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INNOVATIVE SOLUTIONS IN

THE PHARMACEUTICAL INDUSTRY

Soula Kyriacos, B.Pharm, PhD

Head R&D, Pharmaline

May 2017

Next-generation patients demand next-generation innovation

• Patient expectations rise

• We are entering an era of precision medicine – drugs must be made with unique features

• Technologies are already beginning to revolutionize the health industry

– Production technologies – faster production, more reliable products

– Consumer technologies such as mobile phones and wearable devices

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R&D strategies: data collection and analysis

Applying big-data strategies

– optimize innovation: better identify new potential drug candidates and develop them into effective, approved and reimbursed medicines more quickly

– improve the efficiency of research and clinical trials

• predictive modeling of biological processes and drugs

• criteria for including patients based on genetic information to target specific populations, thereby enabling trials that are smaller, shorter, less expensive, and more powerful.

– build new tools for physicians, consumers, insurers, and regulators to support individualized approaches.

.McKinsey Center for Government, 2013

Computers with learning capabilities, such as IBM Watson, are capable of digesting and interpreting millions of pages of scientific literature and data (text from medical journals and clinical trials, historical cases including medical records, patient outcomes and physician's notes,) to assist pharma companies in development of new drugs and repurposing of existing ones.

• Watson has demonstrated the ability to discover previously unknown connections between diseases and as it continues to learn, it can modify its recommendations based on new information.

Reduce costs and significantly improve the discovery process

• discovery of alternative indications for existing drugs

R&D strategies: data collection and analysis

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Clinical strategies: data collection and analysis

Improve safety and risk management

• Safety monitoring is moving beyond traditional approaches to sophisticated methods that identify possible safety signals arising from rare adverse events.

• Early signals regarding safety issues could be detected from a range of sources: patient inquiries on Web sites and search engines, online physician communities, electronic medical records, and consumer-generated media and can provide data on the reach and reputation of different medicines.

• FDA Sentinel Initiative (officially launched in Feb 2016) = innovative method of actively monitoring FDA-regulated products to enhance public safety

• Sentinel Initiative: Medical product safety surveillance

• a legally mandated electronic-surveillance system that links and analyzes health-care data from multiple sources. As part of this system, the FDA now has secured access to data concerning more than 193 million patients nationwide.

• Sentinel enhances the FDA’s ability to proactively monitor the safety of medical products after they have reached the market

• Through Sentinel, the FDA can rapidly and securely access information from large amounts of electronic healthcare data, such as electronic health records (EHR), insurance claims data and registries, from a diverse group of data partners.

Clinical strategies: data collection and analysis

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• Increasingly sophisticated health-measurement devices (with miniaturized biosensors) - smartphones; smartwatches and fitness bands

– Collect large quantities of real-world data (heart rate, sleep, blood glucose, blood oxygen…) not previously available to scientists.

– Engage unprecedented numbers of individuals in large geographical areas, (better representation of a population, and more powerful results)

– remote monitoring of patients participating in a clinical trial in real-time, real-world settings could be used to facilitate R&D, analyze drug efficacy, enhance future drug sales, and create new economic models

Digital Health

Remote-monitoring devices can also add value by increasing patients’ adherence to their prescriptions - one of the major reason behind therapeutic failure.

– smart pills that can release drugs and relay patient data, as well as smart bottles that help track usage.

Digital HealthPatient adherence

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• First Digital Medicine, a drug/device product, combines:

– Otsuka’s ABILIFY® (aripiprazole), embedded with

– Proteus® ingestible sensor (that communicates with a wearable sensor patch and a medical software application)

in a single tablet to digitally record ingestion and, with patient consent, share information with their healthcare professionals and caregivers

provide an objective measure of medication adherence and physiologic response

Digital HealthPatient adherence

US FDA – through the agency’s Emerging Technology Team (ETT) - has released a draft guidance to the industry to help manufacturers implement a variety of technological advancements:

'Advancement of emerging technology applications to modernize the pharmaceutical manufacturing base guidance for industry‘, draft document, Dec 2015 .

• Optimize output– automating processes that were previously manual

• Improve product quality– single-use equipment, reducing risk of contamination and

subsequent batch recalls

Integrating Technologies

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Integrating Technologies

State of Pharmaceutical manufacturing

• In many cases, not state-of-art as compared to other industries

• Able to achieve reasonable product quality –but at a great effort and cost

• Little emphasis on manufacturing –mainly on development although manufacturing is approximately 25% of expenses

• For some products, waste as high as 50%

• Inability to predict effects of scale up on final product

• Inability to analyze or understand reasons for manufacturing failures

Winkle, FDA 2009

Integrating TechnologiesContinuous manufacturing

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Example of traditional tablet manufacturing process

Example of Continuous Manufacturing with On-line Monitoring

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Integrated Technologies

Integrated Framework for Pharmaceutical Manufacturing

• Science and risk-based approaches to process design and product development

• Assurance of consistent product quality

• Robust Pharmaceutical Quality System

• Lifecycle approach to continuous process improvement

US FDA PAT Guidance for Industry PAT- A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance

US FDA Guidance to Industry: Process Validation: General Principles and Practices

ICH Q8(R2), Q9, Q10 and Q11

Integrating TechnologiesAdvantages of Continuous Manufacturing • Integrated processing with fewer steps

– No manual handling, increased safety

– Shorter processing times

– Increased efficiency

• Smaller equipment and facilities– More flexible operation

– Reduced inventory

– Lower capital costs, less work-in-progress materials

– Smaller ecological footprint

• On-line monitoring and control for increased product quality assurance in real-time– Amenable to Real Time Release Testing approaches

– Consistent quality

Potential for reduced cost

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• Significant number of the new brands of drugs introduced on the market are not novel chemical entities but improved versions and altered formulations.

• Potential Advantages:

– improved treatment, therapeutic index

– better patient compliance

– more convenient drug delivery

• New drug delivery systems

– Needle-free devices

– Transdermal delivery technologies (patches, microneedles)– Nanoparticles (New materials and targeting moieties)

Integrating TechnologiesImproving existing products for patients

Integrating TechnologiesNanotechnologies

Cytotoxic Rx previously marketed in conventional form but with dose‐limiting toxicities

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Integrating TechnologiesNanotechnologies

- Targeting of nanoparticles to a tumor-associated protein

Combination Alendronate- Paclitaxel in HPMA copolymer nanoparticles Target metastatic bone lesions in breast and other cancers

- Targeting with heat-sensitive liposomal formulation

Drug is released locally by the application of radio frequency ablation

- Targeting by integrating imaging and therapy

Targeted nanoparticle (ligand for integrin for tumor targeting) and Fluorine (as a means of imaging to confirm delivery of the product to the tumor sites)

Integrating TechnologiesThree-dimensional (3D) printing

• Additive manufacturing

involves precisely adding layer on top of layer to build a 3D product

- computer-aided design and computer-assisted manufacturing are combined to construct complex 3D products without the use of molds, offering a high degree of flexibility in the structural design. - precise spatial compositions

- controllable drug release patterns

- unprecedented customizability

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Integrating Technologies3D Printing Technologies

• Stereolithography, which employs a UV laser that solidifies a photopolymer into a 3-dimentional shape outlined in a computer-aided-design (CAD) file.

– 3-D printers use a powder- or liquid-based substrate which solidifies when hit by a computerized laser designed to form a certain shape, creating a single layer of the pill. The printer repeats this process of laying down layers until the final product is complete.

Integrating Technologies3D Printing Technologies

• Fused deposition modeling (FDM)

Similar to an inkjet printer

Beads of heated material are released from the printheadas it moves, onto powder, building the product in thin layers. Since the material is heated as it is extruded, it fuses or bonds to the layers below. As each layer of material cools, it hardens, gradually creating the solid object as the layers build.

This process is repeated over and over, allowing precise control of the amount and location of each deposit to shape each layer.

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Integrating Technologies

A graphic that shows how the 3-D printed version of the drug was developed (Aprecia Pharmaceuticals)

Future 3D printed drugs –could change not only the way that drugs are manufactured, but also administered - print personalized drugs

1. Personalized drug dosing

• Select the drug/combination of drugs

• Load optimal medication dose

2. Unique dosage forms/drug-eluting devices

• Tailor the size and geometry of the device to completely accommodate the anatomic features and medical needs of patients

3. More complex drug release kinetics

• Targeted and controlled drug release

Integrating Technologies

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Epilepsy drug Spritam

(levetiracetam, Aprecia Pharmaceuticals)= first 3D printed drug to be approved by the FDA

– oral medication obtained through a three-dimensional printing process, which builds the pill by spreading layers of the drug on top of one another until the right dose is reached

– porous design helps medication disintegrate rapidly in the mouth when taken with a sip of liquid

– This technique allows the pill to deliver a higher dose of medicine – up to 1000 mg

•

Integrating Technologies

Barriers for 3D printing in healthcare practice: • Heavy investment

• Safety and security concerns: lack of regulation of 3D printing.

3D printing is one of the fastest growing discipline worldwide

The manufacturing and distribution of drugs by pharmaceutical companies could conceivably be replaced by emailing databases of medication formulations to pharmacies for on-demand drug printing. This would cause existing drug manufacturing and distribution methods to change drastically and become more cost-effective. If most common medications become available in this way, patients might be able to reduce their medication burden to one polypill per day, which would promote patient adherence.

Integrating Technologies

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Pharma industry must think outside the pill box

• To thrive in the increasingly competitive modern pharma market, companies will have to increase external collaborations to develop innovative new products, services, and solutions, as well as share skills and expertise.

• Technologies are being adopted by pharma companies to assist in developing new drugs as well as improving patient outcomes through personalized medicines, enhance overall the effectiveness of the process and increasing patient access through reduced costs.

• Could we app Pharmacy?

"The biggest innovations of the 21st century will be at the intersection of biology and technology“.

Steve Jobs

THANK YOU