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.
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.
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.
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.
Majority of new drug candidates under development are poorly water-soluble. The amorphous state is of considerable interest since it confers higher apparent solubility and faster dissolution than its crystalline counterpart. However, being the thermodynamically unstable form, it runs the risk of crystallization leading to the loss of solubility advantage. In this presentation, we will discuss different approaches to predict the solid-state and solution state physical stability of the amorphous state with case studies
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
The blood-brain barrier restricts the brain delivery of most currently active anticancer agents used in the treatment of brain tumours. • The magnitude of this restriction is extremely large (50-200 fold) for some of the most commonly used agents cytotoxic agents (paclitaxel, doxorubicin, vinorelbine,) and newer molecularly-target agents. • In only a very small subset (<5%) of brain metastases is the barrier sufficiently compromised to allow marked drug accumulation. • This restriction was found in matching human brain metastases. • This drug delivery compromise can be overcome in brain metastases using several approaches, including drug agents which show poor affinity for barrier active efflux transport, enhanced barrier passive permeability, elevated active efflux, or molecularly targeting mechanism, such as those in using LRP, transferrin, insulin receptor, or other mechanisms.
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.
• 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
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.
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
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.
The BioPhorum Development Group (BPDG) is an industry-wide consortium enabling networking and sharing of best practices for the development of biopharmaceuticals. As part of the Formulation Point Share (FPS) activities, an inter-company collaboration exercise was performed with a focus on biopharmaceutical drug product (DP) robustness that included a bench-marking survey and extensive group discussions around the scope, design, and execution of robustness studies. The results of this industry collaboration reveals key common themes: 1) biopharmaceutical DP robustness consists of both formulation robustness and manufacturing process robustness; 2) robustness integrates the principles of Quality by Design (QbD); 3) DP robustness feeds into critical quality attribute (CQA) finalization, development of control strategies, and setting of commercial specifications; 4) most companies employ robustness studies, along with prior knowledge, risk assessments, and statistics to develop the DP design space; 5) studies are tailored to commercial development needs and the practices of each company. Three case studies further illustrate how a robustness study design for a biopharmaceutical DP balances experimental complexity, statistical power, scientific understanding, and risk assessment to provide the desired product understanding and process knowledge. Overall, the BPDG-FPS recognizes the industry challenges with regard to biopharmaceutical DP robustness, and presents some recommendations for best practices. This work may facilitate further industry conversations on biopharmaceutical drug development, with a favorable impact on industry alignment with regard to DP robustness studies. The manuscript is a composite view of opinions shared by the whole of the BPDG-FPS and should not be attributed to the individual positions of the companies.
siRNA is a powerful tool to control cellular processes at a post-transcriptional level. Although siRNA can be used as potential therapeutic agent for different diseases (including cancer), its therapeutic application is still limited because of its instability against nucleases and poor pharmacokinetics. With this in mind, we suggested a novel polymer-lipid-based approach to stabilize and deliver siRNA. We have modified a double-stranded GFP-siRNA with a phosphothioethanol (PE-SH) via the disulfide bond and prepare mixed micelles from such conjugate and polyethylene glycol-phosphatidylethanolamine (PEG-PE) conjugate in order to increase siRNA stability against nucleases and allow for siRNA liberation when inside cells because of the reduction of the –S-S-bond by high intracellular glutathione. siRNA-containing polymeric micelles have been shown to dramatically increase its stability against enzymatic degradation and were able to release free siRNA in the presence of glutathione. We have studied a silencing effect of such micelles after incubating it with C166-GFP endothelial cells. The siRNA-lipid conjugate-containing PEG-PE micelles were well taken up by cells resulting in strong down-regulating of the GFP production in C166-GFP endothelial cell line (50-fold more than the same quantity of the native siRNA. At the same time, the cytotoxicity of such preparations is very low. Similar results can be achieved by using PEG-polyethyleneimine-lipid conjugate for condensing and protecting siRNA. Resuting nanopreparations of siRNA can be used for therapy of multidrug resistant cancers by using siRNA down-regulating the production of proteins involved in cancer cell resistance. Furthermore, such preparations can be used for combination drug/gene therapy of such cancers.
Due to their physicochemical characteristics, peptides are usually administered through the parenteral route, often several times daily. Injectable sustained-release peptide formulations based on biodegradable microparticles or implants have been very successful to enhance patient adherence and convenience, and increase safety and efficacy. They are likely to remain a significant and important part of the new peptide products coming to the market. However, the tremendous developments in alternative non-invasive routes of delivery are likely to result in more and more peptides being delivered by the transdermal, nasal, inhalation and oral routes. The main purpose of this talk will be to analyze and compare the various alternative non-invasive peptide delivery technologies progressing in the clinic, discussing the pros and cons of these technologies in regards to stability, bioavailability, safety/efficacy balance, impact on costs of goods and manufacturability. A special emphasis will be put on oral peptide technologies progressing successfully in the clinic, the key learnings from ongoing clinical studies and the future challenges anticipated for filing and launching oral peptide products in the next years.
Enhancing bioavailability of therapeutic agents by the way of increasing their solubility is one of the commonly used pharmaceutical approaches. Incorporation of suitable permeation enhancers and excipients may be necessary to increase the bioavailability further, to deliver therapeutically required amounts of drugs. Sulfobutyl ether β-cyclodextrin has been known to form inclusion complex with water insoluble drugs to render them highly soluble. In addition to improving the solubility, Sulfobutyl ether β-cyclodextrin is also known to enhance the bioavailability of drugs by unique mechanisms that are attributable to its structure. A few case studies to demonstrate the influence of complexation with sulfobutyl ether β-cyclodextrin on the delivery of drugs via oral and topical routes will be discussed in the presentation.
This talk will provide an overview of Patheon’s Quadrant 2® platform for solubility enhancement of poorly soluble compounds. We have developed an in silico platform that utilizes the chemical structure of the API and known physico-chemical properties in order to guide the appropriate manufacturing Technology selection as well as excipient and formulation choices. The primary advantage of this approach is that it enables a faster, scientifically sound and cost-saving approach for formulation of poorly soluble drug molecules. Insights into navigating performance, stability and scale-up are presented via case studies
In recent years, there has been an increased demand for high concentration liquid antibody formulations to enable subcutaneous (SC) administration of therapeutic doses of antibodies or to facilitate a switch from a commercially approved, intravenously (IV) delivered product to a SC product for self‐administration from a pre‐filled syringe or autoinjector in a home setting. Achieving high concentration solutions of antibodies can be limited by high solution viscosity, presenting challenges for manufacturing, product stability, and administration. In this presentation, multiple case studies will be discussed that support strategies for developing high concentration antibody formulation products. Key development challenges include 1) optimizing stress conditions for high concentration formulations, 2) identifying viscosity reducing strategies and the impact on manufacturing process, and 3) defining a product viscosity profile using a DOE approach to select a formulation which meets delivery device requirements. The learnings from these specific case studies are generally applicable to any high concentration liquid antibody formulation development programs.
This presentation will focus on characterization of dissolution and partition profiles of poorly water soluble drugs and related formulations using a biorelevant two-phase dissolution-partition test. This test is designed to evaluate the dissolution of BCS II/IV drugs in an aqueous, biorelevant compartment that allows physiologically relevant pH changes with simultaneous partitioning (absorption) into a water immiscible organic phase. Case studies will be presented to demonstrate the utility of this method for evaluation of the super saturation and its relevance to in vivo exposure in humans. The presence of the “absorptive phase” in this the two-phase test appears to overcome shortcomings of conventional single-phase in vitro dissolution methods and therefore presents a great opportunity for establishing quantitative IVIVC in drug product development.
Two of Wyatt’s light scattering tools contribute major productivity enhancements in a biopharmaceutical setting, greatly increasing the speed of analysis without sacrificing sensitivity: the µDAWN and DynaPro Plate Reader II.
Vaccination saves millions of lives each year, hence it is extremely important to maintain thermal stability and immunogenicity during manufacturing and cold chain storage of vaccines.
Enhance vaccine product stability is a very challenging task for all formulation scientists. In the past, freeze drying is often used in vaccine industry as gold standard to stabilize labile products. However, freeze dry process can damage those vaccine products with freezing sensitive component(s) such as Aluminum salt(s) adjuvant and emulsions. To avoid this issue, spray dry can be a great potential alternative strategy. It is successfully demonstrated that the feasibility of applying spray dry technology to stabilize different type of antigens and freezing sensitive adjuvants. The dried products were characterized using a panel of assays. The data suggested product stability, antigen potency and adjuvant functionality were well maintained.
Supersaturating drug delivery systems (SDDS) such as amorphous solid dispersions and lipid-based formulations have been successfully used to enhance oral bioavailability of poorly water soluble compounds. However, in general, it has been challenging for pharmaceutical scientists to characterize these systems to establish a good in-vitro and in-vivo performance relationship. The supersaturation maintenance of SDDS is highly dependent on the complex interplay between pH, solubility, degree of supersaturation, high energy forms of drug and their interactions with excipients such as polymers and surfactants. Recent studies have focused on understanding various aspects of this complex interplay of biopharmaceutical factors. This talk will focus on the recent advances in the development of SDDSs and their application in bioavailability enhancement. It will highlight novel in-vitro, in-silico, and in-vivo methodologies to characterize the biorelevant performance of SDDS. The benefits and limitations of SDDS and their characterization methods will also be discussed
Antibody-drug conjugates (ADCs) manufactured with hydrophobic cytotoxic agents are significantly different in their biophysical properties than the corresponding unconjugated monoclonal antibodies (MAb). The hydrophobic cytotoxic agents may lead to non-specific interactions with materials used in drug delivery systems (e.g. intravenous administration sets, in-line filters, tubing, bags). Solubility in common diluents (e.g. saline or dextrose solutions) can be limited resulting in precipitation or surface adsorption. This presentation will discuss several case studies about compatibility of ADCs with a variety of commercially available infusion set materials. The challenges and approaches related to testing and compatibility assessment of the diluted ADCs will also be presented.
Many small molecule drugs developed in the pharmaceutical industry exhibit poor aqueous solubility and are difficult to formulate for parenteral administration. Since early pre-clinical studies for efficacy evaluation often require parenteral formulations, solubilization approaches using strong co-solvents are often used, causing toxic side effects. Nanoparticles offer a safer, fit-for-purpose parenteral formulation platform for drug solubilization to support early screening of these molecules. As interest in this platform has increased, the use of efficient fabrication methods and technology for nanoparticle production has become an important aspect of their pharmaceutical development. This presentation will show the effects of different nanoparticle fabrication methods and composition on resulting nanoparticle physical properties. Case studies using poorly soluble model drugs will be shown with various nanoparticle formulations.