Bio 2018 Programme - click titles for abstracts
08:00 Registration opens
09:00 Opening remarks
Morning session:
09:15 The Past, Present and One Possible Future for Biopharmaceutical Therapies
Ian Tomlinson
Chairman, Stevenage Bioscience Catalyst, formerly co-founder of Domantis and Senior VP at GSK Biopharm
09:45 Lyophilisation of AAV Gene Therapy Product
Tanvir Tabish
Head of Formulation Development, Shire, Austria
10:15 Speed Networking
11:15 Novel Molecules Require Novel thinking! Formulation & Analytical Challenges
Adrian Podmore
Scientist II in the department Dosage Form, Delivery and Devices (DFDD), MedImmune, UK
11:45 Regulation of Drug Device Combination Products within the EU
April Kent
Regulatory Affairs Manager, Amgen, UK
12:15 Lunch Break, Exhibition and Posters
13:30 Introduction to the afternoon session
13:45 Discussion panel
14:45 Exhibitors highlights
15:30 Coffee break, Exhibition and Posters
16:00 Characterisation and Formulation of Virus Therapeutics
Andrea Hawe
Chief Scientific Officer, Coriolis, Germany
16:30 Accelerating the development of intraocular medicines using the PK-Eye
Sahar Awwad
School of Pharmacy, University College London, UK
17:00 Concluding remarks
17:10 Conference ends
The Past, Present and One Possible Future for Biopharmaceutical Therapies
Ian Tomlinson | Chairman, Stevenage Bioscience Catalyst, formerly co-founder of Domantis and Senior VP at GSK Biopharm
In October 1982 the FDA approved the first protein manufactured using recombinant DNA technology. Today over 300 different proteins, including hormones, enzymes and antibodies are licensed for use in the clinic. Indeed 10 of the top 15 best selling therapeutics in 2017 were biologics, with the bestseller, a fully human antibody called Humira, netting almost $18.5 billion.
However, whilst the market for biologics has evolved dramatically since that first approval of recombinant insulin 36 years ago, many of the techniques for their manufacture, formulation and administration have changed very little. Almost all approved biologics are made by fermentation, purified using expensive resin columns, mixed with standard excipients and then administered by needle injection.
One wonders if the next few decades of biologics development will involve a move to more convenient routes and modes of administration with the drug product manufactured by synthetic means....or whether the revolution in treatment effect (and the corresponding sales) are sufficient to justify sticking to tried and tested approaches for manufacturing, formulation and administration for the foreseeable future.
Lyophilisation of AAV Gene Therapy Product
Tanvir Tabish | Head of Formulation Development, Shire, Austria
Background: Biopharmaceuticals show varying levels of stability in aqueous solutions for short periods of time. Lyophilisation is a technique commonly used to improve the stability profile of biomolecules through the removal of water resulting in the increasingly restricted mobility of the reacting species. The gene therapy adeno-associated virus (AAV) subtype 8 containing Factor iX (FIX) (BAX335) was formulated in a new proprietary buffer and lyophilized. A stability study was established with the lyophilized material to determine its stability profile at the accelerated temperature of +5°C over a 10 month period
Aim: The goal of the study was to investigate the feasibility of lyophilizing the BAX335 drug product and to determine the possibility of extended storage/shipment of the drug product at +5°C.
Methods: The formulated BAX335 material was filled into glass vials. These were stoppered and freeze dried in an experimental lyophiliser. The lyo cycle used was not optimized but was based on glass transition and collapse temperature data collated with Differential Scanning Calorimetry (DSC) and Freeze Drying (FD) microscope, respectively. The cycle chosen was relatively long with very slow ramps so as not to stress the viral particles unduly. A stability study was established with the lyophilised material stored at +5°C for a period of 10 months. After a defined time period, the AAV was reconstituted and tested. The stability samples were assayed with the appropriate analytical methods (pH, Appearance, total AAV ELISA, FIX-qPCR (vector genome), SEC (aggregates), WAX (% full AAV), in vivo and in vitro biopotency and % residual moisture) to determine the stability profile of the product over the course of the study
Results: No significant change was seen with the viral drug product following the lyophilisation process. Some variation in the percent residual moisture was detected which was dependent on the position of the vials on the freeze-drying shelf. Over the course of the stability study, no significant change in the pH values and the appearance of the lyo cakes was detected. The % full AAV, aggregates and the total AAV count remained stable over the 10 month period. A recovery of 85% was obtained with the FIX-qPCR assay at the 10 month testing timepoint. The in vitro and in vivo biopotency assays did not show any significant loss in activity; all results were within the assay variation.
Conclusion: This study has demonstrated the feasibility of lyophilisation of the AAV drug product in an appropriate formulation buffer. The freeze dried product displayed an improved stability profile when stored at a temperature of +5°C. Additional studies are underway to optimize the lyophilisation program and to improve the lyo cake appearance through varying the sodium chloride contentration in the formulation buffer.
Novel Molecules Require Novel thinking! Formulation & Analytical Challenges
Adrian Podmore | Scientist II in the department Dosage Form, Delivery and Devices (DFDD), MedImmune, UK
This talk focuses on the challenges facing development units in formulation and analytical sections that must adjust the interface with research units to better understand novel molecule risks on a molecule-by-molecule basis. This is inevitably more labour intensive in the early stages of a project, but it should facilitate the most developable leads progressing from research into development. Case studies are shown from current experience with new formats such as recombinantly produced antibody peptide fusion molecules, Fc-fusions, host-guest chemistry approaches, and peptides. Techniques are shown that can be applied during this research-development interface, where sample is limited, but where it is critical to better understand stability attributes of novel molecules.
Characterization and formulation of viral vectors
Andrea Hawe | Chief Scientific Officer, Coriolis Pharma, Germany
Viruses are used as vectors for gene therapy (ex vivo and in vivo) and virus-based vaccines (live- and attenuated virus, virus-like particles). For gene therapy mainly adenovirus, retrovirus, lentivirus and adeno associated virus are applied to deliver their genome (RNA or DNA) to the cells of interest. Challenges for the (commercial) development of viral vectors are the manufacturing of virus at sufficient high titer and scale, their stabilization during the manufacturing process and storage, and finally the development of stable drug products.
Viral vectors are far more complex than other biopharmaceuticals such as proteins, and require a wide range of accurate and reproducible analytical methods. Analytical testing to monitor quality attributes of the therapeutic products like identity, potency, purity, safety and stability is part of the development. The following aspects should be addressed during characterization: (i) infectious virus titer, (ii) total number of virus particles, (iii) virus with and without nucleic acid (filled and empty virus), (iv) virus with and without functional envelope surface proteins, (v) virus aggregation and viral particle morphology and (vi) presence of host cell debris.
The method of choice for the infectious titer is highly depending on the type of virus and its functionality on the target cells, i.e. TCID50 or plaque assays for virus with cytopathic effect, or fluorescent focus assay for virus that do not lyse cell membranes but form localized clusters (foci) of infected cells, or other relevant biological potency assays such as antigen expression or antigenicity. The total number of virus particles and/or virus aggregation, can be monitored by nano particle tracking analysis (NTA), dynamic light scattering (DLS), size exclusion chromatography (SEC), asymmetrical field flow fractionation (AF4), analytical ultracentrifugation (AUC) or transmission electron microscopy (TEM). Filled and empty virus, virus particle morphology and cellular debris can be differentiated by TEM and AUC, whereas polymerase chain reaction (PCR) is used to get insight into the proportion of nucleic acid containing particles.
So far, most virus products are mainly frozen liquids (often < -70°C), which requires a cold chain and is difficult with respect to container closure integrity. Lyophilization can be an alternative to improve stability and allow storage at 2-8°C.
Within the talk an overview on viral vector for gene therapy purpose, their analytical characterization and formulation is given.
Accelerating the development of intraocular medicines using the PK-Eye
Sahar Awwad | School of Pharmacy, University College London, UK
The treatment of retinal diseases often requires direct intravitreal injection of therapeutic agents. Two important developments in recent years have helped to revolutionise the available treatment options that are available for patients. First, to reduce the number of intravitreal injections, implantable dosage forms have been developed to prolong the residence time of the medicine in the posterior segment. A second important development has been the introduction of antibody-based medicines (e.g. ranibizumab and aflibercept) for ophthalmic use. Prior to introduction of these antibody-based medicines, it was difficult if not impossible to stabilise these blinding diseases. While protein based medicines can be administered monthly or even less frequently, there is intense research activity that is focused on further prolonging the ocular residence time of these medicines. Preclinical research is carried out to develop prolonged forms of protein therapeutics.
Part of the difficulty in determining the best regimen is that there is little understanding of the drug pharmacokinetics in man. Frequent drug sampling from the human vitreous is not possible due to its invasive nature. Animal models are expensive, have ethical problems, but are also limited by the vigorous immune response to foreign proteins by the formation of anti-drug antibodies (ADAs), making estimation of drug half-life challenging, and altering the drug’s biological effect and toxicity profile.
The PK-Eye in vitro model is a two-compartment, aqueous outflow model of the human eye that has been shown to be particularly useful to estimate human protein release profiles (e.g. ranibizumab and bevacizumab) and to determine protein stability properties. The aqueous outflow is main mass transfer mechanism in the eye and responsible for nourishing the lens and cornea. Protein drugs when injected intraocularly clear via the aqueous outflow through the front of the eye. A number of formulations (injectables, microparticles and hydrogels) have been tested. As one example, we prepared injectable thermoresponsive hydrogels in the presence of bevacizumab and determined its release and stability in the PK-Eye model. Given the current design of the PK-Eye, there is now an opportunity to establish correlations with in vivo models using different injectable dosage forms. The PK-Eye model is being used to evaluate new formulations that are being developed to prolong the release a protein therapeutic.
Accelerating the development of intraocular medicines using the PK-Eye
Sahar Awwad | School of Pharmacy, University College London, UK
The treatment of retinal diseases often requires direct intravitreal injection of therapeutic agents. Two important developments in recent years have helped to revolutionise the available treatment options that are available for patients. First, to reduce the number of intravitreal injections, implantable dosage forms have been developed to prolong the residence time of the medicine in the posterior segment. A second important development has been the introduction of antibody-based medicines (e.g. ranibizumab and aflibercept) for ophthalmic use. Prior to introduction of these antibody-based medicines, it was difficult if not impossible to stabilise these blinding diseases. While protein based medicines can be administered monthly or even less frequently, there is intense research activity that is focused on further prolonging the ocular residence time of these medicines. Preclinical research is carried out to develop prolonged forms of protein therapeutics.
Part of the difficulty in determining the best regimen is that there is little understanding of the drug pharmacokinetics in man. Frequent drug sampling from the human vitreous is not possible due to its invasive nature. Animal models are expensive, have ethical problems, but are also limited by the vigorous immune response to foreign proteins by the formation of anti-drug antibodies (ADAs), making estimation of drug half-life challenging, and altering the drug’s biological effect and toxicity profile.
The PK-Eye in vitro model is a two-compartment, aqueous outflow model of the human eye that has been shown to be particularly useful to estimate human protein release profiles (e.g. ranibizumab and bevacizumab) and to determine protein stability properties. The aqueous outflow is main mass transfer mechanism in the eye and responsible for nourishing the lens and cornea. Protein drugs when injected intraocularly clear via the aqueous outflow through the front of the eye. A number of formulations (injectables, microparticles and hydrogels) have been tested. As one example, we prepared injectable thermoresponsive hydrogels in the presence of bevacizumab and determined its release and stability in the PK-Eye model. Given the current design of the PK-Eye, there is now an opportunity to establish correlations with in vivo models using different injectable dosage forms. The PK-Eye model is being used to evaluate new formulations that are being developed to prolong the release a protein therapeutic.