective dosage forms for new therapeutic candidates. A synergistic approach to advance Tarveda’s Pentarin™ platform development, consisting of a strong discovery team with chemistry, biology and fit-for-purpose formulation development, enabled candidate selection. After drug candidate selection for early stage clinical trials, a more vigorous and scrutinizing formulation development assured the successful transition of PEN-221 into clinical studies.

Advancing a drug delivery concept into a viable product can be a lengthy and costly process, compounded by non-clinical screening models frequently failing to accurately predict outcomes in humans resulting in multiple cycles of product development and optimisation. An integrated formulation development, manufacture and clinical testing model can overcome many of these challenges and accelerate the development of both simple and complex drug delivery projects. The integrated approach is both efficient as well as flexible, allowing a development team to make adjustments to further optimise a product or respond to new considerations / risks identified as new data emerges.

This presentation will discuss:
• Formulation development processes to promote bioavailability for poorly soluble drugs, and to modify the shape of the PK profile for modified release
• Constraints of current formulation development processes
• Benefits of real-time adaptive product manufacturing
• Rapid formulation development and optimisation strategies
• Case studies in solubility enhancement and modified release formulation development

• Technical & Business Success Factors for Drug Delivery Programmes
• Fighting the growing trend to outsource in an effort to maintain core skill sets
• Minimizing initial investment to reduce risk and reduce costs later on
• Integrating form with formulation in early development to maximise their values mutually
• Developing a true understanding of both form and formulation for efficient development

Fundamental understandings of the biopharmaceutics, physicochemical and solid-state properties of the drug molecule are necessary to develop and progress a candidate compound from discovery to the clinics. These concepts and a toolbox of enabling pharmaceutical technologies will be explored. Strategies for form selection, formulation development, and biopharmaceutical risk assessment in different development stages will also be discussed.

• Drug delivery decision, including device type can be influenced with different formulation approach

• Formulation constraints should be evaluated early on

• Setting up a Target Product Profile, however broad, at an early drug development stage is critical

• Clinical trial / studies should be planned and designed to accommodate the variability and constraints of drug formulation and drug delivery
Drug delivery decision timing need to be made, with an eye on optimising organisation investment

• Variability in pharmacokinetics (PK variability) in preclinical species can lead to significant issues throughout drug development. It can cause failure to define dose-exposure relationship, or result in overlap in exposures between dose groups which can preclude establishing adequate safety margins. Overall, effects on programs can be significant and lead to increased resources, elongated timelines and/or termination.

• It is therefore critical to act proactively to evaluate the risk of PK variability for any molecule transitioning to development.

• A cross-functional effort was initiated to analyze historical datasets and identify the potential root causes of PK variability in preclinical species. The impact of route of administration, species, dose and physiological parameters was studied; and intrinsic properties of the compounds such as BCS class and solubility were correlated to heterogeneity in exposures.

The presentation highlights criteria established for in vitro and in vivo risk assessment of PK variability as well as mitigation approaches.

• Early-stage formulation screening to formulation development • Buffer preparation, exchange and analysis in one portfolio • Impeccable mass recovery • Analytical data supports protein handling equal to or better than dialysis and Amicon centrifugal devices

Current landscape (who is working in the area/therapeutic indications/current knowledge base)

Regulatory (Where do live-bio-therapeutics sit)

Handling and containment

Contamination and decontamination

Formulation and processing considerations examples of early case studies

Analytical/micro testing
Specification setting (examples and considerations)

Presentation will contain comprehensive study results that evaluated available syringe products to identify the best fit for most biopharm requirements. The benefit is that a platform approach and second source not only ensures continuity of supply but also meets standardization for compliance advantage, minimizes process development and capital investment for new products and enables greater speed of decision making and implementation.

• The importance of process parameters on in vitro and in vivo behaviour of dried nanosuspensions in spray granulation
• Evaluating the effects of spray mode, spray rate and atomizing pressure for spray granulation of drug nanosuspensions
• Use of fluid bed granulation for drying of pharmaceutical particulates on micron-sized granule substrates explores

Understand DS/FDS thawing behavior and determine key model parameters

Estimate DS/FDS thawing time scale-up parameters from small scale to commercial scale

A mechanistic protein freezing and thawing model using CFD was developed to predict thawing behavior

The model was successfully validated by predicting the thawing time in 6 L bag at commercial scale

The thawing time is mainly controlled by latent heat (thawing) not by sensible heat
Freezing Temperature does not significantly alter the thawing time

For biopharmaceuticals, time out of refrigeration (TOR) is a Critical Process Parameter (CPP) due to its instability upon exposure to ambient temperature. The parameters required for freezing and thawing of the frozen formulated drug substance (FFDS) needs to be thoroughly evaluated and optimized before transferring the process to commercial DP manufacturing site.
The thawing time of a monoclonal antibody has been studied in a 30mL bag to obtain difficult to measure parameters like heat transfer coefficient, heat capacity, conductivity and thawing heat which are same for any scale provided the material of construction, composition of substance being thawed and the thawing procedure are consistent.
These parameters are then incorporated into the thawing model for a commercial scale configuration (6 L bag) to predict the thawing time and temperature-time profile during thawing.
This model can also capture the change in liquid volume fraction with time and has the potential to accommodate both dynamic and static thawing

• Effect of physicochemical properties of API and excipients

• Implications of disproportionation on oral bioavailability
• Alternative formulation approaches

A major challenge with the development of salts of weakly basic compounds is its propensity to dissociate to the free base form in the drug product, which may impact the quality and bioperformance of the product. A significant number of compounds in the discovery pipeline are weakly basic so continued effort is required in this area to investigate and understand the key factors and formulation approaches to mitigate these risks. This presentation will highlight the mechanistic understanding and gaps in salt disproportionation utilizing multiple case studies as examples.