Global Drug Delivery Formulation Summit

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Biologics
Small Molecules
Device Development
Technology & Innovation

7:40 AM - 8:40 AM

Registration & Refreshments.

8:40 AM - 8:50 AM

Chair's Opening Remarks

8:50 AM - 9:25 AM - Keynote

Biologics

How Next-Generation Biotherapeutics will Influence Formulation and Device Development

In the last couple of years the development of Biotherapeutics moved away from standard monoclonal antibodies to more complex formats, which led to the need of miniaturized and high throughput screening systems in the early stage of formulation development. Also the need for predictive tools like in-silico today plays an important role in the formulation development. At the same time the need for patient self-administration got to play a very important role, not necessary limited anymore to a few indication areas. Based on novel constructs the probability for high concentrated formulations might be limited and therefore high volume devices are taking a more important role. Also co-formulations of multiple monoclonal antibodies into a single drug product brings certainly convenience to the patients, however brings also the need for new analytical methods. At the same time it can also be observed a trend to advanced therapy medicinal product (ATMPs), which is a new area and the pharmaceutical development of such compounds is challenge.

9:25 AM - 9:30 AM

Please Move to your Next Session

9:30 AM - 10:05 AM - Case Studies

Small Molecules

Optimisation of Industrial Freeze Drying Cycle - Two Real Life Examples

Comparing two dated lyophilized products (60’s) with historical cycles that exhibit distinct complications
Development and optimization of manufacturing processes to overcome the lack of physical chemistry data from dated products
Applying product knowledge, new freeze dryer knowledge, simulation and process modelling

Device Development

Facilitating Meaningful Differentiation of Products by Establishing a Culture of Innovation

Facilitating meaningful differentiation of products by establishing a culture of innovation:

Challenges specific to the area of rare diseases
Case study on fostering a culture of innovation
Approach & Guiding Principles
Selected examples of how building on existing platforms allows to differentiate existing products and deliver value to the patient
Observations & take aways

Technology & Innovation

Parenteral Sustained Release of Peptides – Getting It Right

Parenteral depot formulations are often characterized by a relatively high degree of complexity. Hence, getting formulation and device as well as manufacturing processes right is far from trivial despite the long history in this field dating almost 90 years back to the first protacted insulin protamine formulations.

Technology landscape for parenteral depot formulations of peptides and proteins
Driving and blocking factors for making the perfect match between active and sustained release technology
Strategies for developing parenteral sustained release formulations (drug delivery by design)
Examples of studies from formulation development
Future directions within parenteral sustained release of peptides and proteins

Biologics

In-Silico Modelling to Support Protein Formulation Development

• Challenges with protein therapeutics

• In-silico modelling and molecule design

• Current approaches to support developability

• Some real cases

10:05 AM - 10:10 AM

Please Move to your Next Session

10:10 AM - 10:45 AM - Case Studies

Technology & Innovation

2D Inkjet Printing for Patient Centric and Translational Drug Delivery

Inkjet printing of drug formulation for oro-mucosal and gastro-intestinal drug delivery
Flexibility and technological limitations of inkjet-printed formulations
Solvent selection and ink development approach integrating formulation and jettability considerations for printing amorphous solid dispersion on to the edible substrate
Demonstration of dose escalation by tailoring process parameters and substrate properties for film-foldability
Hyperspectral imaging as an exploratory tool for non-destructive drug content and homogeneity analysis of the inkjet-printed formulations

Device Development

Drug Delivery Devices for Innovative Parenterals and Biosimilars: Patient-Centered Technical and Business Opportunities

Innovative Biologics versus Biosimilars - understanding and delivering on emerging customer needs
Smart devices – who is the customer
Changing biologics portfolios inline with new device technologies
Intravitreal injections as special challenge with recent advancements

Small Molecules

Nanoparticle Formulation Development: A Closer look at Pharmaceutical Fabrication Methods

Nanoparticle formulation for drugs with poor aqueous solubility
Comparison of polymer nanoparticle fabrication methods and composition
Effect of nanoparticle fabrication method and composition on nanoparticle physical properties

Biologics

More Than Just Down-Scaling – Miniaturization of Methods in a High-Throughput Setting Requires Creative Concepts and Holistic Thinking

Formulation screening
Biotherapeutics
Robotics
Analytics & stress assays

10:45 AM - 11:45 AM

iSolve & Networking Break

11:45 AM - 12:20 PM - Case Studies

Biologics

Mind the Gap - How to Assure Data Integrity in a High-Throughput Formulation Screening for Biotherapeutics

Data handling
Data evaluation
Formulation screening
Biotherapeutics

Small Molecules

Polyoxazoline: A Potent Alternative to PEG-based Formulations of Hydrophobic Drugs

Chemistry of Polyoxazolines (POx)
POx as a double amphiphile
Toxicity, immunogenicity and endocytosis of POx
POx conjugates
POx for the formulation of strongly hydrophobic drugs
POx nanoformulations: Preparation, stability, profile
Preclinical evaluation of POx nanoformulations vs. commercial formulations
Perspective

Polyethylenglycol (PEG) is still the gold standard for many polymer therapeutics (drug-polymer or protein-polymer conjugates) and PEG-containing polymer amphiphiles are widely used for the solubilization/formulation of hydrophobic drugs. This is because of early reports of the “stealth-effect”, advantageous biocompatibility and low immunogenicity of PEG. However, the widespread use of PEG and PEG-derivatives not only in therapeutics but in cosmetics, body care products, food additives and countless technological applications results in a constant exposure of humans to PEG. A constant growing number of reports evidence that the immune system can produce antibodies that specifically bind to PEG and an “accelerated blood clearance” (ABC) leads to failure of PEG-based therapeutics. Thus, there is an urgent need for alternative polymers with a similar or even better pharmacological profile. One of those is polyoxazoline (POx) for which the same “stealth-effect” was early reported. This talk will briefly outline the chemistry, toxicity and immunogenicity of POx and then focus on the use of amphiphilic POx as an exipient for the nanoformulation of strongly hydrophilic drugs. Besides unparalleled drug loading capacities of POx-based nanoformulations, long-term stability and facile formulation procedure, results of the preclinical evaluation of POx-based nanformulations for the treatment of cancer will be presented.

Technology & Innovation

Development of Polymeric Nanoparticles for Intravenous Administration

Formulation optimisation, physical & chemical composition analysis
Developing a robust manufacturing process
Biopharmaceutics & critical quality attributes

Device Development

A Self Anchoring Microneedle Patch (StAMP) Offering Precise and Sustained Transdermal Drug Delivery

Development of StAMP which offers precise skin penetration and sustained mechanical adhesion
Comparison of conventional microneedle with StAMP
Formulation assessment of drug coatings on StAMP
Exemplary delivery of high molecular weight, protein drugs using StAMP

12:20 PM - 12:25 PM

Please Move to your Next Session

12:25 PM - 1:00 PM - Solution Spotlights

Small Molecules

New Surfactants in Wet Ball Milling and an Innovative Embedding of Nanocrystals into a Granulate Matrix

Key words: screening methods, DoE, wet ball milling, nanosuspensions, granulation, dissolution

The Nanocrystal Technology by wet ball milling is getting more and more interest and importance for experts in formulation screening, tox study and clinical trial sample supply for low soluble API´s with a problem in bioavailability. The reason is a fast set-up and scale-up of the manufacturing process, the easy application of the liquid Nanocrystal formulations in such studies and the available down-processing possibilities to come to the final dosage form (capsules, tablets, stickpacks). Losan Pharma has invented in a cooperation a new and fast screening system for nano-milling which has meanwhile reached commercialisation (Zentrimix 380R® from Hettich Labs, Germany). In order to widen the application of the Nanocrystal system new surfactants with improved toxic and hemolytic properties in comparison to the reference sodium dodecyl sulfate (SDS) have been used with a model drug substance to evaluate their potential as stabilisers in the Nanocrystal suspensions. As SDS is very limited in use due to its toxicity especially for tox studies or parenteral applications new surfactants need to be developed to improve this situation. In addition a new down-processing approach is presented to embed the obtained Nanocrystal suspensions via a extrusion like process into a granulate (with the possibility of a continuous granulation) and a comparison has been made to the conventional fluid bed spray drying process which has been implemented before.

Biologics

Trehalose and Sucrose: Essential Components of Platform Biopharma Formulations

Commercial Biotherapeutics Stabilized with Trehalose
Commercial Biotherapeutics Stabilized with Sucrose
Key Issues in Biopharma Formulation Development
Essential components of a “Platform Biopharma Formulation”
Understanding important physicochemical properties of Trehalose and Sucrose
- Instability of sucrose at low pH – free glucose, protein glycation
- Phase transition and crystallization of trehalose

Purity, Quality, Consistency in Pfanstiehl’s Trehalose and Sucros
- β-glucans in sucrose – interference with endotoxins
- Trace metal specifications for Sucrose and Trehalose

Advantages of Trehalose over Sucrose
Pfanstiehl’s Biopharma Stabilization Portfolio

Technology & Innovation

Oral Thin Films – Tailoring Therapy Need

Oral drug delivery technologies form an important part of the pharmaceutical industry representing the largest share of the overall market. In particular oral transmucosal drug delivery systems have recently gained a lot of attention. One of the key driving factors is the preference for non- invasive routes of drug delivery. Although oral thin films have been available in the forms of breath freshening strips, vitamin strips and other over-the-counter products for the past two decades, pharmaceutical companies have recently directed their focus towards formulating prescription products into oral thin films.

Oral mucosal drug delivery provide several advantages over traditional oral drug delivery methods such as the ease of self-administration, increased bioavailability, rapid onset of action, no water required and improved patient compliance. Oral thin films provide fast accurate dosing and are expected to increase compliance, especially among elders and children. Given the specific advantages offered by these films and their ability to overcome the current unmet needs, the future holds significant potential.

This presentation will show the components and science of OTFs and how it can be used to provide a genuine alternative to current drug delivery methods – and be considered as a genuine alternative dosage form.

Features and benefits of using OTFs to address disease areas will be discussed, highlighting the market potential and increased market share associated with the development of the product.

Device Development

Rubber Components Selection for Optimal Drug Packaging

Composition of rubber components
Extractables and leachables from rubber
Fine tuning of rubber composition to adapt to the rubber use

When a drug packaging is selected a particular attention is needed for the selection of rubber products. Indeed, a wrong choice of such products can lead to the compounds not performing according to the expectations, high amount of leachables or even incompatibility with the drug resulting in failed stability study.

Several topics will be discussed, starting from the rubber composition and its impact on extractables. Over the years, rubber formulation have changed to reduce the amount of products leaching from the rubber. This phenomenon can be further reduced by applying a coating on the rubber.

Finally, the rubber composition can be further tuned depending on the intentional used. For examples, rubber products for lyophilized drugs have been optimized for fast drying. Whereas rubber products for needle shield need to be permeable to EtO gas to ensure a sterilization of the drug packaging.

1:00 PM - 2:00 PM

Networking Lunch

Lunch & Learn Round Table with ADM SIO

Management of Contaminants in Plant based Excipients

Example of vegetable oils
Composition of vegetable oils
Undesirable compounds : Contaminants from culture origin & Process Origin

Special focus on the contaminants generated by the process : Glycidyl fatty acid esters

Management of these contaminants by process control (importance of GMP)

Moderated by: Stephanie Bureau, R&D Director, ADM SIO

Hervé Limouzin, Sales & Marketing Manager, ADM SIO

2:00 PM - 2:35 PM - Case Studies

Small Molecules

Inhalable Dry Powders for the Improvement of Lung Pharmacokinetics in Preclinical in-vivo Experiments

The pharmacokinetic profile of NCEs administered by the inhalation route depends on multiple factors, including the physico-chemical properties of the formulation, especially when the NCE is delivered as a powder. In this case, solubility of the compound may influence its bioavailability, efficacy and safety. Compound A reported in this study is a NCE designed for inhalation for the treatment of respiratory diseases. Good in vitro pharmacological and ADME profile supported the progression of the compound to in vivo evaluation. Intratracheal administration to rodents as a blend of crystalline micronized API resulted in a lung half-life longer than 120 hours and limited systemic exposure, suggesting that the lack of reproducibility observed during the in vivo PD tests was mainly due to the low solubility of the powder. In light of these data, two different formulations were investigated in order to increase the solubility of Compound A: 1) conversion of the crystalline API in amorphous powder by a lyophilization process, and 2) formulation of composite particles including Compound A with mannitol and DPPC by spray-drying of a solution. The crystalline micronized material, the amorphous powder and the spray-dried formulation were administered intratracheally to rats using the innovative PreciseInhale system.

The formulation of Compound A with mannitol and DPPC showed shorter lung t1/2 (19 hours), compared to amorphous (t1/2 = 44 hours) and crystalline API (t1/2 > 120 hours). Systemic exposure was comparable between the amorphous-based formulations and 10-fold lower for the crystalline powder. Moreover, a good correlation was found between lung PK parameters (lung t1/2, lung MRT) of the administered powders and their dissolution profile determined in simulated lung fluid.

The results obtained suggested that the spray-dried formulation with DPPC and mannitol represents a useful platform to overcome solubility issues of poorly water-soluble compounds during in vivo PD experiments and it could be extended to other poorly water-soluble molecules, in order to investigate their real efficacy in vivo and avoid discarding promising compounds due to sub-optimal powder characteristics.

Biologics

Long Recombinant Homogeneous Linkers for Dual Protein Conjugations, to Replace Heterogeneous PEG

Dual protein conjugations
Orthogonally reactive linkers
Long homogenous linkers
Yeast expressed chemical linkers

Polyethyleneglycol (PEG) linkers are the classical tools for linking peptides and proteins, for example to other biomolecules or spectroscopic probes.

In some cases long linkers (> 5 kDa) are preferred for steric reasons or for pursuit of avidity effects, but available PEG linkers longer than 5 kDa are heterogeneous.

Long XTEN linkers (mixed sequences of GEDSTAP residues giving PEG-like properties) have been described with dual functionalities, thus enabling cross-linking of proteins etc.

However, XTEN sequences are rich in Ser and Glu, and we found that Ser/Glu have drawbacks for our use. Our main expression platform is based on yeast, and sequences with multiple Ser get partially O-mannosylated during yeast expression, thus leading to heterogeneous products. Also, we find that multiple Glu in linkers can increase the viscosity of solutions when high protein concentrations are needed, probably due to charge repulsion of multiple Glu's, and thus relatively stiff linkers. To solve these problems, we designed linkers based on repeats like (GQAP)n. Such sequences could be expressed as either long extensions from proteins (proteins with "recombinant PEG"), or (GQAP)n could be equipped with orthogonally reactive terminals to be used as linkers for dual conjugations.

We exemplify this with H-(GQAP)49-GQEP-Cys (MW 17848), which we expressed in high yield in yeast. The isolated product had mixed disulfides at Cys (paired with free Cys, glutathione or as homodimer), but we transformed the mixture to a material with homogeneous disulfide using excess 4-mercaptophenylacetic acid (64-69 % yield). The N-terminal amine was then transformed to azide (74-85 %), the disulfide was reduced to free Cys (60-86 %), and the dually reactive linker was conjugated to iodoacetyl-insulin in one end (Cys alkylation, 44-52 %), and conjugated as triazole in the azido end, to a trypsin inhibitor with alkyne functionality (47 % yield). Data for enzymatic stabilization of the insulin-trypsin inhibitor conjugate will be reported comparing to simple insulin/trypsin inhibitor mixtures. The described linkers could find broad use in dual peptide/protein conjugations.

Technology & Innovation

DNA-Based Nanoassays for Biomarker Detection in Liquid Biopsy and Therapeutic Drug Monitoring

We developed multiplexed nano-immunoassays based on the nanografting of short single stranded (ss) oligos on gold thin films and the DNA-directed bioaffinity binding of the complementary DNA sequences conjugated to specific protein markers/protein binders, to detect circulating biomarkers from non-invasive liquid biopsy. An atomic force microscope is used to quantify the biomarkers by detecting with high sensitivity the topographic height changes at the nanospots. As an example, we are applying such devices to the quantification of the shed extracellular Her2 fragments in the serum of Her2-positive tumor patients and correlate the measured Her2 levels to the progress of the disease. To bind Her2, antibodies and nanobodies (single domain antibodies) from camelid as well as from recombinant origin were used, optimized for high affinity binding in silico (Dr. Sara Fortuna, University of Trieste). Nanobodies selective for different Her2 fragments derived by proteolitic cleavage and by alternative splicing of Her2, respectively, are being produced and soon tested on the nanoassay. As another example, the monitoring in serum of the level of a Infliximab, a therapeutic Anti-TNFα drug, in the treatment of pediatric inflammatory bowel diseases (IBD).

A similar strategy for surface biofunctionalization based on the grafting of ssDNA and on DNA bioaffinity immobilization has been developed and optimized also on gold nanoparticles (AuNPs). We created a controlled assembling of AuNPs in solution and monitored in real time the disruption kinetics of NPs aggregates upon loading of a helicase enzyme, by means of a simple colorimetric assay (AuNPs of different size absorb light with different frequencies). Such assay can be used to test enzyme inhibitor efficacy by comparing enzyme kinetics with and without inhibitor. A proof of concept of this strategy has been given for the RecQ helicases, whose inhibition reinforces the efficacy of chemotherapy agents.

Device Development

Predicting the Future: Learning about Challenges with Injectable Formulations to select better Primary Packaging

When the packaging becomes more than just a container closure system
Selection of primary packaging platforms from various options available in the market
Case studies of challenging formulations with primary packaging
Current directions for understanding drug container interactions

2:30 PM - 2:40 PM

Please Move to your Next Session

2:40 PM - 3:15 PM - Solution Spotlights

Small Molecules

The Perks of a One Stop Shop: From Low Solubility APIs to High Performance Formulations

Close to 90% of drugs coming out of the drug discovery pipeline, have solubility limitations translating to poor bioavailability, which may ultimately result in clinical failures. Amorphous solid dispersions (ASDs) are an established platform to address bioavailability challenges due to low aqueous solubility. The complexity of ASD development, added to the concerns on physical stability, pose as perceived risks, however, the clinical and commercial success of ASD-based formulations stands as driving force: to date, 24 FDA-approved therapies are commercially available

This presentation will address the main challenges in the formulation of ASDs, and highlighting the importance of integrated development and the synergies between pre-formulation and commercial manufacturing expertise. The science-based development platform for ASDs will be presented. This platform relies on the integration between formulation and analytical development, from API to drug product, coupled with the use of computational models, formulation databases and miniaturized high-throughput in vitro techniques.

Small Molecules

How do I Quickly Develop First-in-Human (FIH) Dosage Forms and Bridge to Drug Products for Proof-of-Concept (POC)?

Choosing the appropriate dosage form for first-in-human/Phase I trials – fit for purpose, fit for phase?
Compounding or GMP manufacturing – how to balance cost, time and dose flexibility?
Challenges with poorly soluble molecules in early development – what technologies can we deploy?
Bridging to robust and scalable Phase II drug products – how to avoid losing time in development?
Highly flexible and adaptive clinical manufacturing strategies for patient trials – how can real-time manufacturing be used?

Small Molecules

Simplifying Tablet Formulation Strategies with Avicel® SMCC and METHOCEL™ DC2

Excipients play an important role for the development of streamlined and improved production processes like direct compression and continuous manufacturing of tablets.
Avicel® SMCC is a silicified microcrystalline cellulose derived from co-processing MCC and colloidal silicon dioxide (SiO2). The co-processing yields in a high-functional excipient that exhibits performance attributes unmatched by a simple blend of MCC and SiO2 like optimum flow, superior compactability, and excellent binding properties. It is therefore the binder of choice for direct compression and continuous manufacturing.
METHOCEL™ DC2 is a pure Hypromellose for sustained release matrix tablets which was engineered by designing the particles morphology to improve flow without the use of additives or additional granulation steps.
In case studies the benefits of Avicel® SMCC and METHOCEL™ DC2 for enhanced productive processes for immediate and sustained release oral solid dosage forms are shown.

Device Development

Combination Products – Global Regulatory Landscape

This presentation will introduce the global concept of “combination Product” and it’s understanding per different regions’ regulatory perspectives. It also covers the latest status of the evolving combination product regulatory landscape of relevant regions. Challenges resulting from global regulatory divergence are highlighted as well as risk mitigation strategies.

3:15 PM - 4:15 PM

iSolve & Networking Break

4:15 PM - 4:50 PM - Case Studies

Small Molecules

Understanding Material Properties for HME Process Optimization in ASD Formulations

Demonstrate connection between ASD thermodynamic properties and HME manufacturing process
Application drug/polymer phase diagram as a tool for HME risk assessment
Demonstrate correlation between drug/polymer phase diagram, drug load, rheology, and HME process.
Correlating drug product CQA (residual crystallinity, chemical/thermal stability) to drug/polymer phase diagram and HME process parameters

Biologics

Root Cause Investigations for Visible Particles and Aggregation in Drug Containers – Case Studies

The first case study will describe root cause investigations to identify a novel cause for visible particles in polysorbate containing formulations
For root cause investigations unconventional approaches may be more successful than the beaten path
Broad unbiased screening may be necessary to identify novel causes for unexpected results
In a second case study inorganic leachables from a sterile filter were identified as cause for aggregation/particle formation
This highlights the importance of a broad method portfolio for characterization of dimers/aggregates/particles and to successfully investigate the root cause of aggregate formation
The described findings might be relevant in general for biologics drug product development and will contribute to the improved quality of biopharmaceuticals

Technology & Innovation

New Generation of Safer Drug-Eluting Mesh Implants by Electrospinning and 3D Printing

Development of rapid manufactured and systemic release systems.
Electrospinning and 3D printing in Drug Delivery and Tissue Engineering applications.
Mesh implants.
Nano-CT & TOF-SIMS Characterisation and Imaging.
Prevent biofilm formation on implants.

The current mesh implants are composed of polypropylene (PP), polyethylene terephthalate (PET), expanded polytetrafluoroethylene (ePTFE) and polyvinylidenefluoride (PVDF). Mesh implants have been widely used, but given the number of complications associated with mesh insertion, and the recent media coverage relating to the lawsuit against Health Services worldwide, pursuing research for the development of a new generation of mesh inserts is now of the utmost importance for the future of patient care and recovery. Potential mesh-related complications include chronic infections, chronic pain and mesh rupture. There is a need to have a mesh implant that is softer with characteristics that resemble native muscles, and on the same time reduce the risk of infection, with bespoke production for cost reduction. Moreover, the mechanical properties of the mesh and the compatibility between the materials and the tissues are critical in healing. These limitations stimulate research into new methods of fabrication (e.g. 3D printing and Electrospinning), and by incorporating biomaterials and drug encapsulation in these mesh matrices. The particular case will focus on the preparation of drug-loaded polymeric meshes for Drug Delivery and Tissue Engineering applications. The purpose of this study is to examine any potential effects, chemical and mechanically, of drug-loaded electrospun & 3D printed scaffolds. The meshes were characterized through various advanced characterization techniques (e.g. Bio-AFM, ToF-SIMS, NanoCT) and methods in order to measure the drug efficacy and antibacterial properties, and investigate any changes in mechanical and chemical properties and drug-polymer interactions.

Take Home Message:

By using new technologies (e.g. electrospinning and 3D printing), in the future, the doctors will be able by scanning an area to request each time an accurate mesh implant that could be potentially prepared in hospitals by trained staff with the intention to have a bespoke production that is patient focused in the hospital / locally.

Small Molecules

Solid Lipid Solutions as Formulation Platform for Poorly Soluble Drugs

Vast majority of new active pharmaceutical ingredients (APIs) entering development pipeline from discovery possess insufficient water solubility and/or low dissolution rate. These cause challenges in achieving desired bioavailability.

Formulating API as a lipid-based formulation is often taken as approach to achieve desired bioavailability. This is achieved mainly by enhancements in drug solubilization and dissolution rate. In addition, LBF can stimulate intestinal lymphatic drug transport (thereby reducing first-pass metabolism), and merging evidence suggests a potential role for components of LBF (primarily surfactants) in the inhibition of intestinal efflux and metabolism. Most common way to formulate the LBFs is soft capsule approach where API is dissolved or suspended in liquid vehicle. However, using a semi-solid or solid carrier to form solid lipid solution (SLS) can offer many advantages such as possibility for manual filling at small scale in lab environment for purpose of pre-clinical and early clinical studies. Selection of excipients for SLS is made based on automated solubility screening of API in solid lipid excipients. Combination of these two techniques significantly reducing time and cost for development and manufacturing of pre-clinical and early clinical formulation of ‘difficult-to-formulate’ compounds.

4:45 PM - 5:20 PM - Case Studies

Small Molecules

Session TBC (Janssen)

Biologics

Emerging technologies to aid formulation development

Technology & Innovation

Overcoming Barriers of Acetylcholinesterase Inhibitors for Alzheimer’s Disease

Reasons for the continued success of Acetylcholinesterase inhibitors as NCE
Most common issues with solubility and low bioavailability
Crossing the Blood Brain Barrier

Device Development

Dealing with the Changing Regulatory Landscape around Combination and Medical Devices

Challenges of developing combination products through a changing regulatory landscape.
Working across boundaries to achieve common goals.
Case study on the review of human factors protocols by regulators.

4:50 PM - 4:55 PM

Please Move to your Next Session

4:55 PM - 5:30 PM - Keynote

Biologics

Challenges and Opportunities for the next Generation of Oral Peptide Delivery

A patient-centric approach and the patient benefits of oral drug delivery of peptides
Current development challenges
Outcome of current oral drug delivery technologies
Why have so few technologies reached the market?
Science based selection process of drug delivery technology
What the future holds?

5:30 PM - 5:35 PM

Chair’s Closing Remarks

5:35 PM - 6:35 PM

Drinks Reception

8:00 AM - 8:45 AM

Registration & Refreshments

8:45 AM - 8:50 AM

Chair's Opening Remarks

8:50 AM - 9:25 AM - Keynote

Small Molecules

Drug Delivery – Recent Technology Trends and Solutions

What is new – recent market entries of drug delivery products incl. generics
Patient centric development with focus on children and the elderly e.g. mini tablet dispenser
Unmet need in parenteral drug targeting (focus on brain, solid tumors)
Progress in continuous manufacturing technologies (tablets & lyo)
Oral delivery of peptides and beyond
Data as an asset from F.A.I.R. data format to augmented intelligence

9:25 AM - 9:30 AM

Please Move to your Next Session

9:30 AM - 10:05 AM - Case Studies

Small Molecules

Modelling and Control of Fluid Bed Granulation Processes

Fluidized bed processes are a complex equilibrium between thermodynamics, hydrodynamics and atomization.

A simple model based on mass and heat balances on the equipment is proposed to find the perfect alchemy to control granulation, coating and drying processes in Fluidized bed.

3 cases studies:

Application to a granulation process
Application to a coating process
Application to a drying process

Biologics

Design of Long-acting GLP-1 Analogs Applicable for Once Weekly and Oral Dosing

The discovery journey towards once week semaglutide
Preclinical and clinical data
The ambitious challenge to oral delivery of semaglutide

Technology & Innovation

Insights in Protein-Protein Interactions at High Protein Concentrations: The Relevance of Surrogate Parameters

The differences with crowded solutions
Protein-protein interaction and colloidal properties
The significance of surrogate parameters
Relevance for drug product development

Device Development

MDR – Notified Body Opinion – Article 117

The number of drug delivery devices, also known as ‘combination products’, entering the global market has grown significantly due to advances in medical technology as well as an increase in user demand. While these products have benefited millions of patients and hold great promise for the future of healthcare treatment, bringing them to market still involves a number of regulatory challenges, particularly within the European Union (EU). This presentation will discuss how a drug delivery device (e.g. prefilled syringe, on-body injector) is currently regulated within the EU as well as the impact of the new Medical Devices Regulation (Reg. 2017/745). In particular, the impact and challenges of the Notified Body Opinion requirement (Article 117) for prefilled devices will be discussed from an industry perspective

10:05 AM - 11:05 AM

iSolve & Networking Break

11:05 AM - 11:40 AM - Solution Spotlights

Small Molecules

Reactive Twin-Screw Melt Extrusion in Drug Delivery

Two case studies to illustrate the reactive between drug and excipients during twin-screw melt extrusion to improve the quality attributes of melt extruded amorphous solid dispersions. In the case of meloxicam, the presence of meglumine improves the chemical stability of meloxicam and enhances its dissolution rate. In the case of naproxen, the presence of meglumine enhances its physical stability of naproxen and enhances its dissolution rate.

Biologics

Hydroxylpropyl ß-cyclodextrin: A Promising Excipient for Protein Stabilization

Formulation challenges in drug development of biologics
What is hydroxylpropyl ß-cyclodextrin and its role in protein stabilization
Case studies of KLEPTOSE®HP/HPB in various therapeutic protein formulations: Two-prong approach to establish correlation between high throughput screening and conventional chromatographic methods

Protein stability is a major challenge to overcome during manufacturing, upstream and downstream processes, formulation, transportation and storage of biopharmaceuticals. Proteins may aggregate during these activities in addition to chemical changes. Aggregation is often irreversible leading to inactive and potentially immunogenic species, resulting in to reduced efficacy and toxicity to patients. Formulation development involves selection of appropriate excipients to stabilize the protein drugs throughout its recommended shelf life against potential excursions in its life cycle and aid in the delivery of therapeutics into the patient. While role of many excipients in the stability of formulation is well documented, scares information is available on role of Cyclodextrins in stabilization of therapeutic proteins such mAbs. Cyclodextrins play a vital role in reduction of interfacial tension with the environment and hydrophobic interactions among the protein molecules. In the present study stabilizing effects of novel Cyclodextrins, KLEPTOSE® HPB and HP in various therapeutics protein formulations have been investigated. Physical-chemical stability was influenced under different stress conditions such as thermal and agitation for monoclonal antibodies and human growth hormone. We employed a two-prong approach, high throughput screening and conventional chromatographic methods to establish validation. This study provides insight in to both methodologies to understand interplay between protein and surrounding environments. We attempt to provide role of novel Cyclodextrins to reduce aggregation and develop therapeutically effective and safe protein formulations.

Technology & Innovation

Solid Dosage Forms for Heterogeneous Patient Groups: Challenges and Solutions

In the frame of patient centric approach, formulators are dealing with different solid dosages forms like mini-tablets or oral dispersible tablets. For those forms the standard manufacturing or analytical processes aren’t always suitable.

The presentation will review common challenges and provide solutions based on cellulose derivatives for administrating medicines to heterogeneous population in terms of:

- Mini-tablets:

o   Coating of mini-tablets

o   Taste masking formulations and analysis

- ODT:

o   Content of uniformity with low dosage API

o   Analysis of ODMT

-Bi-layer tablets formulation

Device Development

Platform for Change and Improved Patient Experience

The enFuseTM platform, an on-body drug delivery system, is a unique technology being developed for patient self-administration of high-volume biologic drugs from 5 - 50mL. The system is designed with novel features to provide comfort, convenience and simplicity for the patient. Some of these unique features will be discussed in terms of their impact on patients, drug development and the overall healthcare landscape.

11:40 AM - 11:45 AM

Please Move to your Next Session

11:45 AM - 12:20 PM - Case Studies

Small Molecules

Small is the New Big: Case Studies of two Nanotech Products from Lab to Market

Self-assembly strategies for insoluble drug delivery
Fast disintegrating particles in bio-systems
Uncompromised pharmacokinetics, safety and efficacy
Data package bridge enabling approval
IP protection

Take Home Message: Critical role of drug delivery technology in differentiation without

Abstract:

Poor aqueous solubility is the most trivial looking problem in the pharmaceutical world. The sheer number of technologies reported in literature is mind boggling. The space has become increasingly crowded with hundreds of buzz words. The challenge is to navigate through those complexities and constraints to derive a new idea that translates to a product. Another challenge is also to protect the scope of the idea i.e. creating reasonable space within the narrow space. The presentation will cover case studies of two nanotechnologies, one from the oncology and the other from ophthalmology space which has successfully navigated a path from ideation to the market passing through stringent or moderately stringent toxicology and clinical tests. Technologies are quite different yet based on common knowledge of physical chemistry driving the self-assembly phenomenon. Both of them solve solubility problem yet are distinct in their application and approach to solve patient compliance problem.

Biologics

Challenging Transfer of a Fill & Finish Process for a Highly Fragile Bispecific mAb

Utility of extensive comprehension of the mAb aggregation law
Set-up of a temperature control process to prevent aggregation
Impact of temperature variations on fill weights during Time-pressure filling

Device Development

Micro Array Patches: Delivering High Drug Doses Transdermally

This presentation describes production of unique microneedle array patches prepared from crosslinked poly(methylvinylether-co-maleic acid) which contain no drug themselves. Instead, they rapidly take up skin interstitial fluid upon skin insertion to form continuous, unblockable, hydrogel conduits from attached patch-type drug reservoirs to the dermal microcirculation. Importantly, such microneedles, which can be fabricated in a wide range of patch sizes and microneedle geometries, can be easily sterilised, resist hole closure while in place and are removed completely intact from the skin. Delivery of macromolecules is no longer limited to what can be loaded into the microneedles themselves and transdermal drug delivery is now controlled by the crosslink density of the hydrogel system rather than the stratum corneum, while electrically-modulated delivery and the potential for minimally-invasive extraction of skin interstitial fluid for monitoring purposes are also unique features. This technology has the potential to overcome the limitations of conventional microneedle designs and greatly increase the range of type of drug deliverable transdermally, with ensuing benefits for industry, healthcare providers and, ultimately, patients. A second important technology to be described here is high dose dissolving microneedles, used to deliver long-acting nanoparticles into the viable skin layers for sustained administration of clinically-relevant doses over weeks or months. This technology has clear utility in prevention and treatment of HIV, contraception and management of schizophrenia, amongst several other indications.

Technology & Innovation

Challenges and Opportunities to Include Patient Centered Design in Industrial Drug Development

Challenges and opportunities: An industry in transition
Patient focus: The needs to get to the future state
Roadblocks in drug development
Patient centricity: Impact on drug product development
Lessons learnt from pediatric drug product development
Examples, Conclusion and Outlook

12:20 PM - 12:25 PM

Please Move to your Next Session

12:25 PM - 1:00 PM - Solution Spotlights

Small Molecules

How-to Use Oral Drug Delivery Technology Innovatively

Pulsatile drug delivery for desired biopharmaceutical performance: Insights to achieve ideal pharmacokinetics, encourage patient compliance and generate new intellectual property.

Focus on the use of oral pulsatile release design as a way to leverage chronotherapy, mimic bid or tid dosing, create a challenge to generic competition
Timed delivery of two different active ingredients and provide both quick onset of action and quick termination of action
Target delivery to a specific GI site of action
Adare Proprietary Pulsatile Release Technology featured case studies to be presented

Biologics

Hard-to-Stabilize Proteins and Peptides: Can Recombinant Human Albumin be an Effective Approach?

The expanding field of peptide and protein therapeutics gives promise for improvement of treatments against several diseases. Many of the biopharmaceuticals found to be efficacious continue to face ex vivo instability challenges despite advancements in protein and peptide engineering. In this respect a lot of the drug development efforts are devoted to pre-formulation and formulation studies aiming at maximizing the stability of the biopharmaceutical. This is not an easy task and therefore, they form a critical objective of any drug development program.

It is well-known that recombinant human serum albumin can stabilize proteins in solution preventing adsorption, aggregation and oxidation. The stabilizing ability stems from some of the roles albumin performs in blood, such as a carrier of small hydrophobic entities, participation in the control of pH and osmotic pressure and affording the majority of the antioxidant capabilities present in blood. Recombinant human albumin is therefore a promising stabilizer for hard-to-formulate biopharmaceuticals.

In this talk we will illustrate the use of Albumedix® Recombumin®, a recombinant albumin product, as a stabilizing agent for model biopharmaceuticals. We will present data on the use of Recombumin showing its versatility as an advanced excipient.

Technology & Innovation

Reimagining your Orally Dispersible Tablets Formulation Excipients, Introducing a New Lactose Product (SuperTab® 50ODT)

An orally disintegrating tablet or orally dissolving tablet (ODT) is a drug dosage form available for a limited range of over-the-counter (OTC) and prescription medications. ODTs differ from traditional tablets in that they are designed to be dissolved on the tongue rather than swallowed as a whole. The regulatory condition for meeting the definition of an orally disintegrating tablet is that ODT drugs should disintegrate in less than 30 seconds for US ODT products and less than 3 minutes for European ODT products. ODT’s are a novel way for product line extensions and a new manner helping to deliver medication to pediatrics and geriatric patients, or to those who suffer from Dysphagia.

ODT manufacturing can be split into two distinct areas. The initial technology used involved lyophilization. The first ODT form of a drug to get approval from the U.S. Food and Drug Administration (FDA) was a Zydis ODT formation of Claritin (loratadine) in December 1996. The second technology and most cost effective technology uses the standard tableting process equipment.

SuperTab® 50ODT is a specifically designed spray dried lactose which has characteristics that facilitate the production of ODT’s . Utilizing proprietary spray drying techniques a lactose monohydrate product has been developed with a typical porous nature due to which a fast disintegration time can be established in combination with a smooth tablet perception. The balance is to have a formulation that produces tablets with low friability, to aid packaging / transportation and the desired fast oral disintegration time coupled with a pleasant mouth feel and texture.

New in the development of excipients is the usage of large trained sensory tests panels evaluating product from prototypes to final products with CATA (Check All That Apply) and RATA (Rate All That Apply) testing protocols and use of MVA (Multi Variant Analysis) to monitor, evaluate the sensory and physical behavior of tablets. The study shows that using these CATA & RATA screening techniques the Organoleptic properties of commonly used pharmaceutical excipient such as lactose can be modified to suit ODT application.

Historically, these type of formulations have used polyols such as Mannitol etc. Unlike polyols, lactose does not decrease the small intestinal transit time[1].

[1] Dissolution Testing and Acceptance Criteria for Immediate-Release Solid Oral Dosage Form Drug Products Containing High Solubility, Drug Substances - 2018

Device Development

Human Factors - Trends, Optimization, ROI and the Future

Trends in drug delivery and the impact on HF
Optimizing HF activities to go beyond risk
Combining HF studies with Market Research (User Acceptance) Studies
Presenting the ROI of HF activities
New technologies and perspectives on the evolution of HF

1:00 PM - 2:00 PM

Networking Lunch

Lunch & Learn Round Table with Capitsol a Ligand Technology

What’s New with Captisol?

Aseptic filled concentrated Captisol solution available for development
Approved Chinese Captisol Drug Master File and first approved Captisol enabled product in China
Redundant validated commercial manufacturing sites
Established a new European Captisol distribution site
New Captisol safety white papers on pediatric populations, renal observations and oral use
Own Captisol enabled product development program for CE-Iohexol

Vince Antle, PhD, Senior Vice President of Technical Operations
JD Pipkin, PhD, Vice President, New Product Development

2:00 PM - 2:35 PM - Case Studies

Technology & Innovation

Fill and Finish Process Development for Biologic Products : Derisking Approach

Fill and finish step following downstream processing is a critical step of the biopharmaceutical manufacturing. Appropriate development studies based on product and technologies knowledge are essential to ensure successful industrial transfer.

Risks associated to fill and finish processing
Studies to be performed (lab scale trials and calculations)
Case studies

Device Development

MDR Impact on Pharma Companies

With the introduction of new EU MDR pharma companies must ensure readiness for the implementation in May 2020. However, specifically for single integral medical products with a device component there is still many unknowns. This talk will include an industry perspective as well as case studies of how MDR Art 117 readiness can be approached in this time of uncertainty.

Biologics

Electrospinning of Biopharmaceuticals

Parenteral administration of biopharmaceuticals for intestinal diseases is associated with numerous disadvantages e.g. low patient compliance, and toxicity caused by high systemic bioavailability. One alternative that can potentially overcome these limitations is oral administration of biopharmaceuticals, where the local delivery will reduce the systemic exposure and furthermore the manufacturing costs will be lower.

Electrospinning is a new promising drying technology for biopharmaceuticals as drying takes place at low temperature coupled with a possibility to make nanosized fibers. The technology will be discussed and compared to traditional drying technologies.

Biologics

Oral Semaglutide: Realising the Potential of Oral Peptide Delivery

Peptides such as insulin and glucagon-like peptide-1 (GLP-1) receptor agonists are used in the treatment of type 2 diabetes.
The inherent physicochemical properties of these peptides (high molecular weight, enzymatically labile, hydrophilicity, and low permeability) have hampered attempts to deliver peptides via the oral route and necessitated that they be administered by injection.
Recently, oral semaglutide, a GLP-1 analog, coformulated with the absorption enhancer sodium N-[8-(2-hydroxybenzoyl) aminocaprylate] (SNAC) in a tablet has been developed.
This coformulation provides unique, site-directed release and absorption in the stomach and effectively surmounts inherent challenges relating to solubility, molecular size, and proteolytic lability to achieve therapeutically relevant plasma exposure of semaglutide.

2:35 PM - 2:40 PM

Please Move to your Next Session

2:40 PM - 3:15 PM - Solution Spotlights

Technology & Innovation

New Silicone-Free Plunger Option for Delivery of Sensitive Biologics in Bare Glass Pre-Filled Syringes

The industry predicts that 10-15% of large molecules (biologics) are sensitive to silicone. With the logarithmic rise in biologic molecules in the pipeline, there is a technical need for alternative packages that are free of silicone. Gore has commercialized a silicone free, PTFE-based fluoropolymer encased plunger that enables BARE glass syringes for sensitive large molecules (biologic and conjugate vaccines). This technology eliminates silicone oil, cross-linked silicone, baked-on silicone from the primary package. Data will be presented to show the logarithmic reduction in particles and more consistent injection time across aging conditions. Eliminating the silicone also removes a significant root cause of protein aggregation and conjugated vaccine precipitation.

Biologics

End to End Solutions in Freeze Drying: From Cycle Audit through Formulation, Process Optimisation and Scale up

The presentation will describe a case study about the process development of a lyophilised protein product. The different phases from formulation to cycle development and technology transfer will be covered outlining challenges and commercial benefits.

Small Molecules

Mesoporous Silica: An Option for Liquisolid Systems

Adsorption on solid adsorbent carriers is one of the emerging techniques for delivery of oils, solubilisers and lipids. Carriers should display high surface area, strong adsorption capacity, ease of processing and generation of liquid loaded free flowing powder which can easily be processed to solid dosage forms like tablets, capsules and sachets. Hence, solid adsorbents are increasingly gaining the attention of formulators for design of oil & lipid based oral drug delivery system. The ideal carrier is one which demonstrates maximum release of adsorbed component in GI tract to initiate drug dissolution and absorption process. In a direction to ensure the same there was a need to develop a new Mesoporous silica gel (MSG) carrier. We evaluated towards different carriers like Granulated fumed silica(GFS) and Magnesium aluminum silicate (MAS) for its adsorption, desorption and release property. Also the effect of humidity and silanol groups on oil adsorption and desorption was studied. SYLOID® XDP silicas are engineered with specific pore size, adsorption, and desorptive capacity that creates the ideal carrier for lipids and converts liquid ingredients into free flowing powder

Device Development

Device Development Using In-Silico Techniques within an FDA Framework

Solving some of the industry’s most complex device design challenges using In-Silico (virtual) techniques
Reporting of computational modelling within an FDA regulatory submission - FDA V&V40
Digital evidence and the digital twin
Acoustic design and simulation
Will modelling and simulation ever be accepted as credible evidence of safety or clinical benefit?

3:15 PM - 4:15 PM

Networking Break

4:15 PM - 4:50 PM - Case Studies

Technology & Innovation

Transporter-Mediated Brain-Targeted Prodrugs

Diseases of the central nervous system (CNS) are one the greatest threats to public health and the direct and indirect healthcare costs of these are expected to increase as the population ages. However, most brain disorders and diseases lack effective drug therapies. The blood-brain barrier (BBB) prevents the uptake of numerous drug molecules into the brain. Therefore, there is an enormous and growing unmet need to improve CNS drug delivery to provide better medicines for humankind in future.

L-Type amino acid transporter 1 (LAT1) is a sodium- and pH-independent heterodimeric transmembrane protein that carries bulky and neutral amino acids into the cells. It is highly expressed on the cell surfaces that require a constant amino acid supply, such as endothelial cells of the BBB, neurons and glial cells, and over-expressed in several cancer cell types. In addition to amino acids, LAT1 also carries drugs and therefore, it can have a major role in drugs’ brain disposition. If a drug is not a LAT1-substrate, it can be converted as a LAT1-utilizing prodrug to improve its brain uptake and intra-brain targeting.

In this presentation, several examples of LAT1-utilizing prodrugs of neuroprotective agents are presented. Their LAT1-utilization, BBB permeation, target cell selective uptake, brain-targeting efficacy and pharmacokinetics are summarized. Moreover, the bioconversion of the LAT1-utilizing prodrugs in targets cells as well their premature bioconversion due to the first pass metabolism and the species differences of bioconverting enzymes are discussed. Finally, it will be demonstrated that by converting neuroprotective drugs, such as antioxidants, anti-inflammatories and immunomodulative agents, to LAT1-utilizing brain-targeted prodrugs can yield to improved efficacy followed by selected biomarkers.

Device Development

Human Factors Engineering for Medical Device Development

Human Factors Engineering: overview & regulatory framework
Patient-centricity in Device Design and Development
Case study

Small Molecules

Importance of Establishing the Stability of Drug-Loaded Nanoparticles

To allow targeting of drugs by nanoparticles and triggered release at the site of action, one must ensure that drugs are stably encapsulated before reaching the target site. Usually change in pharmacokinetics and biodistribution are the prime outcome parameters to indicate stability of drug-loaded nanoparticles. However, to prevent excessive use of animals, reliable in vitro measurements are required that carefully predict in vivo stability. We will show that asymmetric flow-field flow fractionation (AF4) may do the trick. Furthermore, we will show examples of ways to improve stability and enable triggered release of drug-loaded polymer micelles.

Biologics

Biosimilars – Regulatory Primer for Formulation Scientists

The EU regulatory pathway for marketing authorization of biosimilar medicinal products was established in 2005. This presentation will illustrate how the principles have been applied in practice to authorize different products, including implications for product formulation.

EU regulatory framework for biosimilars
Practical considerations for choice of Reference Product
Case examples to illustrate multidisciplinary weight of evidence for authorization
Considerations for justifying differences in drug product formulation

4:45 PM - 4:50 PM

Please Move to your Next Session

4:55 PM - 5:40 PM - Panel Discussion

Device Development

EU Medical Device Regulations impact on Combination Products – What to be Aware of Across Drug Delivery Development

Article 117 of EU MDR introduces the need for single integral medicinal products with a device component of class IIa and above to have a Notified Body opinion – what does this mean for combination product manufacturers? And what can manufacturers do to be ready for this change in regulations?
Notified Bodies will have to apply for MDR designation – what will the impact on this have on the availability of Notified Bodies to meet growing demands and timelines?
What will Rules on up classification mean for development and continued marketisation of Devices which will be up classified from class I to class IIa or b such as Rule 20 for inhalers?

5:40 PM - 5:45 PM

Poster Presentation Award

5:45 PM - 5:50 PM

Chair’s Closing Remarks and End of Day 2

5:50 PM - 6:50 PM

Drinks Reception

8:00 AM - 8:50 AM

Registration & Refreshments

8:50 AM - 8:55 AM

Chair’s Opening Remarks

8:55 AM - 9:30 AM - Keynote

Device Development

Formulation & Device Lifecycle Management

Globally, the pressure on healthcare costs and resources is increasing and aspects such as limited infusion capacity or complex drug preparation procedures markedly contribute to this challenging situation. Especially with a large number of biologic agents being developed for intravenous infusion and frequently for combination therapy, companies are more and more looking into simplifying drug delivery with the aim to improve access and to reduce healthcare costs and resources. Today, subcutaneous versions are available for a number of biotherapeutics even in oncology there is the desire to explore whether these presentations can be administered in the home setting. Typically, in case a treatment is well tolerated, given in monotherapy, and patients live far from an oncology center, such a flexible care setting would be appreciated in a number of countries. A key requisite for enabling home- or self-administration would be the availability of a suitable injection device that can administer larger dosing volumes exceeding 5 mL or more (i.e., ideally ready-to-use with limited administration steps required). In addition, connected device features, such as dosing reminders, adherence trackers, and electronic patient diaries, that also allow an ongoing dialogue with healthcare professionals can be of value in this context. The keynote presentation will present an update of the current status in the field, discuss related opportunities and challenges, and outline future perspectives.

9:15 AM - 9:50 AM - Case Studies

Technology & Innovation

Bringing Drugs to Market Sooner

Advanced screening to reduce the number of compounds wasted in discovery phases
Advanced predictive modelling to reduce costs per drug brought to market
Saving most time and money can happen at pre-clinical and clinical tests

9:30 AM - 9:35 AM

Please Move to your Next Session

9:35 AM - 10:10 AM - Case Studies

Technology & Innovation

Biopharmacy of New Chemical Entities for Oral Route Administration: Contributions of Predictive Tools to Confirm Developpability and Support Proof of Concept Clinical Studies

In the early preclinical development pharmaceutical industry, biopharm scientists support project teams at several timepoints in the pre-development and entry in to development stages, helping choosing the right molecule, the right formulation(s) for safety studies and early clinical development, minimizing trails & errors and therefore allowing to keep a fast pace.

In this presentation we will illustrate in particular:

The use of Drugability Classification System at precandidate stage
How good physicochemical profiling followed by selective drug absorption in Dog studies combined with ACAT & PBPK Dog modelling can allow to refine expectations for a given formulation strategy in Human
How dissolution & modelling can provide support during phase I

The presentation will rely on a multi-API analysis to better grasp the presented models strength & limits.

Small Molecules

3D Printing as an Investigative Tool in Particle Detachment

3D printing at the micro scale
Particle detachment from a 3D printed surface
Evidence for Rock and Roll particle detachment
Impacts of surface rugosity on entrainment of particles (detachment) using the controlled customised 3D printed surfaces

Biologics

Impact of ABC Transporters at the Blood Brain Barrier

Expression and function of ABC-transporters at the blood brain barrier are essential for the barrier function. Both are subject of complex signaling cascades and nuclear receptors (orphan receptors) play a pivotal role in these processes. They respond to internal and external stimuli including metabolites, xenobiotics, pollutants and drugs. To date 48 nuclear receptors have been identified in humans. Exposing brain capillaries to ligands of the pregnane X receptor, one of these nuclear receptors, increases p-glycoprotein expression and Pgp–specific transport of substrates into capillary lumens. In vivo dosing of rats with nuclear receptor ligands results in increased p-gp expression and function in brain capillaries. A second nuclear receptor at the BBB is AhR, Aryl hydrocarbon receptor, which responds to a large variety of environmental toxins, including DDT or TCDD. In rat capillaries, incubation with AhR-substrates results in increased expression of Pgp, Mrp2 and Bcrp, which can be suppressed by AhR antagonists. These results show that ABC transporters at the BBB are target genes of nuclear receptors, which act as cellular xenosensors. Ligand activation of the receptors results in an upregulation of transporters and thus, for substrates that are toxicants or potentially toxic metabolic wastes, increased transporter expression should be protective for the brain. Function of ABC transporters is also regulated by trace elements such as Zinc. Exposure of brain capillaries to Zn²+ results in a significant functional upregulation of Pgp, Mrp2 and Bcrp at the BBB.

To enhance drug transport across the BBB, ABC transporters can be bypassed by use of surface modified colloidal carriers, such as liposomes or polymeric nanoparticles. E.g., administration of biodegradable polybutylcyanoacrylate nanoparticles results in significant drug accumulation of otherwise poorly permeable drugs in the brain.

Device Development

Benefits and Challenges from Pharmaceutical Industry Perspective

The presentation will provide an overview about Software (e.g., Apps) which is regulated as a medical device or as device-constituent part of a combination product and is either being used in conjunction with drug-delivery devices or as a support tool for patients, HCPs or other users in the course of the use of drug products. Main topics will be an overview of the applicable regulations and practical experience gained from an existing medical software solution.

10:10 AM - 10:15 AM

Please Move to your Next Session

10:15 AM - 10:50 AM - Solution Spotlights

Small Molecules

Silica Carrier for Solubility Enhancement – Graduating from Lab to Production Scale

The drug carrier technology is a valuable option to address the challenge of low solubility of APIs. At small scale, there are various ways available to load the API onto the carrier surface. However, at larger scale, challenges typically arise in process configuration and scale-up operations. A process has been developed which allows for a stable, reliable one-step loading process and up-scaling to clinical & production scale manufacturing. After the loading process, the API-loaded carrier can finally be formulated as a tablet.

Biologics

Soteria®: Delivery of Antibodies in an Easy to Swallow Oral Pill

The pill is enteric coated to provide release of antibody in the colon
Once in the colon, excipients in the core protect the antibody from microbiome derived enzymes
High luminal antibody levels combined with active receptors transport the antibody into the mucosa and lamina propria
Hope for patients in the future to switch to a pill rather than take frequent injections for lifelong chronic diseases

Oral delivery of biologics, let alone monoclonal antibodies, is still considered as the ‘holy grail’ in biopharmaceutical industry, although very few products have reached the market. The primary reason has been the plethora of barriers presented by the human gastrointestinal (GI) tract that have proven to be very challenging to be overcome till date.

Intract has been developing a platform technology called Soteria® that involves targeted delivery of antibodies (IgG, Fab, VHH domain) to the colon using commercially validated Phloral® enteric coating that is applied on the outside of the pill. Upon release of the antibody in the colon, certain excipients that have been carefully screened and selected, provide protection against microbiome derived protease degradation and subsequently active receptors lining the colonic epithelium allow effective transcytosis of antibody into the mucosa and lamina propria to achieve sustained and high levels of antibody in the tissue with potential for absorption into the systemic circulation via lymphatic system transportation.

The platform technology provides hope for patients to be able to swallow antibody in the form of a safe and simple pill and rid them of having to take frequent and lifelong injections to treat/prevent relapse of chronic diseases of the GI tract such as inflammatory bowel disease, pathogenic infections and bowel cancer which are currently treated with high dose injections of antibodies.

Technology & Innovation

Targeting Specific Patient Populations for Distinct Oral Dosing Formulation Challenges – Flexible Technology is Key

Review of the key trends in regulatory guidance driving patient-centric drug development
Key requirements for oral solid patient-centric product
Insights into the evidence of patient-centric formulation for the pediatric populations
Formulation approaches and technology platforms available for meeting target product profiles factoring in clinical targets, special populations and weight based dosing
Formulation and technology considerations for ensuring viable and scalable manufacturing for specialized dosage formats.
Case studies demonstrating technology and formulation approaches and rationale for meeting target product profiles with two different problem statements

Device Development

Solution Spotlight Session TBC

Session TBC

10:50 AM - 11:50 AM

Networking break

11:50 AM - 12:25 PM - Case Studies

Small Molecules

Control Strategy Approaches in Continuous Manufacturing of Oral Solid Dosage Forms

General introduction to continuous manufacturing
Introduction to principles of control strategy elements
Insight to building a robust control strategy

Technology & Innovation

Controlling the Formation API Solvates and Hydrates

Drying of solvate-forming APIs
Influence of hydrate and solvate formation on API solubility
Water sorption in hydrate-forming ASDs
Hydrate formation in ASDs during long-term storage at humid conditions

Device Development

Harnessing the Power of the Digital Exhaust and Digital ATM in Wellness Programs

Clinical decision-making using diagnostic, prognostic, and monitoring biomarkers requires coordination between the healthcare and technology industries and careful design of longitudinal efficacy studies. Community health providers and pharmacies are poised to play a pivotal point‑of‑care role by helping capture prodromal diagnostic data and incorporating biomarker monitoring into wellness programs. A model for the pharmaceutical industry to embrace these patient engagement opportunities is outlined together with recent advances in connected care and digital enabled treatment solutions.

Technology & Innovation

Bispecifics Drug Product Development; Challenge of Low Concentration Analysis and Formulation

Glenmark’s BEAT format – advantages, flexibilities, applicability etc.
Formulation and stability aspects of bispecifics.
Strategies to overcome analytical and formulation challenges for a highly potent molecule.
Preparation for clinical trials for extremely low FIH starting dose.

12:25 PM - 12:30 PM

Please Move to your Next Session

12:30 PM - 1:05 PM - Solution Spotlights

Small Molecules

Transmucosal Delivery – Using the Mucofilm® Technology to Bypass the First Pass Effect

The oral mucosa seems to be the ideal location for delivering large APIs systemically and still avoiding the first pass effect. Certain challenges arise when developing such a dosage form. The product has to adhere on a wet and high mobile surface, needs to resist enzymatic degradation and increased saliva flow and has to simple disappear after a few minutes or a few hours. Challenges that can be overcome to develop the next generation of large molecule application systems.

Technology & Innovation

Early Evaluation of Clinical Performance for Modified Release Products

Rapid assessment of absorption characteristics through the GI tract
Early stage testing of variations of candidate formulations
Solutions to overcome formulation challenges

Technology & Innovation

Risk Mitigation in Topical Product Development

Understanding the differences in semi-solid and solid dosage form development
The risks associated with topical formulation development
The use of performance testing to optimise product safety, efficacy and quality

Device Development

Solution Spotlight Session TBC

Session TBC

1:05 PM - 2:05 PM

Networking Lunch

1:50 PM - 2:25 PM - Case Studies

Device Development

Future Potential for Wearables

Key drivers for adopting wearables
Using data to design better treatments
Wearable drug delivery

2:05 PM - 2:40 PM - Case Studies

Biologics

In-use Studies: Some Case Studies

Challenges of in-use studies: how to well design them.
Several adsorption case studies (mAb, ADC and highly potent product)

Technology & Innovation

Digital Design of Pharmaceutical Products and Processes

In silico API design
Continuous manufacturing
Pharmaceutical formulation design
Large-scale process simulations
Artificial intelligence and machine learning

Pharmaceutical companies have started to embrace digital design of products, and especially “big pharma” is leading the way in using advanced computational methods for a wide variety of objectives, including target identification, in silico API design and prediction of API properties, as well as biopharmaceutics. Formulated product design and the effect of processing have received less attention, yet are increasingly becoming embedded in modern product development pathways. In my talk I will present state-of-the-art methods for the design of pharmaceutical formulations (e.g., with respect to stability or biopharmaceutics) and for the analysis and control of pharmaceutical manufacturing operations, with a focus on continuous manufacturing.

These methods combine molecular design approaches with large-scale process simulation methods (e.g., high-fidelity discrete element methods coupled to advanced CFD, including smoothed particle hydrodynamics of Lattice-Boltzmann methods), as well as state-of-the-art control methods. Examples are given (e.g., hot-melt extrusion, fluid bed operations, blending, bioreactor technology) and open challenges are highlighted. Also the promises of AI are critically reviewed.

Small Molecules

Crystallisation Kinetics in ASDs

Several approaches exist to increase the bioavailability of poorly-water-soluble active pharmaceutical ingredients (APIs). A promising approach is to transform the -usually crystalline- API into its amorphous form, which is better water soluble, but at the same time only metastable against crystallization. A common stabilizing strategy for this type of APIs is to embed the amorphous API in a polymer matrix resulting in a so-called amorphous solid dispersion (ASD). However, as the API loading usually exceeds its solubility in the polymer, the API tends to recrystallize during storage. In order to estimate the shelf life of such metastable ASDs, methods are required to determine the crystallization velocity during storage.

In this work, spray-dried ASDs composed of the API nifedipine and the polymer poly (vinyl acetate were transferred into a magnetic suspension balance, where the water sorption in the ASD was measured as function of time at fixed temperature and relative humidity conditions. ASDs with different drug loadings were exposed to different temperatures and RHs. The water content in the ASDs first increased quickly and then slowly decreased over time. In previous works, we could show that the water sorption of ADSs differs depending on the physical state of the ASD (amorphous vs. crystallized) and can be predicted with adequate thermodynamic tools, e.g. the PC-SAFT model. By coupling the measured water content with thermodynamic predictions and mass balances, it was possible to determine the amount of crystals in the ASDs form the water-sorption measurements only without any additional measurements. This method is completely calibration free and thus is a very cheap and easy method to estimate the amount of API crystals in an ASD.

Device Development

Benefits of Early Integration of Human Factors: A BYDUREON® BCise case study

This presentation will provide a case study of a HF program for the development of a combination product used to treat type II diabetes
This product was initiated in 2009 and has therefore been developed during a period of evolving HF guidance. The presentation will discuss evaluations that were conducted at multiple design stages with representative users, as well as iterations to the design user interface to mitigate observed performance issues
This presentation will include an overview of interactions with regulators as well as the importance of having a dialogue with regulators throughout the development process.

2:30 PM - 3:05 PM - Case Studies

Small Molecules

Optimisation of Industrial Freeze Drying Cycle - Two Real Life Examples

Comparing two dated lyophilized products (60’s) with historical cycles that exhibit distinct complications
Development and optimization of manufacturing processes to overcome the lack of physical chemistry data from dated products
Applying product knowledge, new freeze dryer knowledge, simulation and process modelling

2:40 PM - 2:45 PM

Please Move to your Next Session

2:45 PM - 3:20 PM - Case Studies

Technology & Innovation

Formulation Design and Evaluation of Low Dose Aspirin Loaded Wafers for Oral / Buccal Delivery in Geriatric Patients With Dysphagia

Recent studies have reported that dysphagia is an increasing problem among ageing population who are a growing demographic. Therefore alternative solutions specifically tailored to the special needs of older populations, are required by enhancing the development of novel delivery systems and doses. Composite freeze-dried wafers comprising combinations of metolose (MET), carrageenan (CAR), and low molecular weight chitosan (CS) have been developed for potential delivery of low dose aspirin via the oral route and buccal mucosa. Optimised wafers have been functionally characterised using scanning electron microscopy, X-ray diffraction, mechanical strength, in vitro mucoadhesion, swelling capacity, drug dissolution and release, in vivo taste masking, permeation of aspirin released from wafers using three different models (ex-vivo and in-vitro). Overall the optimised lyophilised DL wafers seems to be a very promising system for the administration of low dose aspirin for older patients with dysphagia.

Biologics

Characterization of Subvisible Particles: Old Challenges and Newest Improvements

The talk will give an overview on commercially available counting methodologies for detection of sub visible particles (SbVP). This species, ubiquitously present in protein formulations, had been in focus due to immunogenicity and quality attributes of Biotechnological products. Thus, the analytical toolbox to characterize them undergoes constant renewals and innovations. Their applicability towards the assessment of a meaningful array for particle counting characterization will be discussed including examples of their use in the frame of immunogenicity studies.

Technology & Innovation

Polysorbate Degradation: Implications and Control

Polysorbate degradation
Impact of polysorbate degradation on drug stability
Improving stability of polysorbate

Small Molecules

Smart Delivery of Actives by Polyrotaxanes Providing New Options for the Treatment of Niemann-Pick Typ C Disease

The systemic treatment of a disease with small molecule drugs is often limited by rapid renal clearance. High and frequent doses are necessary for drug activity, however that in turn augments the cellular toxicity and the side effects of the drug in an organism.

Polymeric delivery vehicles have been employed to improve both the solubility and the bioavailability of drugs to improve their efficacy and/or diminish their toxicity. These vehicles can also improve the retention of the drug in the human body due to reduced renal clearance because of their higher molar mass. Targeting is also possible through incorporation of ligands that promote active transport into specific cells via receptor-mediated endocytosis.

Besides various polymeric carriers, polyrotaxanes are interesting alternative carrier entities that can act as supramolecular prodrugs. Polyrotaxanes are molecules where many macrocyclic rings are strung onto a polymer chain. They are kinetically less stable than polymeric prodrugs because there are no covalent bonds that have to be cleaved to release the active, but by far more stable than physical mixtures due to the topological bond between the threaded rings and the polymeric backbone.[3] The dissociation rate of a polyrotaxane can be controlled by the type of stopper groups attached along the polymer or at the chain ends to allow slow release of the threaded rings. An example for such a macromolecular prodrug is our new Hydroxypropyl-β-Cyclodextrin (HP-β-CD) polyrotaxane. It was designed to act as a slow release formulation of HP-b-CD in the treatment of the Niemann Pick type C disease. The polyrotaxane is based on a polyalkylene phosphate core to improve the pharmacokinetics of this HP-β-CD construct. Our findings show that HP-β-CD was slowly released from the polyrotaxane over a 30 day period. The polyrotaxane showed no toxicity in MTS assays and persistently diminished cholesterol levels in NPC1 cells by 20% relative to untreated cells. These results demonstrate the therapeutic potential of these novel polyrotaxane constructs as supramolecular drug delivery system.

3:10 PM - 3:45 PM - Case Studies

Technology & Innovation

Optimising Formulation and Drug Synthesis Using Artificial Intelligence

Optimising engineering processes
Using AI for non-linear relationship predictions and modelling

3:20 PM - 4:20 PM

Please Move to your Next Session

3:45 PM - 4:15 PM

Networking break

4:20 PM - 4:55 PM - Case Studies

Device Development

Combination Products: Design and Patient Experience

Start troubleshooting with your end goal (the patient!)
Human Factors testing in mock-ups
Simplify design to reduce cost and improve syringe reliability

Small Molecules

Nanoparticle Based Formulations: Special Emphasis on Bioavailability Improvement and Delayed Release upon Parenteral Administration

Nanosuspension based formulations

What do we know about nanosuspensions and preparation thereof
If one method is suited to formulate Nano suspension all the drugs
How efficiently nanosuspensions could be used enhance bioavailability of the poorly soluble drugs
Is it possible to use nanosuspensions for delayed release upon parenteral administration

Biologics

Enhancing the Oral Bioavailability of Peptide and Protein by use of Functionalised Self-Emulsifying Drug Delivery Systems (f-SEDDS)

Self-emulsifying drug delivery systems (SEDDS) can inherently contain permeation enhancers, which are needed for facilitating peptide and protein absorption across the gastro-intestinal epithelium.
Incorporating a hydrophilic protein into a lipophilic matric represents a challenged, but is achievable by complexing the protein with a lipophilic emulsifier.
Functionalising the SEDDS with protease inhibitors, lipase inhibitors and mucus enhancing/permeating molecules has shown feasible and will incorporate the desired functionality into the SEDDS (f-SEDDS)

Technology & Innovation

Miniaturized Capacitive Devices for the Detection of Circulating Biomarkers, Enabling Real-Time Kinetic Measurements, Integrable with Microfluidic Systems

A label-free device has been developed, based on differential double-layer capacitance readout at micro-fabricated gold electrodes, to detect biomarkers in serum or other bio-sample volumes. By means of electrochemical impedance spectroscopy (EIS) measurements in a three electrodes set-up, the device functionalized with self-assembled monolayers of DNA has been calibrated, by measuring in real time the differential capacitance changes at variable concentrations of DNA in a saline buffer, obtaining a dynamic range extended over few orders of magnitude. Micro-RNAs has then been quantified in human plasma of patients with heart disease, demonstrating a limit of detection (LOD) of 1 pM and the possibility to detect single base mismatch in the target sequence. The same platform was successfully used to detect Her2 in serum, by means of a Her2 directed nanobodies (single domain antibodies) conjugated with the DNA strand complementary to that immobilized on the microelectrode. A further device development towards multiplexing read-out, integrated with a paper-based microfluidic set-up is in progress

4:45 PM - 5:20 PM - Case Studies

Technology & Innovation

Nanomedicines - Are We Ready for The Market?

Nanocarrier production
Scale-up
Critical quality attributes
Process parameters
IVIVC

Small Molecules

Disproportionation of Salts in Solid Oral Dosage Forms

Drug efficacy deterioration as a result of salt dissociation
Dissolution changes

Biologics

Regulatory Considerations of Nanomedicines

Licensed medicinal products exploiting nanotechnologies – current guidelines
Challenges of regulating ‘nanomedicines’
Considerations of the information required for development / licensing

Nanotechnology has greatly advanced in the past decade and provides immense potential for the development of improved therapeutic and diagnostic tools for the treatment, prevention and diagnosis of various diseases of the central nervous system, cardiovascular system and cancer. Due to their small size in dimension, it is believed that nanoparticles are able to interact with cells at the molecular level more efficiently and provide better targeting ability towards desired cells and tissues with greater precision and efficacy. Nano-based delivery systems using polymers (e.g. polymeric micelles and polymer-drug conjugates) and lipids (e.g. liposomes, and solid lipid nanoparticles can help: i) increase solubility; ii) improve tumour targeting; (iii) decrease toxicity; (iv) overcome drug resistance, and v) prolong circulation half-life by modifying the surfaces of these nanoparticulate drug delivery systems and increasing drug payload to the target cells. The complexity of nanomedicines requires a holistic assessment of the quality, safety and efficacy of the product. This talk will focus on the challenges of developing these advanced drug delivery systems to match with the current regulatory expectation.

4:55 PM - 5:00 PM

Please Move to your Next Session

5:00 PM - 5:45 PM - Panel Discussion

Technology & Innovation

Are We Prepared for the Regulations on Patient-Focused/Patient-Centric Drug Development?

With the recent first FDA draft Guideline on Patient-Focused Drug Development (PFDD) and three additional guidelines to follow as well as the finalization of the EMA Reflection on pharmaceutical development of medicines for use in the older population”, patient centric drug product development is becoming mandatory for the pharmaceutical industry
What does it mean to the pharmaceutical industry, how do we build a framework of patient centric/focused drug product development
Take an opportunistic view how this can help to create a competitive advantage by adding real value to patients and payers
Debate on how to best take advantage of the emerging regulation and influence its implement

5:20 PM - 5:25 PM

Please Move to your Next Session

5:45 PM - 5:50 PM

Chair’s Closing Remarks

Program 2019

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