Vaccine manufacturing can be a costly and complex process, often making life-saving vaccines unaffordable for resource poor countries. To help address these issues, the International Vaccine Institute (IVI) of Seoul, South Korea, and Merck have recently entered into a research agreement.
We spoke to Priyabrata Pattnaik, Ph.D., Director, Worldwide Vaccine Initiative, Merck, to learn more about the agreement and the role that Merck will play.
AM: Can you tell us about some of the complexities of manufacturing vaccines?
PP: Because, in general, vaccines are large molecular entities, they are naturally complex. Vaccines are not easy to characterize, even with the best techniques available, and it can be difficult to measure how the manufacturing process impacts the safety and efficacy of the finished product. Vaccines need to be made affordable while maintaining the best quality, and there is certainly room for improvement there.
Additionally, when considering therapeutics like biologics or small molecules, it is fairly easy to characterize their safety and efficacy because they are given to a sick patient who either recovers or does not, or extend the survival and then you know whether the drug works or not. But when you give a vaccine to a healthy individual the benefit is not immediately known and that definitely adds a layer of complexity.
AM: What are the aims of the research agreement between Merck and the IVI?
PP. We are really looking to change the way traditional vaccine manufacturing is done. The goal of this collaboration is to develop a standardized, next generation manufacturing process that will allow us to avoid the use of organic solvents and detergents. We are hoping to see whether the ideas we have to address these challenges are economically feasible, scientifically viable, and whether they improve productivity. Progress will take time, but we believe we are on the right path.
AM: What role will Merck play in the agreement?
PP. Merck is providing funding for this project and, perhaps more importantly, supplying our technical know-how. We have a strong understanding of the purification space and a strong market position in filtration and chromatography. We believe that IVI is the right collaborator which whom to leverage our expertise and technology to advance the process of vaccine manufacturing.
AM: What will the initial vaccine focus be? Why was this chosen?
PP. Initially, the project will focus on a vaccine for typhoid, with the goal of applying findings to the processes for pneumococcal, meningococcal, haemophilus, staphylococcus, streptococcus B and other conjugated polysaccharide vaccines. Right now, the manufacturing process to develop these vaccines requires the use of organic solvents and detergents, and variations in the manufacturing process contribute to difficulties in standardization. The regulatory landscape is changing, and among these changes are environmental concerns around organic solvents and their disposal. The aim is to standardize a new manufacturing process that does not require the use of these organic solvents and detergents.
AM: Can you tell us more about Merck's corporate responsibility program?
PP. In realizing Merck's corporate responsibility, we focus our strengths on those areas where we can have the greatest impact. While our IVI partnership is not one of our Corporate Responsibility initiatives, it does align nicely with our goals. At Merck, we pursue three strategic spheres of activity, namely health, environment and culture. For instance, many people in low- to middle-income countries lack access to high-quality health solutions, so we leverage our expertise and collaborate with strong partners to create solutions for patients in developing nations. We also work non-stop to improve the sustainability footprint of our products while helping our customers achieve their own sustainability goals, and we consistently support cultural initiatives and educational programs across the globe. At Merck, acting responsibly means looking, listening and doing things better.
Priyabrata Pattnaik was speaking to Anna MacDonald, Editor for Technology Networks.
Despite aiming to include a broad and inclusive population of patients, clinical trials often exclude certain groups and are therefore not always representative of the wider patient population. NorthWest EHealth hopes to help overcome this issue, with the adoption of Electronic Health Record (EHR) enabled clinical trials.
We spoke to Martin Gibson, NorthWest EHealth Chief Executive, to learn more about their Linked Database System and the benefits of EHR enabled Randomised Controlled Trials (RCT). AM: Can you tell us a little about NorthWest EHealth and how it was formed?
MG: NorthWest EHealth (NWEH) is a UK-based Academic and NHS collaboration that specialises in leveraging existing EHRs to develop medicines more quickly, with improved safety monitoring for the benefit of patients, pharmaceutical companies, and approvers.
Established in 2008, NWEH was set up to develop links between academia and the NHS in the area of health informatics, to identify opportunities for improving health outcomes. NWEH now employs over 70 staff, including software engineers, database analysts, statisticians, researchers and support staff who develop leading software and services for our partners and the wider health research community.
Our focus is the innovative and trustworthy use of routinely collected healthcare data. We have recently delivered the Salford Lung Study, the first late-phase RCT using EHRs, with GlaxoSmithKline.
AM: Can you tell us more about the Salford Lung Study?
MG: The SLS is the world’s first digitally enhanced RCT to include a broad and inclusive population of patients in an everyday clinical practice setting. It examined the safety and effectiveness of a new treatment for chronic obstructive pulmonary disease (COPD) in over 2800 consenting patients around Salford, England.
It was designed to include those patients who would often be excluded from a traditional randomised trial, for example individuals also being treated for other chronic diseases. This inclusive approach to a trial is important because it is representative of a much wider patient population.
This collaborative study was placed in Salford because of the existing infrastructure of integrated EHRs. The study relied on a Linked Database System (LDS), developed by NWEH and securely hosted within the NHS network that integrated the EHRs of consenting patients across all of their interactions with their GPs, pharmacists and hospitals. This bespoke software allowed close monitoring of patients’ safety in near real-time, but with minimal intrusion into their lives. AM: What is ‘routinely collected healthcare data’ and how does the LDS help to collect this?
MG: Every patient interaction with a healthcare provider produces data. The LDS makes use of these existing, routinely collected healthcare records to minimise contact with patients, whilst extracting as much trial data as required “directly from source”. This therefore reduces time and money spent transcribing, checking and approving data.
There is a growing interest in using EHRs to enhance clinical trials to allow drugs to get to market faster. NWEH’s extensive expertise in EHR-enabled clinical trials, combined with its proven LDS technology, could be a game-changer for the way future clinical trials are conducted. Using LDS technology in clinical trials enables rapid patient recruitment, reduced clinical development time and costs, and increased responsiveness to patient safety through real-time monitoring. This technology has the potential to revolutionise clinical trials by ensuring drugs get to market faster, and improving patient outcomes as new treatments become available earlier.
AM: How can the LDS support new approaches to running trials, in addition to enhancing traditional RCTs?
MG: Compared to some traditional RCTs, EHR-enabled RCTs can deliver the following benefits:
• Access source data directly so reducing the need for large-scale electronic Case Report Forms (eCRF) and accompanying transcription errors. • Richer and more inclusive data. • Healthcare utilisation data. • Availability of historic data on enrolment. • Potential to follow up trial cohort at a much reduced cost at study end if required. • Adaptive study design. • Significantly improved real-time safety monitoring. • Lower trial monitoring costs. • Fewer trial resources needed (which enables trial resources to be re-assigned to other study tasks such as subject recruitment). • Real-time data from multiple sources. • Better-managed trials and better business intelligence on the trial.
Traditional RCTs require trial data about each patient to be entered into an eCRF. This information is either created specifically for the trial or is transcribed from existing "source" data normally held within an EHR. When transcribed, the data must be independently checked through Source Data Verification (SDV) before being reviewed and approved by a Principal Investigator (PI). Entering data into an eCRF is time consuming, expensive, and is prone to human error. This error is removed using NWEH’s fully validated LDS as the data is extracted “directly from source”. It also removes the need to expend time and money to transcribe, check and approve data.
In addition to these benefits associated with using source EHR data, there is an opportunity to expand the type of data that is normally captured in clinical trials. For example, it is highly likely that historic patient data will be available, enabling tracking of disease progression and treatment for patients several years before they entered the study. Depending on the healthcare system or country that the data is sourced, it may also be possible to accurately identify detailed healthcare utilisation costs at a patient level throughout, before, and following their time on the trial. The ability to reliably extract additional data even when patients have left the study creates the opportunity to utilise adaptive study design.
Due to the design of the LDS (and supporting services) patient safety can be monitored in near real-time. As patient records are received daily from the healthcare locations engaged in the trial e.g. hospitals, primary care, community pharmacies and others, it is possible to determine if there has been a Serious Adverse Event (SAE) and to automatically report this to the PI for further investigation. Near real-time safety monitoring by LDS creates an opportunity for study designs that simply could not be delivered using standard RCTs.
Using existing EHR data enables studies to be designed that do not require interventions from trial staff. These studies can be designed where patients are closely monitored, and data captured, without them being aware of the influence of a researcher on a day-to-day basis. This means that the possibility of the "Hawthorne effect" can be significantly reduced leading to a study that reflects more closely the normal care pathway.
AM: As the world’s first digitally enhanced RCT, what challenges did you face?
• Information Governance: ensuring system compliance with regulatory standards. • Satisfying the MHRA that we would provide adequate safety reporting for a late phase III trial and complying with NHS Information Governance. • Managing volume of patient safety data in a clinical trial, through near real-time (24h) monitoring. • Developing cooperative and collaborative partnerships with healthcare providers. • Accessing and making sense of everyday patient data: linking multiple, disparate data sets across 229 sites, comprising primary care, secondary care, pharmacy and out of hours services.
Find out more about NWEH:
Martin Gibson was speaking to Anna MacDonald, Editor for
During the drug design process, to probe about and know the structure of proteins is of great importance to grasp the specific medical potential and performance, as well as their safety profiles. Crystallization and X-ray crystallography are commonly involved in such inspecting and testing. But they are preferred by big crystals that are hard to be formed for complex proteins and are incline to be influenced by the radiation beam.
A new tech x-ray serial crystallography is innovative in this aspect in recent years to increase the capturing times of the protein structure. However, a big issue was encountered to achieve the best result with this new tech. When transfer the crystals from their growing chips, there is lose caused by the damages in their structure. And to grow the crystals right on the chip where they will be x-rayed is limited by the thickness of the device, which will bring new problems like limited signal to noise ratio, sample evaporation and so on.
To better address this problem, research team from the University of Massachusetts Amherst led by Sarah Perry found a solution that can assist the tech to achieve its most potential by adding a graphene layer into the crystallography device.
The outstanding characters of the upgraded device lie in its strong ability to preserve the hydration state of the crystals that are significant in protecting the molecular integrity and its high transferring ratio from signal to noise. “
In the experiments with hen egg white lysosome, the team collected a great signal-to-noise level with X-ray diffraction measurements in the optimized device. Being highly thought of by the professionals in this field for its simple adjustment but great advance in performance, the new tech will be widely applied for more flexible researches.
It’s reported that the team is now working to make the device smaller in size and more comprehensive in protein structure analysis while accessible to more various proteins.
BOC Sciences is a comprehensive chemical and related services provider in the field. Crystallization and related analysis services are among the featured ones offered by the company. Following the latest advancements in the field, BOC Sciences can always provide the most practice and effective solutions.
Fast Prototyping of Fluidic Devices Using Fluidic Factory 3D Printer 28 Jun 2016
Quick fabrication of microfluidic devices has always been challenging: existing fabrication methods for microfluidic devices such as injection moulding, micromilling and bonding involve long and costly fabrication processes. 3D printers using SLA and SLS methods on the other hand are not able to print embedded microchannels in a single step, hence leading to relatively long fabrication times, high costs as well as limitations to material selection. Other FDM printers have a critical limitation in the milli- and micro- fluidic industry: structures created with such devices inevitably leak when trying to contain fluid.
To address these challenges, Dolomite Microfluidics recently introduced Fluidic Factory 3D printer, capable of fabrication of fluidically sealed devices in just minutes. Furthermore, the printer uses COC – and FDA approved, transparent, robust polymer suitable for biological applications.
We spoke to Mark Gilligan, CEO of Dolomite Microfluidics to discuss the benefits of the printer.
JR: Why is the Fluidic Factory 3d printer so unique?
MG: Fluidic Factory is the only platform in the 3D printing industry able to 3D print with COC. COC is FDA approved material for implantables, and is often the material of choice of diagnostic device developers. It is also suitable for biological applications and features great transparency as well as very low water absorption.
The 3D printer has been designed specifically for fluidic sealing in one step.
The intelligent software analyses the 3D geometry of the device to be printed and identifies the internal voids and surfaces. It then creates print paths from the inside of the device outwards and the print head deposits filaments in a continuous, leak-proof manner.
The FDM (fluid deposition modelling) method melts the polymer at high temperatures and ejects it through the nozzle to the print bed, which then solidifies at temperatures below 75°C.
The printer nozzle head is extremely accurate in its movement and allows precise features to be printed (with an accuracy of less than 1 µm). The nozzle is also disposable, which ensures that printing quality is preserved.
JR: What benefits does Fluidic Factory have when compared to traditional FDM printers?
MG: Many traditional FDM printers deposit the molten polymer beads in circular cross sections, which results in leak paths and, consequently, an inadequately sealed device. Fluidic Factory is unique in dispensing a ‘squashed’ section bead which eliminates these leak paths, creating a reliably sealed device that will contain any fluids passed through it.
JR The printer has a very small footprint, but how easy it is to set up and use?
MG: Fluidic Factory is a true out of the box solution – get started in just a few minutes! As the footprint is very small, it can be used either in an office or a lab and can be easily transported.
We have designed the printer so it really is easy to use with a very simple workflow. Fluidic Factory enables the user to have ultimate design creativity by letting them design a device using virtually any CAD software on their PC. Design files are saved as .stl files, which carry information about the surfaces of the model which then will be uploaded to the Fluidic Factory Software. The Software creates a graphic illustration of the device and calculated optimum print paths to ensure fluidic sealing. Once the file is ready – it can be transferred to Fluidic Factory via a USB drive.
The design can be then selected for print using the touch screen. Once printing has started, the screen displays the time left to print, real-time status and filament use, with an auto-alert when the COC is running low. The polymer reel contains 60 m of polymer and can be changed in seconds.
When printing has finished, Fluidic Factory will indicate this, which allows the user to remove the print tray and immediately insert another one to begin printing a new device whilst waiting for the completed one to cool down off the machine.
JR: What sort of devices can I create using Fluidic Factory 3D printer?
MG: A very wide range! Unique devices such as 3 dimensional mixers, non-rectangular chips, unique channel geometries and features not possible using etching, embossing, moulding or machining can be created using Fluidic Factory. Circular, triangular or rectangular channel geometries can be printed (dependant on the mode of printing) and other cross-sections are also possible. By following some simple rules to optimize your design, the possibilities to create unique fluidically sealed devices quickly and in a cost effective way are endless! JR: Will Fluidic Factory evolve to enable future functionality?
MG: Yes! Fluidic Factory features a replaceable head and bed and upgradeable software to enable future functionality e.g. on-line chip design files shop, printing alternative polymers high definition printing, micromilling, fluid dispensing and bio-printing.
JR: What else should I know about Fluidic Factory?
MG: We believe Fluidic Factory 3D printer is the future of fast prototyping for micro-and milli fluidic industry and with additional future functionality, a cost-effective, efficient and reliable alternative to traditional microfluidic prototyping alternatives.