Pharma Focus Asia - Issue 32

ISSUE 32 2018

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REGULATORY REFORM HOW CHINA IS INVESTING IN ITS PHARMACEUTICAL MARKET

The Future of Pharma R&D How external innovation changes pharma R&D

Future of Pharma 3D printing opens the doors of possibility www.pharmafocusasia.com

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Foreword China's Regulatory Reforms Promoting pharma innovations In recent years, China’s investment in drug innovation has been on the rise. The country’s pharmaceutical market is second only to the US at approximately US$125 billion as of 2016 and is expected to increase at a CAGR of 30 per cent to US$575 billion by 2022. Interestingly, China has become the leader in API manufacturing and exports. Historically, the pharmaceutical market in China was inward-looking and lack of favourable regulatory climate deterred foreign investors from making strong in-roads. Of late the government has begun to reform the regulations to encourage innovation and decrease the regulatory burden on the life sciences industry. While entry to the market has not been a major concern, foreign companies have always been troubled by delayed drug approvals, IP violations, and lack of transparency.

The biggest challenge was companies being forced to conduct local clinical trials in spite of receiving approvals in other countries.

In 2015, the China State Council brought about a new directive titled ‘Opinions on Reforming the Review and Approval System for Drugs and Medical Devices’, aiming to create a business environment that is conducive to high-quality generics and make the approval process more transparent. The China Food and Drug Administration (CFDA), the administrative body responsible for the regulation of medical devices and pharmaceuticals in the country, released a notice that aimed at deepening the review and approval system reform and encouraging innovation in drug development.

This was the beginning of many such reforms or regulatory changes. There have been significant outcomes for the proposed regulatory changes.

Acceptance of foreign clinical trial data for drugs, drug classifications, implementation of a marketing authorisation holder system, strengthening of

IP protection etc., are some such changes. All these reforms brought in recently will have significant implications for innovation in the country’s pharmaceutical and medical devices markets.

Research & development activity in the country has picked up as the number of contract research organisations (CROs) has increased. Historically, Chinese pharma companies remained focused on generics and now they have slowly started investing and building capacities for innovative drugs. It is expected that by 2020, innovation in the biotech and pharma companies will move to a new phase and a lot of breakthroughs and innovative drugs are poised to be available for patients by 2025. While on the one hand research capability in the country has seen improvement, on the other hand there’s still a gap in clinical research between China and the developed markets. To spur innovation further, enhancement in the quality of research from academia coupled with increasing the knowledge transfer towards commercialisation of research is required. In all, domestic and foreign pharmaceutical companies are presented with growth opportunities thanks to the changing regulatory reforms that propel innovations.

Cover story of this issue by Mingping Zhang, Vice President of Technology, PAREXEL Regulatory Consultant discusses the nuances of clinical and regulatory product development in China, and its similarities and contrasting aspects in comparison to the rest of the world.

Prasanthi Sadhu Editor

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CONTENTS COVER STORY 10

MANUFACTURING

REGULATORY REFORM

24 GEP Models for Scaling Up Wet Granulation Processes in Planetary Mixers

How China is Investing in its Pharmaceutical Market Mingping Zhang Vice President of Technology PAREXEL Regulatory Consultant

Mariana Landin, Associate Professor, Dpt. of Pharmaceutical Technology, University of Santiago

30 Multifunctional Nanoparticles for Check Point Inhibition and CAR-T Therapy

Samaresh Sau, Research Associate, Department of Pharmaceutical Science, Wayne State University

Arun K Iyer, Director, U-BiND Systems Laboratory

34 Ushering in the Future of Pharma

3D Printing opens the doors of possibility for pharmaceutical and medical device industries

Tom Egan, Vice President, Industry Services, PMMI

39 Residence Time Distribution (RTD) Model

Novel applications to continuous pharmaceutical manufacturing

STRATEGY 06 Why Quality Standards of Drugs has to be the Primary Focus Area for Pharmaceutical Industry

Sanjeev Gupta, Managing Director, Kusum Group of Companies

RESEARCH & DEVELOPMENT 14 The Future of Pharma R&D

How external innovation changes pharma R&D

Alexander Schuhmacher, Professor, Reutlingen University

Michael Kuss, Partner, PwC’s Governance, Risk & Compliance (GRC) Practice

CLINICAL TRIALS 20 Innovation in Clinical Trials

Kemi Olugemo, Senior Medical Director, PAREXEL

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Ravendra Singh, C-SOPS, Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey

INFORMATION TECHNOLOGY 43 Creating Better Clean Label Soft Gels Without Gelatin Crosslinking

Claude Capdepon, EMEA-SEA Application Laboratory Manager Rousselot

EXPERT TALK 48 The Pharmaceutical Supply Chain from a CDMO’s Perspective

Michael Schmitz, Vice President, Planning & Logistics Vetter Pharma-Fertigung GmbH & Co. KG

50 Exploring BYOD

Is it a credible option for my study?

Bill Byrom, VP, Product Strategy and Innovation at CRF Health

54 How SMEs Can Achieve Regulatory Compliance through a Risk-Based Approach

Patrick Hughes, CCO, CluePoints 57 Books

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Advisory Board

EDITOR Prasanthi Sadhu Alan S Louie Research Director, Life Sciences IDC Health Insights, USA

EDITORIAL TEAM Debi Jones Grace Jones ART DIRECTOR M Abdul Hannan

Christopher-Paul Milne Director, Research and Research Associate Professor Tufts Center for the Study of Drug Development, US

PRODUCT MANAGER Jeff Kenney

Douglas Meyer Associate Director, Clinical Drug Supply Biogen, USA

SENIOR PRODUCT ASSOCIATES David Nelson Peter Thomas Sussane Vincent

Frank Jaeger Regional Sales Manager, AbbVie, US

PRODUCT ASSOCIATES Austin Paul James Taylor John Milton

Georg C Terstappen Head, Platform Technologies & Science China and PTS Neurosciences TA Portfolio Leader GSK's R&D Centre, Shanghai, China

CIRCULATION TEAM Naveen M Sam Smith

Kenneth I Kaitin Professor of Medicine and Director Tufts Center for the Study of Drug Development Tufts University School of Medicine, US

SUBSCRIPTIONS IN-CHARGE Vijay Kumar HEAD-OPERATIONS S V Nageswara Rao

Laurence Flint Pediatrician and Independent Consultant Greater New York City

Neil J Campbell Chairman, CEO and Founder Celios Corporation, USA Phil Kaminsky Professor, Executive Associate Dean, College of Engineering, Ph.D. Northwestern University, Industrial Engineering and the Management Sciences, USA

Rustom Mody Senior Vice President and R&D Head Lupin Ltd., (Biotech Division), India

In Association with

A member of Confederation of Indian Industry

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Sanjoy Ray Director, Scientific Data & Strategy and Chief Scientific Officer, Computer Sciences Merck Sharp & Dohme, US

Stella Stergiopoulos Research Fellow Tufts University School of Medicine, USA 4

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STRATEGY

Why Quality Standards of Drugs has to be the Primary Focus Area for Pharmaceutical Industry Time and again, Indian pharmaceutical industry has faced concerns due to its manufacturing standards and quality, which have led to penalties and drops in export figures. For the industry to realise its potential to capture world markets, the primary focus has to be towards improving quality standards to international levels.

Sanjeev Gupta, Managing Director, Kusum Group of Companies

P

erhaps not as rampantly in the developed countries, but definitely in the developing countries, and especially in India, access to medicines comes first, even earlier than the access to healthcare facilities or doctors. This essentially means that come illness, most likely one would swallow a pill first and then visit a doctor, if at all deemed necessary.

With consumption of medicine taking precedence, the quality of drugs need to be the primary focus area for the pharmaceutical industry. Not that the industry encourages the unregulated consumer 6

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habits of purchasing over the counter drugs,but the onus of manufacturing high quality medicines with fewer adverse effects has to be borne by the industry.

When composing a medicinal drug, the most important considerations invariably are identity and purity. The slightest deviations from the set norms by the originator can be damaging to masses, if the same goes unchecked during research and development. The creation and accessibility of comprehensive pharmacopoeias themselves is a matter of much care and complexity. It is of the wider

public knowledge and understanding that export quality of products non-exclusive to pharmaceutical drugs is different to what is either imported or sold domestically. In products as essential as medicines, it becomes all the more important to evaluate the quality standards of the drugs exported to those being sold to one’s own citizens.

Quality Standards of Drugs: Brief Context

It is estimated that 70 per cent of pharmaceutical drugs in India is generic, with

STRATEGY

9 per cent being oriented and 21 per cent being over the counter drugs. The entire generic drug industry is estimated to be of around US$30 billion.

The pharmaceutical industry is very export-oriented; however, in recent years, various factors have contributed to an export slump, with export figures dropping from US$6,488 million in 2015 to US$2,082 million in 2016.

The dropping of export figures is reflective of the various challenges faced by the industry in re-establishing the Indian pharma brand and culture as one

which is quality-oriented. In an otherwise flourishing and growing industry, the quality standards of drugs remains a hot area.

India remains the largest supplier of pharmaceutical drugs to the United States. Until last year, US Food and Drug Administration (FDA) had sent 42 warning letters to its global manufacturers of drugs, nine of which were directed towards Indian facilities. In light of repeated concerns, FDA inspections in India have increased by over 20 per cent.

While other developing countries including, CIS (Russian Commonwealth) nations, Latin American nations, African countries have favoured India for importing pharma products,—keeping the immediate competitor, China, fairly behind—it is only fair that the reputation of being a quality affordable drugs provider be sustained with consistent quality delivery, even though the quality assessment procedures in these countries may not be as rigid as the US. www.pharmafocusasia.com

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STRATEGY

Challenges and Solutions

To maintain the credibility of the industry in the long run,it is important that challenges are identified and a roadmap is worked upon to address them in a timebound manner. Some of the common challenges that have been ailing the industry include: Low government investment in healthcare

The government investment in healthcare is still shying away to touch the 2 per cent of the GDP, which is not only affecting the hospital industry but the pharma industry as well. A 1 to 2 per cent increase of investment in healthcare, and perhaps a minimum dedicated investment for pharmaceutical industry, will give the industry the required boost to strengthen its manufacturing output and upgrade the quality standards across the board.

Ensuring a level playing field

The existing focus has been on promoting low-scale indigenous manufacturing enterprises to push unbranded generic medicines at a much cheaper rate. While the same may seem beneficial for the poorer masses, it should be allowed only when the domestic entities match the quality and uniform standards of those that export to a global consumers. Lower quality standards is not only detrimental to the credibility of the industry at large but also to the health of the nation. A robust quality framework for domestic markets also helps in creating larger and better global impression of Indian pharmaceutical industry as a reliable player, as exporters face higher quality compliance requirements to maintain export competitiveness and international credibility. Regulatory authorities such as the Central Drugs Standards Control Organization (CDSCO) should be empowered to ensure the compliance of established law.

Another important benefit of ensuring a level playing field is that Indian population has been suffering for long due to lower standard cheap drugs that have reduced or no efficacy. It is only right that the best quality product is made available first to the nation and then exported elsewhere. This will also 8

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help offshore companies to invest heavily in India, noting the volume that India drives.

Limit the range of medicines that are subject to price control

Research and development, coupled with a complete manufacturing process, and added quality checking mechanisms such as pharmacovigilance adds to the manufacturing cost of the final product. Extending the number of medicines, which is now 20 per cent of drugs by sales volume, that are subjected to price control will adversely affect the production of quality products in order to maintain sustainability. High margin combination drugs will also suffer from this.

Ensuring efficacy of Indian manufactured drugs, data integrity, and hygiene

These three form one of the strong pillars for ensuring quality standards in Indian drugs. Stronger guidelines for manufacturing drugs, due diligence in maintaining data integrity, and implementation of strong hygiene policy from the time of importing of raw materials to the time of packaging and finalising batches for sales, are essential elements to ensure quality.

The Good News

The government has recently provided much hope and positivity to the entire industry and the world by initiating the drafting of Pharmaceutical Policy 2017, which provides significant focus to the quality concerns challenging the industry today. The draft is yet to mature, but

it will only happen when the industry leaders across the board, policy makers, healthcare experts, government, domestic, and private players, all come on board to engage and debate severely in order to resolve the quality challenges of the industry. The announcement by Drug Controller General of India’s (DCGI)to start a single window facility for providing consent, approvals, and other information will further ease the process for Indian manufacturers, allowing them to focus their energy on other matters. Digital integration of pharmacies will not only ease the flow of drugs with a proper track from one point to another but also help regulate pharmacies.

With the launch of latest government policy, small and medium scale pharma companies will get interest-free loans of upto five crores to upgrade their infrastructure and technology. The interest will be borne by the government.

However, the pharma companies have to obtain World Health Organization / Good Manufacturing Practices (WHO /GMP) certification within three years of disbursement of the loan.

Moves like this will go a long way in improving the image of Indian pharma industry worldwide. What this step is essentially doing is to encourage the around 250 small and medium level pharma enterprises with a budget of Rs.144 crore for 2018-2020 to upgrade the quality of products to international standards.

STRATEGY

This will expand international markets from developing countries to developed countries of Europe and the USA. It will not only boost our economy but also will improve the standing of the pharmaceutical industry of India.

India should advance to become a Pharmaceutical Inspection Co-operation Scheme (PIC/S) member, which is a non-binding, informal cooperative arrangement between regulatory authorities in the field of GMP. This is to ensure common standards of drugs manufacturing across the member countries. Today, smaller economies like Thailand, Malaysia, Indonesia, Iran, Turkey, and Ukraine are part of the PIC/S group while India is falling behind.

India has a huge potential for manufacturing pharmaceutical products thanks to massive manpower and

advanced technology, and can become a world leader in producing high quality medicines at relatively economical cost.

For this to happen, as an industry we need to show intent to grow internationally. More initiatives are required at a quicker pace for India to dominate the world, as countries like China are closing in on us with aggressive moves.

The government is making its decisions but policy making also depends on how the industry creates advocacy for a common objective. Quality of drugs needs to be the primary focus for the next decade, and it is only by ensuring quality that India can grow further.

It is important to understand that the efforts of the pharmaceutical industry has a direct impact on lives worldwide and it is the primary reason why we need to be one of the most responsible stakeholder in ensuring national health.

You like improving lives.

AUTHOR BIO

Inculcating the very persevering values of rigor, ambition and discipline in all his endeavours, Sanjeev Gupta is the man responsible for the success of the Kusum Group of Companies. In a sea of upbeat entrepreneurs, Sanjeev stands tall as a veteran in the pharmaceutical industry with over 30 years of experience.

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COVER STORY

STRATEGY

REGULATORY REFORM How China is investing in its pharmaceutical market

The nuances of clinical and regulatory product development in China, and its similarities and contrasting aspects in comparison to the rest of the world are discussed in this article. The specifics within risk management and the global regulatory authorities that contribute to this complex landscape were also explained.

Mingping Zhang, Vice President of Technology PAREXEL Regulatory Consultant

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R

ecent legislation has forced the Chinese regulatory environment to evolve, establishing a friendlier environment for pharmaceutical development. These changes may opendoors for pharmaceutical companies, but they also create the need to adapt to the fast-changing regulatory requirements and the uncertainty that comes with legislative change.

The root cause of these changes lies in China’s economic growth. China is set to have the largest middle-class group in the world, which will significantly alter the needs of people and as a result, reshape the market. China’s healthcare spending in 2016 was four times the level of 2008 – making it no surprise that experts anticipate China will become the second largest pharmaceutical market by 2020.

STRATEGY

Catalyst for Change

Policies

China’s economy needed a reboot and the healthcare and pharmaceutical industries were key to leading the growth. However, compared to many other areas, the pharmaceutical industry is one of the weakest in China due to extremely long and unpredictable regulatory timelines. To help address some of these issues within the industry, the Chinese government issued a series of regulations and reorganisations that aim to make fundamental changes to the Chinese regulatory administration system. The aim was to cater to the needs of the Chinese people and encourage pharmaceutical development.

In April 2018, Premier Li Keqiang proposed several policies for imported drug products to China. These policies include the following: • Since May 1 of this year, there are zero tariffs on oncology products imported to China, including new products and generics.

• Government and industry leaders also announced on May 1a new regulation that reduced the value-add tax (VAT) on oncology pharmaceutical products (API & DP) from 17 per cent to 3 per cent.

• Based on CFDA Order No 12 (2018), all the import chemical products are exempt from sample testing for every import batch, except the first import batch (risk-based testing may require for later batches) effective April 24, 2018.

• The Chinese government added 44 high-priced drugs to the National Reimbursement Drug List (NRDL) – a sign that China is expanding its coverage and improving Chinese patient benefits.

Chinese Regulation Timelines

2015: The State Council initiated the China regulatory reform.

2017:In October of 2017, China CPC Central Committee & State Council made another important announcement of regulatory reform.

2018: Based on the decision by the 13th National People's Congress, the Chinese government was reshuffled in March of this year. Since this change, the China State Council consists of 26 ministries and commissions in addition to the General Office of the State Council.

With this shift in power there was a reorganisation of the pharmaceutical industry. To start, the State Market Regulatory Administration (SMRA) was established and set to report directly to the State Council. Furthermore, the China National Drug Administration (CNDA), formerly the China Food and Drug Administration (CFDA), will report to the SMRA. The Resulting Reforms

The efforts of the Chinese government over the past few years has resulted in substantial change throughout the industry. From protocols, to access, to speed-to-market, the reform of the Chinese pharmaceutical industry has affected the policies and structures of organisations across the pharmaceutical continuum.

Regulatory Reviews

Other efforts by the government include expedited reviews for urgently needed therapies. If drugs and devices offer new solutions for treating life-threatening diseases or address critical unmet medical needs, they can be eligible for conditional approvals. This holds true as long as early and mid-stage study data indicate their efficacy and predict their clinical value.

This initiative not only shortens regulatory approval time, but also lowers the regulatory approval requirements. For some drugs, companies will have chance to use foreign data to support Chinese market access approval directly with post approval commitment. Even if the data package falls in to the ‘partially accept’ category after the ethnical sensitivity analysis, foreign data could be admissible.

Drug Access

One of the most aggressive approaches was announced in April 2018, allowing certain hospitals in Hainan province

to import drug or medical devices for unmet medical needs without CNDA review and approval. The clinical data collected in these hospitals could support Chinese registration if it can meet certain criteria. This kind of policy not only gives Chinese patients the chance for early access and advanced therapy, but also gives more flexibility for Chinese development.

In order to protect patients, however, the Chinese Court has endorsed a death penalty for falsification of drugs. Before regulatory reform, the most serious punishment for this kind of crime was that companies were not allowed to submit any new submission for three years.

The government also expanded drug access to investigational products.

Patients not enrolled in a clinical study may have access to investigational products if they give informed consent and if the investigational product is intended for treating life-threatening diseases with no effective treatments. The safety data generated from this expanded use can be used to support marketing authorisation applications.

Stricter Approval Criteria

One of the measures taken by the CFDA includes establishing stricter approval criteria. This implies that CNDA will implement internationally aligned requirements. With this, CNDA also joined the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 2017 and 5 of ICH’s guidelines were officially implemented in China based on CFDA Order NO 10 in 2018. Up to now, CNDA published about 120 guidance and translated over 500 WHO, ICH, FDA, EMA guidance. It is mutually agreed that global guidance can be referenced if certain specific Chinese guidance is not available.

Documentation

In addition, the ‘China DMF’ is implementing a rule which requires companies handling API, excipients and package materials to file their www.pharmafocusasia.com

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STRATEGY

Drug Master File (DMF) document to CNDA. This API DMF document should follow the CFDA Order 80, 2016 requirements – noting the application dossier requirement for the new classification of the chemical drug.

Similarly, the excipients and package materials DMF should follow the CFDA Order 155, 2016 requirements – noting the application dossier requirement for the pharmaceutical package material and excipients.

Addressing Drug Lag

In March 2016, the Chemical Drug Registration Category changed based on CFDA order NO 51 (2016), which aims to solve the drug lag and encourage innovation in China. For generic medicine, the approval criteria has changed from ‘meet specification’ to ‘demonstrate the similarity in both quality and clinical performance.’ For innovative drugs, the definition has evolved from ‘never marketed in China’ to ‘never marketed anywhere.’ New drugs will receive the ‘data protection,’ which is the extra regulatory benefit that CNDA offers.

Implementing Data Protection

On April 26 2018, CNDA announced public consultation for the new draft regulation of Drug Trial Data Protection.

During the data protection period, CNDA will not approve any other sponsors which intend to refer to the originator’s label, unless it generates all original clinical data or gets the originator’s authorisation. Innovative chemical drugs, orphan drugs or paediatric drugs with non-medical needs in China may be awarded up to six years of data protection –innovative therapeutically biologics may be awarded up to 12 years of data protection. One of the key considerations of the data protection period is whether China has been integrated into the global synchronised development – one of the key criteria to receiving the longest protection period. Additionally, the data protection period will depend on the length of the drug lag in China – the protection period will be deducted from the China drug lag time.

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CFDA GCP inspection progress * Issue

Pass

Total

Pivotal

12(~ 4%)

281

293

BE

26(~ 28%)

67

93

Total

38 (~10%)

348

389

Table

*2017 Nov CFDA presentation in China ISPE annual conference

Expanding Trial Sites

Data protection is just part of the ongoing effort by the CNDA to create a friendly pharmaceutical development environment in China. There are about 1.4 billion people in China; as a result, the ability to quickly recruit patients is one of the major advantages of running clinical trial in China. Prior to the reform, only 619 certificated clinical sites were allowed to perform clinical trials. With the China regulatory reform, all GCP compliant hospitals are allowed to perform clinical trials without certificate. The ‘hospital’ here refers to over 2000 Grade III hospitals (tertiary referral centres), over 8000 Grade II hospitals and over 20000 Grade I hospitals. In addition, the hospitals and principle investigators are incentivised to perform clinical trials because clinical research receives credit and counts towards KPI. Speed of Process

It used to take two to three years to get the Clinical Trial Application (CTA) in China and the average start-up timeline is four to six months. To start a clinical trial in China, sponsors need to go through the sequential process: CTA (two to three years), Ethnical Committee (EC) approval (one to three months) and Human Genetic Resources Administration Committee (HGRAC) approval (two to three months), before the first patient even enters through the doors. After reform, the CTA & EC can go in parallel, and the HGRAC can also go through the partially parallel process – expediting the process significantly. This action is expected to reduce HGRAC approval time to one to two weeks.

In addition, the CTA approval timeline has been shortened to six months in 2017 and it will drop to 60 working days in 2018. Companies used to get EC approval from each clinical site, which was bottle necked by non-standardised protocols. Now the new regulation encourages a central/ regional ethical committee, which will help to simplify and standardise the EC approval process. Ideally, CTA & EC approval goes in parallel which cost 3 month, then HGRAC approval and site initiation for 1 month; the total timeline from submission to First Patient In (FPI) could be four months in 2019.

Not only has the timeline shortened for Chinese trials, but certain technical requirements have helped smooth the Chinese trial startup process. CNDA used to require comprehensive CMC information even for early phase clinical trials. Now the draft Phase I and Phase III application guidance standardises requirements on different phase clinical trial applications.

Similarly, mandatory sample testing used to be the holdup of CTA approval, especially with bio-products. After reform, the sample testing will be risk-based for most products.

Additionally, regulators established the measure to ‘accelerate approval for innovative drugs.’ The NDA approval timeline used to be two to three years, but after reform, the new NDA timeline could be 120 working days for accelerated approval and 200 working days for standard approval.

Additionally, foreign clinical data could support Chinese registration if

STRATEGY

Improved Data Integrity

Clinical trial data integrity use to be a concern of pharmaceutical companies and health authorities. As a result, CFDA initiated the China GCP inspection for all the Market Authorized Application (MAA) in 2015 by implementing the ICH aligned GCP requirements. About 70 per cent of clinical trials which were performed under less strict GCP environments have been withdrawn. The rest of the applications need to go through GCP inspection.

Table 1 provides the inspection results, which imply that China clinical sites

are capable of generating high quality clinical data and fully complying with ICH GCP requirements.

As the Chinese pharmaceutical market expands to be one of the top markets in the world, regulators need to keep pace and facilitate growth.

With reforms that address the biggest

AUTHOR BIO

the efficacy and safety are adequate and could extrapolate to Chinese patients. Ethical sensitivity should be well addressed, and all the clinical sites must comply with ICH GCP requirements and should be ready for CNDA inspection.

pain points of the industry, China will be able to embrace technology and international data to improve processes and ultimately enable more scientific discoveries to help patients.

References are available at www.pharmafocusasia.com

Zhang has more than 15 years of regulatory experience in the pharmaceutical industry and health authority. He currently serves as the Vice President (Technical) in PAREXEL Consulting and is mainly responsible for regulatory strategy and CMC consultant in China. Previously he was the CMC Director at BeiGene where he was responsible for development relevant CMC activities; including drug substance & drug product manufacturing, clinical supply & regulatory CMC. He has previous experience as a DRA CMC Manager and supported the CTA, NDA, supplemental application, variation management, and other regulatory relevant CMC issues for Novartis China. Zhang received his Master’s Degree in Chemical Engineering from the National University of Singapore and his Bachelor’s Degree in Biochemical Engineering from Beijing University of Chemical Technology.

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RESEARCH AND DEVELOPMENT

The Future of Pharma R&D

How external innovation changes pharma R&D Research and Development (R&D) is crucial for the growth and future success of research-based pharma companies.

To maintain their R&D organisations efficient, pharmaceutical companies started to hedge the potential of open innovation to cut R&D costs and to access external knowledge. These new strategies could be divided into several categories: open source, innovation centres, crowd sourcing and virtual R&D. Alexander Schuhmacher, Professor, Reutlingen University Michael Kuss, Partner, PwC’s Governance, Risk & Compliance (GRC) Practice

R

&D has traditionally been and will continue to be (probably even more) crucial for the growth and future success of research-based pharma companies. Given the industries’ traditional R&D strategy, that was built on internal innovation, and the rising regulatory hurdles, pharma companies continuously increased their financial input into R&D related work with the hope to produce a higher nominal R&D output. Today, the total worldwide R&D spend of pharmaceutical and biotechnology companies amounts to US$150 billion, the global average R&D rate (R&D as per cent of sales) of pharma and biotech companies is 10.6 per cent (for the big players up to 20 per cent) and 15 companies in the top 30 R&D investors worldwide based on their R&D rate are pharma companies [1]. Two simple comparisons with the automotive and the chemical sectors illustrate the importance of R&D in the pharma industry:

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RESEARCH AND DEVELOPMENT

• The top pharma companies (figures in brackets= number of employees) Novartis (136,000), Roche (94,000) and Pfizer (90,000) invest comparable amounts in their R&D as the much larger car manufacturers Volkswagen (642,000), Daimler (290,000) and Toyota (338,000).

This is remarkable as both industries’ growth depends to the same degree on product innovation. And it is even more surprising as in addition the automotive industry faces major R&D challenges such as new mobility concepts or the technology shift from the combustion engine to the electric motor that should impact the car companies’ R&D investments significantly.

• Or take the example of BASF, the world leader in chemistry that also heavily benefits from innovation. With its 115,000 employees (total sales EUR 64.5 billion) it invests significantly less in R&D (EUR 1.8 billion) than the multiple times smaller (relating to number of employees and total sales) Boehringer Ingelheim (45,000 employees; EUR 15.9 billion sales; EUR 3.1 billion R&D costs), a German leader in the pharma sector.

Why are the R&D costs of pharma so high? Relatively low R&D success rates and long development timelines explain to a large extent pharma’s high R&D costs. The combined probability of technical and regulatory success for all R&D phases is on average 4 per cent[2]. This low success rate is based on various reasons, comprising the lack of efficacy or safety issues of new drug candidates, changing R&D strategies that impact the R&D project portfolio negatively or business reasons that let die commercially unattractive new drug concepts. R&D lasts on average more than 10 years (not including the time for basic research or postapproval Phase IV trials). Due to its direct link to opportunity cost and reduction of the patent life, the long time-lapse for pharma R&D impacts various other factors negatively: the total R&D costs, the risk of industry rivalry, and the uncertainties of generic competition. Any investment in a

Today, the total worldwide R&D spend of pharmaceutical and biotechnology companies amounts to US$ 150 billion, the global average R&D rate (R&D as per cent of sales) of pharma and biotech companies is 10.6 per cent (for the big players up to 20 per cent).

new drug project before regulatory approval happens many years before drug commercialisation and, thus, needs to be capitalised for years. This capitalisation of R&D costs leads to an enormous increase in the total R&D costs. The long period for pharma R&D increases the risk that competitors may be faster to market, and, in consequence, may reduce the market potential of a new drug. And the typical early patent application filing for the drug substance in lead discovery in combination with the long timelines usually results in an effective patent term of 8-12 years after market launch. Any delay before market authorisation negatively impacts the effective date of generic competition and, thus, the commercial success of a drug. Both the low success rate of pharma R&D in combination with long development timelines result in enormously high costs for discovering and developing a new drug. Older calculations (not including all costs of pharma R&D)indicate that the cost per new molecular entity (NME) are at around USD1.8 billion [2]. Newer analyses found significantly higher cost for drug innovation of US$3 billion and more [3].

Pharma’s high R&D investment (input) as such is only a part of the

problem. The real issue becomes apparent when one compares(1) the inputto (2) the output-figures of pharma companies, the number of new drugs launched, to (3) the investors’ expectations for an adequate return-on-R&D investment. In fact, the industry as a whole did not live up to these expectations and failed to come up with a reasonable output/input-ratio that has been rated positively by investors. In consequence, the average stock prize of the top twelve pharma companies (+39 per cent) developed below the S&P 500 (+67 per cent) or the German DAX (+66 per cent) in the past 5 years (Table 1).More concrete, most of the top pharmaceutical companies did not launch enough new drugs in the past years to meet their growth expectations only by product innovation[4]. And those market actors which were successful in providing NMEs, needed to invest so much in R&D and marketing for new products that they obviously find themselves in an R&D double windmill (the enormous investments in high-risk R&D today necessitate high R&D costs tomorrow). In consequence, the output/ input-mismatch put a principle question mark on the sustainability of the traditional pharma R&D model that is based on hiring the best scientists, doing R&D by the company itself, developing own ideas, generating own IP and trying to be first-to-market. At least some of the top pharma companies challenged their R&D models and realised that there is a need to open up their R&D organisations towards innovation that comes from external sources.

Today, pharma companies use both internal and external ideas to solve problems and to provide innovation to markets. Internally, they ask their scientists for new ideas and improvements. Or they look for existing technical solutions within the whole project portfolio (and not only within a technical field) that might be transferrable to the given problem. Or they ask their customers to get proposals for new ideas. At once, pharma companies analyse their competitors’ www.pharmafocusasia.com

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RESEARCH AND DEVELOPMENT

situations for troubleshooting. Or they collaborate with competitors to learn how to circumvent risks and problems.

Or they even go beyond the pharma sector and search in other industries for stimulation of how to solve problems.

More specifically, pharma companies use open innovation models, such as open source, crowd sourcing, public-privatepartnerships and innovation centres to broaden their innovation basis, to access external knowledge and to bring down R&D costs: • Open source approaches have been used to access knowledge of worldwide experts in a joint project approach.

Examples are the Human Genome Project or various initiatives to develop drugs for neglected diseases, such as the Special Program for Research and Training in Tropical Diseases (http://www.who. int/tdr/en/), the Medicines for Malaria Venture (https://www.mmv.org), the Global Alliance for Tuberculosis Drug Development (https://www.tballiance. org), or the Drugs for Neglected Diseases Initiative (https://www.dndi.org). These examples show both the important social function that the pharmaceutical industry has to play in developing new medications in financially unattractive markets and its ambition to experiment with new open R&D models.

• Pharma companies use crowdsourcing to post questions or problems to a large group of external experts (that are not part of the company) and invite them to provide solutions. The external experts solve the problems in return for financial gratification. Some of the most known examples are Eli Lilly’s Innocentive, YourEncore, and Open Innovation Drug Discovery (https://openinnovation.lilly.com/dd/https://openinnovation.lilly.com/dd), AstraZeneca’s open innovation platform (https://openinnovation.astrazeneca.com), or Bayer HealthCare’s Grants4Targets (https:// grants4targets.bayer.com), Grants4Leads (http://www.grants4leads.com), and Grants4Apps (https://www.grants4apps. com). Other pharma companies, such as Novartis, Merck & Co., Sanofi or 16

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GlaxoSmithKline (GSK) use this open innovation model in more project-related applications, such as to access patient information.

• Public-private-partnerships are a kind of research collaboration of academic or publicly funded institutions, charities, and pharmaceutical companies. The industry is actively supporting this open innovation models, as it helps to integrate external (academic) knowledge while sharing risks amongst the partners in research fields that are either outside the main franchises of the pharma companies or are exploratory. In addition, pharma companies can access public funding and affecting public reputation positively. In the past years, this open innovation model got more attention in the industry and numerous initiative were started, such as the Biomarker Consortium (source: www. biomarkerconsortium.org), the Innovative Medicine Initiative (www.imi.europe.eu),

the Serious Adverse Events Consortium (www.saeconsortium.org), or the FDA initiated the Critical Path Initiative (https://www.fda.gov/ScienceResearch/ SpecialTopics/CriticalPathInitiative/ default.htm).

• Another new type of open innovation is the innovation centre, which is an advancement of the traditional research collaboration, as it doesn’t focus on a specific project task or technology transfer, but on the long-term integration of external competencies usually provided by a world-class academic institution.

Innovation centres allow the access of external cutting-edge know-how and resources that could not be easily built internally. Pfizer with its Centers for Therapeutic Innovation, GSK with the Center of Excellence for External Drug Discovery or the Takeda’s Center for IPS Cell Research Application at Kyoto University are the most prominent

Stock prize (USD) May 31, 2013

Stock prize (USD) May 27, 2018

Stock prize development past 5 years

Novartis

55

65

+18%

Roche

192

187

-3%

Pfizer

21

30

43%

AstraZeneca

39

63

62%

GlaxoSmithKline

19

17

-11%

Sanofi

83

65

-22%

Takeda

45

41

-9%

Bristol-Myers Squibb

36

44

22%

Abbvie

35

88

151%

Gliead Sciences

39

57

46%

Amgen

74

152

105%

Johnson& Johnson

64

104

63%

Average S&P 500 Table

39% 1630

2728

67% Source: Wallstreet online

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RESEARCH AND DEVELOPMENT

• The clear-cut model: Recruit an expert team from the old R&D organisation and from outside the company to start the new virtual R&D and downsize or close the old organisation.

• The fund model: Establish an R&D fund that is company independent and sponsors new external ideas.

Conclusions

examples of the industry. Bayer Healthcare, the German Merck or Johnson & Johnson, have also experimented with this new concept with innovation centres in the U.S. and Germany.

And Novartis had a pioneering role with its long-lasting partnerships with the Massachusetts Institute of Technology (MIT) or the Dana-Farber Cancer Institute, just to name two examples.

The advantages of all these open innovation models are the access new ideas and external knowledge, the acquisition of new technologies, the problem solving and the reduction of overhead costs (and hence of R&D costs). The related risks are the typical challenges in project, alliance and IP management that come along with all kinds of external partnerships. Or companies need to deal with the uncertainties of their own staff that appear in the not-invented-here and not-sold-here syndromes.

What is surprising, however, that probably the most effective new form of open innovation, at least with respect to accessing external knowledge und cutting R&D costs, the virtual R&D model, has so far only be applied by Eli Lilly and a small number of mid-sized pharma companies, such as Shire [5] or Debiopharm[6]. When virtualising R&D, companies aim at reducing complexity and increasing efficiency by focusing on internal core competencies that provide a competitive edge, reducing fixed overhead costs, increasing projects-dedicated budgets, and selecting the best external service providers to leverage economies of scale 18

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and scope and to access the best quality.

Eli Lilly applied that open innovation model when starting Chorus in 2002.

Chorus manages a considerable portfolio of around 15 drug projects with worldwide clinical trials with a small number internal staff of 40 full-time equivalents[7]. Apparently, it delivers a higher output when compared with the traditional Eli Lilly R&D organisation: (1) a higher probability of success for the proof-of-concept trials (54 per cent Chorus vs. 29 per cent traditional Eli Lilly) and (2) a 3 to 10 times higher overall productivity.

The advantages of virtualising R&D are clear and proof-of-principle is given by the success of Chorus, Debiopharm and Shire. The question is why other pharma companies have not yet implemented this open innovation model?

The answer to this question is as apparently: there is too much risk to fail!

Changing an organisation’s R&D model to a completely new one is a suicide mission as the old R&D strategy is hardwired in the DNA of the organisation and the culture of its people. And the costs of gradually restructuring a global R&D group located at different sites to become a slim virtual organisation would be substantial. The three solutions to this are: • The start-up model: Start a new organisation that is geographically and structurally separate from the original R&D organisation. If the virtual entity succeeds, gradually redirect investment funds towards it and away from the old operations.

Given the situation that pharma companies have limited influence on the environmental spheres, pharma is forced to improve their R&D output/ input-ratio either by reducing costs as a combination of releasing relevant R&D personnel and out-sourcing project-related R&D activities to service providers in low-cost countries or to find new of ways for R&D, such as crowd sourcing, public-privatepartnerships, innovation centres or virtual R&D. The examples illustrated herein provide an indication that these new open innovation models can help to reduce R&D costs and increase access to knowledge and new technologies. In any case, any new R&D model needs to be linked to a new open-minded culture of how the new strategy is implemented.

Thus, to leverage from these models, pharmaceutical companies need to make the following cultural modifications: • hire people who are open-minded and that know of how to work with different stakeholders and different cultures • make clear that innovation need to be accessed globally and does not come from internal source only • push back not-invented-here and notsold-here syndromes • promote the entrepreneurial spirit in the company • stimulate the openness in the organisation to share ideas • encourage teamwork • develop managerial skills to better utilise external partnerships • increase the absorptive capacities by implementing open innovation processes, and • form more strategic alliances and active involvements in innovation networks.

RESEARCH AND DEVELOPMENT

innovation in the pharmaceutical industry. Drug Discovery Today, 2010; 18: 1133-1137 [6] Schuhmacher A, Gassmann O, McCracken N, Hinder M. Open innovation and external sources of innovation. An opportunity to fuel the R&D pipeline and enhance decision

AUTHOR BIO

Literature [1] European Commission— Joint Research Centre. The 2017 EU Industrial R&D investment scoreboard. http://iri.jrc.ec.europa.eu/ scoreboard17.html.

[2] Paul SM, et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nature Reviews Drug Discovery,2010;9:203–14.

[3] Harper M. The truly staggering cost of inventing new drugs.

2012. http://www.forbes.com/ sites/matthewherper/2012/02/10/ the-truly-staggering-cost-of-inventingnewdrugs/#2ce906714477.

[4] Schuhmacher A et al. Changing R&D models in research-based pharma companies. Journal of Translational Medicine, 2016; 14:105; doi: 10.1186/s12967-0160838-4.

[5] Schuhmacher A, Germann PG, Trill H, Gassmann O. Models for open

making? Journal of Translational Medicine. Journal of Translational Medicine, 2018; 16:119.doi: 10.1186/s12967-018-1499-2 [7] Owens PK. A decade of innovation in pharmaceutical R&D: the Chorus model. Nature Reviews Drug Discovery, 2015;14:17–28.

Alexander Schuhmacher graduated in biology at the University of Constance (Germany) and in pharmaceutical medicine at the Witten-Herdecke University (Germany); he is also a graduate of the Executive MBA program at the University of St. Gallen (Switzerland).

As professor at the Reutlingen University, Alexander teaches in pharma management with a focus on innovation management.

Prior to his academic career Alexander worked for 14 years in the pharmaceutical industry in various R&D positions.

Michael Kuss is a Partner leading PwC’s Governance, Risk & Compliance (GRC) practice in Switzerland. Amongst other industries, he is serving major pharmaceutical corporations on their GRC strategies, capabilities and transformations. He graduated in Computer Science at the University of Applied Science Furtwangen (Germany); he is also a graduate of the Executive MBA program at the University of St. Gallen (Switzerland).

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CLINICAL TRIALS

Innovation in Clinical Trials Digital technology is increasingly used to improve clinical trial efficiency. Its use spans all phases of drug development, and impacts areas such as recruitment and retention of patients, wearables, virtual clinical trials, and health economics outcomes research.

Leveraging emerging data sources and technology can reduce development costs and time to market.

Kemi Olugemo, Senior Medical Director, PAREXEL

C

linical trial development has evolved significantly over the past few decades. Digital technology is increasingly used to improve clinical trial efficiency. Its use spans all phases of drug development, and impacts areas such as recruitment and retention of patients, wearables, virtual clinical trials, and health economics outcomes research.

Leveraging emerging data sources and 20

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technology can reduce development costs and time to market.

Early Clinical Trials

Reports of clinical trials pre-date the digital era, with James Lind being credited by many to have conducted the first controlled clinical trial in 1747 (Collier 2009).This study involved rudimentary data collection from 12 sailors with

scurvy, who were assigned to one of six different forms of treatment. The men who were treated with citrus recovered after 6 days of therapy, whereas, the other treatments had no demonstrable effect.

Although the number and nature of successful clinical trials proliferated in the ensuing years, the adoption of digital record keeping during the industrial revolution introduced key efficiencies into the data collection and analysis required for drug development.

Digital Technology

A critical element of trial design is ensuring the study population is accurately diagnosed with the indication of interest, and that any biomarkers predictive of response to treatment are correctly identified. Electronic health records are real-time, digital, patient-centred records that can be created and managed by several providers. Anonymised electronic health record databases permit strategic searches to evaluate and quantify the impact of protocol specific inclusion/ exclusion criteria on the patient recruitment potential of a given clinical trial protocol. They are used during protocol design and can also be informative in the event of protocol amendments that involve eligibility criteria.

A specific example relates to the use of various computer-based cognitive assessments to monitor cognitive health.

This data, when confirmed to be psychometrically valid, is critical in selecting patients appropriate for new therapies in Alzheimer’s disease and other neurodegenerative disorders. Computerised tests can be administered remotely, and in many cases, are more sensitive than paper tests.

Trial sponsors and contract research organisations have also gradually increased the adoption of electronic informed consent and EDC systems to collect electronic patient-reported outcomes (PROs). A PRO is any report of the status of a patient's health condition that comes directly from the patient, without interpretation of the response by anyone else. Per the

CLINICAL TRIALS

Digital technologies involve computer-based solutions, which are available at various stages in drug development: Digital tool

Study Phase

Advantages

Electronic Health Records (EHR)

Recruiting patients

Provides accurate, up to date, and complete patient records from multiple sources

Handheld Devices

Screening and Study Execution

Portability Speed of capturing patient data and test results Eliminates source data verification requirement

Electronic Informed Consent

Screening and Study Execution

Consistency in documenting patient comprehension and retention Forms and data easily accessible via web portal Improved version control

Computer-based Assessments

Screening and Study Execution

Increased quality of tests via engaging multimedia Online data storage

Electronic Source data

Study execution

Direct interface with electronic databases eliminates transcription errors

Applications Telehealth Tools

Study execution

Real-time and consistent patient outreach for post screening guidance and study updates

Wearable Devices

Study execution

Monitoring and diagnostic capabilities Real-time data collection Improves patient engagement and compliance in clinical trials

Analytic Platforms

Study execution

Detect correlations across the data points being collected.

Potential to identify digital biomarkers Data-driven insights easily accessible, and able to inform drug development decisions

Patient Registries

Late phase/ commercialisation

Source of real-world data on treatment patterns and natural history of disease Long-term safety data, including rare adverse event incidence

Technology Platforms

Late phase/ commercialisation

Aggregates and integrates data from different sources including Electronic Data Capture (EDC), Electronic Medical Record (EMR), wearable devices, imaging, and laboratory data Enables additional exploration of amassed data through the application of advanced analytics

U.S. Food and Drug Administration’s (FDA) guidance, clinical trials using reliable PRO instruments may be used to support medical product labelling claims. In addition to paper-based PRO instruments being replaced by electronic versions, there has been increased use of data from wearable devices to supplant paper-based outcome measures, as well as other physician-rated instruments.

Wearables sensors have been used to a large extent as monitoring devices for heart rate, sleep activity, step count, blood pressure, oxygen saturation and temperature measurements. In neurodegenerative diseases like Parkinson’s disease, devices incorporating accelerometry and electromyography are capable of measuring motor activity, yielding critical objective assessment of disease severity and response to therapy. The sensors in these devices can be paired with other applications (such as those in mobile phones) to measure tremor, dyskinetic movements, gait and balance (Kubota 2016).

Other types of wearable devices can be used in a diagnostic or biomarker capacity, including assessments of walking speed in Multiple Sclerosis, seizure detection via wearable ECG devices, and measurement of perspiration in Cystic Fibrosis.

The adoption of sensitive and efficient instrument scan increase study power, thereby requiring fewer participants and accelerating study conduct.

Digital technology has transformed how companies approach clinical development by incorporating valuable insights from multiple sources of data.

Data analytics can be used to inform virtually every facet of the clinical trial.

Companies want more efficient ways to capture, aggregate and manage the right data. Analytic platforms provide a single source of operational study data that is used to guide decisions through visualisation tools. For example, study metricscan be analysed and communicated in a dynamic way to www.pharmafocusasia.com

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CLINICAL TRIALS

ensure key decision-makers understand them. These insights can also come from aggregated data over numerous studies in the same indication or therapeutic area.

Data analytics can also be adopted in the early stages of study conduct. In studies involving the central nervous system, the quality of psychometric rater data is optimised by periodic audio and video surveillance. Outliers are therefore easily identified, with the opportunity to correct issues earlier during study conduct. This algorithm is easily applied to other studies with similar assessments.

Site-less Trials

Virtual (or direct-to-patient) clinical trials are emerging as a valuable development tool, as these studies use technology for patient engagement, and for collection of safety and efficacy data, while eliminating the need for face-to-face clinic visits. They are of particular interest in orphan diseases, and in study populations with limited travel ability. Data collected in patient registries can offer insights into the natural history of disease, and outcome-based data may be linked to other data sources such as electronic medical claims data. As a consequence, registries enable transfer of real-world data sources into evidence that can improve health outcomes. Another advantage of patient registries is the ability to identify new biomarkers and clinical endpoints from the repository of data. This further stimulates new research on the causes, treatment, and outcomes of various conditions.

With use of DNA resources from EHR, the Myocardial Infarction Genetics Consortium Investigators (Stitziel2014) were able to make inferences about how the pharmacologic action of ezetimibe mimics the genetic inhibition of the Niemann–Pick C1-like 1 protein. These naturally occurring genetic mutations that confer a reduced risk of coronary artery disease were previously unknown prior to the completion of the prospective cohort studies using samples from 22,092 patients.

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Collaborative Approaches to Success

In 2012, a number of major pharmaceutical companies formed the nonprofit collaboration TransCelerate BioPharma in order to investigate how digital technology could be leveraged to improve clinical trial efficiency. Various initiatives have grown from this collaboration including an industry wide information sharing and clinical data standard to drive efficiency and consistency in data collection, and to promote interoperability and integration of EHR/EMR. The placebo and standard of care initiative is building a collection of anonymised patient data from the control arms of hundreds of clinical trials. Reuse of data from previous studies can reduce the number of patients required in a clinical trial via access to historical controls. This is of particular relevance in studies with rare disease populations, where use of placebo is infrequent, challenging, or both.

Opportunities for the Future

Genomic medicine involves the application of genetics to diagnose and treat disease. Early application of genomic medicine in drug development can expe-

dite regulatory and payer approval by identifying those individuals most likely to benefit from a therapy. Personalised medicine involves “therapeutic products for which the label includes reference to specific biological markers, identified by diagnostic tools that help guide decisions and/or procedures for their use in individual patients” (PMC 2017). In 2017, there were a record number of FDA approvals of such personalised medicines, including approval of the first three gene therapies. The European Union regulatory framework for pharmaceuticals has outlined a number of tools to help companies develop personalised medicines. Japan is using its largest biobanks to collect genome data in support of clinical research on genomic and personalised medicine.

It is anticipated that in the near future, detailed individualised biological and physiological data using a combination of genomics, personalised electronic health records and wearables will drive efficiencies in the drug development process. Well planned virtual studies, using endpoints acceptable to key stakeholders (i.e., patients, physicians, payers, and regulators) are poised to accelerate clinical development in a cost-effective way.

References are available at www.pharmafocusasia.com AUTHOR BIO Kemi Olugemo is a Neurologist and Senior Medical Director at PAREXEL. She received her Bachelor’s degree from the University of Massachusetts and her MD from the University of Maryland School of Medicine.

Her current responsibilities include: medical monitoring; consulting in clinical drug development from pre-clinical through post-marketing, support for protocol development, regulatory submissions, and manuscript development; training on therapeutic areas, specific disease states, adverse events assessment/management, and addressing medical and scientific questions for PAREXEL. Olugemo is certified by the American Board of Psychiatry and Neurology.

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MANUFACTURING

GEP MODELS FOR SCALING UP WET GRANULATION PROCESSES IN PLANETARY MIXERS The utility of Gene Expression Programming (GEP) for predicting the endpoint of the granulation process in planetary mixers has been demonstrated. GEP allows modelling the impeller power of the equipment as function of operation conditions and wet granule properties, providing general experimental equations of high predictability for granulators of increasing bowl capacity.

Mariana Landin, Associate Professor, Dpt. of Pharmaceutical Technology University of Santiago

W

et Granulation (WG) process is a critical step for the production of many pharmaceutical dosage forms. During this stage, a liquid, usually water, is combined with a blend of active ingredients and excipients to form homogeneous granules, with suitable properties to further processing.

The establishment of the end point of the wet granulation process is difficult scaling up; however, it is of high relevance within the pharmaceutical industry and often involves time-consuming empirical studies.

It has been pointed out that scaling up of a granulation process is facilitated by maintaining geometric, dynamic, and kinematic similarity. On this purpose, the suppliers design the equipment of increasing size (bowl height/diameter ratio, impeller design) to achieve geometric similarity. On the other hand, the dynamic and kinematic similarity, are directly related to the control of impeller speed, which determines the forces and/or collision energy experienced by the granules and the particles velocity inside the granulator, respectively.

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MANUFACTURING

In a previous recent work we have demonstrated the utility of Artificial Intelligence (AI) tools for predicting the endpoint of the granulation process in high speed mixer-granulators of different scale. The use of these new technologies has proven to be more useful than the classical procedure based on dimensionless Power number/ Reynolds number relationship.

AI tools allowed modelling the machine impeller power as function of operation conditions and wet granule properties, providing a unique experimental equation of high predictability for high shear granulators of different size and similar, or even dissimilar, geometries. In this situation, it is possible to predict the end point of the process in a large granulator, calculating the power of the impeller necessary to obtain wet granules of certain characteristics using the results of experiments carried out in small granulators.

As an extension of that work, we present here successful results derived from applying the same technology,

The Gene Expression Programming introduced by Ferreira has been proposed as a technology capable of providing experimental equations of high predictability, that relate the variables involved in a process with the parameters that characterise the results of that process, and consequently, generating transparent models.

Gene Expression Programming, to experiments carried out in geometrically similar Collette planetary mixers with increasing bowl capacity between 20 and 200 liters.

The Gene Expression Programming introduced by Ferreira has been proposed as a technology capable of providing experimental equations of high

predictability, that relate the variables involved in a process with the parameters that characterise the results of that process, and consequently, generating transparent models. A full explanation of this methodology and its pharmaceutical applicability can be found in Colbourn and collaborators work.

Materials and Methods

A range of planetary mixers (Machines Collette MP 20, MP 90, and MPH 200 models, Wommelgem, Belgium) of different capacities between 20 and 200 litres were used for this study. All the bowls were regular in shape with similar relative ratios for the blades/ bowls dimensions (Figure 1).

A formulation consisting of dicalcium phosphate dihydrate (64.4 per cent), mannitol BP (21.6 per cent), maize starch (12.0 per cent) and pregelatinised starch (2.3 per cent) was used. The total weight of dry powder mix was fixed at a constant proportion of the bowl volume, giving batches of 6.0, 27.0, and 60.0 kg in weight for the 20-, 90-, and 200-liter bowls,

MPH 200L

P U ING L A SC MP 90L

MP 20L

Geometric Similarity

+

GENE EXPRESSION PROGRAMMING

Figure 1 Schematic representation of the scaling up process in Collette planetary mixer–granulators.

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MANUFACTURING

A database of 53 records was generated with the variables and results

respectively. Collette planetary mixers have four speeds and the blades have rotational and translational movement.

Two or three speeds were used for each machine. A constant flow rate of water was selected in order to add 18.4 per cent of water in 10 min for all the machines.

The power consumption was recorded when the machine is running at specific blade rotational speed. The raw materials were introduced in the bowl and dry mixed for 5 min and the power consumption recorded again. Water was then sprayed on at a constant rate. Wet mass samples were taken at pre-set times equivalent to different endpoints. The amount of liquid added was estimated (per cent liq). The differential power consumption for each sample was calculated (∆P, Watts). The bulk density of the collected samples (ρ, kg m-3) was determined by weighing a glass vessel of known volume, empty and full with flush wet mass as previously described.5 The consistency of wet masses (η, Nm) was measured using a mixer torque rheometer (Caleva MTR, Sturminster Newton) as described previously. Briefly, to generate a baseline torque value, the rheometer was run empty at 52 rpm for 20s. Then 30g of wet mass sample was added and the instrument was running for 30s before initiating the data capture process (30s). Each measurement was conducted in duplicate.

Artificial Intelligence Tool: Gene Expression Programming

A commercial software INForm® v5.01 (Intelligensys Ltd., UK) which implement Gene Expression Programming was used in this study.

For the GEP training, the database (53 records) including results from 20L, 90L and 200L was randomly split in three groups: 43 facts for training, 7 to test the error (15 per cent) and 8 as a validation dataset.

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Table 1

Continued ...

MANUFACTURING

computed f-ratio value higher than critical f value for the degrees of freedom of the model indicates not statistical significance between predicted and experimental results and hence, good accuracy of the model.

Validation of the GEP model was performed by predicting the differential power consumption results for unseen data (validation dataset) and analysing the correlation between experimental and predicted values of the validation dataset.

Results and Discussion

Table 1

Training and test datasets were used for the GEP software to obtain a model for the output (differential power consumption,) using the impeller diameter, the gate speed, the percentage of liquid, the wet mass weight and density, and mean torque as inputs. The GEP model was obtained using the parameters in Table 2. The GEP model was expressed as an experimental mathematical function.

The quality of GEP model was tested using the determination coefficient (R2) for the training, test or validation data-

sets and the f-ratio of the ANOVA for the model. R2 is defined by equation 1 where y is the actual point in the data set, y’ is the value calculated by the GEP model and y” is the mean of the dependent variable. R2 value is indicative of the percentage of the variability of the differential power consumption that is explained by the selected variables. The larger the value of the Train Set R2, the more the model captured the variation in the training data. Values between 70 and 99.9 per cent are indicative of good model predict abilities. A

Training parameters setting for GEP software (INForm® v5.01) GEP general parameters Number of Populations: 10 Population Size: 1000 No. Generations: 200 Head length: 7 Nº. Genes: 3 Random Seed: 1 Fitness Type: Mean Squared Error Proportion of Elite: 0.05 Proportion Regenerated: 0.1

Genetic Operators One point Crossover: 0.3 Two point Crossover: 0.3 Gene Crossover: 0.1 Transposition of IS: 0.1 Transposition of root: 0.1 Gene Transposition: 0.1 Mutation: 2 Constant Mutation: 1 Using Random Number Constants? Yes Function Set: +, -, * Connected Inputs: Equipment, D, N, %Liquid, ρ, η

Table 2

GEP is an evolutionary algorithm proposed by C. Ferreira that evolves complex computer programs, as neural networks from the present work, and encodes them into linear forms named chromosomes. GEP technology is able

Equation 1

to generate populations of mathematical functions by the introduction of mutations, transpositions or recombination of the operators and to select them, according to their ability to solve a specific problem. The result is an empirical equation that expresses the relationship between the variables (inputs) and parameters (outputs), which can be used to predict outcome of the process.

INForm® succeeded in generating a predictive GEP model (empirical polynomic function, Table 3) for the differential power consumption (∆P).

As it can be seen, high determination coefficients were found for both training and test data (R2>85.90 per cent), which is indicative of a high predictability of the model. The ANOVA performed in order to compare experimental against predicted results also indicates good performance. The predictability and accuracy of the GEP www.pharmafocusasia.com

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Table 3 Parameters to assess the quality of the model (predictability and accuracy) together with GEP equation. Where m is the wet mass (Kg), N is the gate speed (rps), % liq is the percentage of the liquid, Ď is de bulk density of the wet mass (kg m-3) and Ρ is the mean torque of the wet mass (Nm)

equation point out the high quality of the model. Additionally, GEP model can properly predict, with high determination coefficient, the validation data set (R2 = 93.54 per cent), that includes previously unseen data obtained with the same equipment.

wet mass weight, the gate speed, the proportion of the granulation liquid and the properties of the wet mass (bulk density and consistency), independently of the size of the bowl.

The GEP equation allows estimating the endpoint of the granulation process

in Collette planetary mixers of different size but similar geometry, through adequate predictions of the impeller power.

The principles and the methodology proposed here can be applied to understand and control manufacturing process, including continuous granulation process, using any other granulation equipment.

The good results obtained with the planetary mixers in addition to the high shear mixer-granulators presented before, are highly indicative that the AI methodology is generalisable and innovative to understand and control the end point of the wet granulation process in industrial equipment.

Acknowledgements The experimental data of this study were obtained during the development of one of projects supported by the International Fine Particle Research Institute (IFPRI) entitled "Granulation using mechanical agitation", led by Prof.

P. York from University of Bradford, which involved researchers from Zeneca Pharmaceuticals, Prof. RC Rowe and Dr. M.J. Cliff, and from AromaticFielder Ltd, Mr. A.J. Wigmore.

As it can be seen in Figure 2, the correlation coefficient between experimental differential power consumption and the values predicted by the model is high for the GEP approach (r=0.9885). Moreover, the slope of the linear function for the GEP approach is close to 1 (slope=0.9934) indicating an excellent fit to the experimental results.

The results show that Gene Expression Programming was able to find an experimental polynomic equation (transparent model) that properly predicts the differential power consumption values as a function of the 28

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References are available at www.pharmafocusasia.com

Mariana Landin is an Associate Professor in the Dpt. of Pharmaceutical Tecnology at the University of Santiago (Spain). Her research interest has been recently focused on the application of Artificial Intelligence as Neural Networks, Neurofuzzylogic, genetic algorithms or GEP for modeling pharmaceutical processes for rational design of new and/or optimised dosage forms.

AUTHOR BIO

Figure 2 Correlations between experimental values of differential power consumption and those predicted by the GEP model, for the training, test and validation data sets.

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Multifunctional Nanoparticles for Check Point Inhibition and CAR-T Therapy The recent advent of immunotherapies has transformed the landscape of cancer treatment. In 2017, 469 new clinical trials were reported on immunotherapy. Although the effect of immunotherapy on cancer has been transformational, they account for only a few percent of cancer patient population. Thus, nanoparticles can play a leading role in immunotherapy, CAR-T generation and immune check point modulation.

Samaresh Sau, Research Associate, Department of Pharmaceutical Science, Wayne State University Arun K Iyer, Director, U-BiND Systems Laboratory

R

ational of Reprogramming TumourImmune System The important role of our immune system is to recognise the foreign substance from the healthy cells and eliminate the foreign object from the body while maintaining the normal cells unharmed. To do this, the body immune cells, such as lymphocytes and monocytes utilise unique check point molecules which function in a regulated way to either activate or quiescent the immune response against the foreign cells. Cancer cells sometimes dysregulate the function of immune check point molecules and reprogram me the checkpoints to escape being attacked by the immune cells. The discovery of check point inhibitors is a smart tool for selectively blocking the immune evasion mechanism in between the cancer cell and the immune cells, 30

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more importantly the T-cells and the Macrophages in order to resurrect and sustain the anti-tumour response.

Modulation of Immune Check Point Molecules

Programmed death-1 (PD-1), programmed death ligand 1 (PDL1), T-lymphocyte-associated antigen 4 (CTLA4) and B7-H3 are few examples that has been utilised in developing selective inhibitors to stop the immune evasion of cancer cells.

Several monoclonal antibody inhibitors, such as nivolumab and pembrolizumab against PD-1, atezolizumab against PDL-1 and ipilimumab against CTL4 have been approved for clinical use of some cancers such as melanoma, lung cancer and bladder cancers. Clinical advancement of immune check point

inhibitors has evolved over the time with improved therapeutic efficacy and safety. The first FDA approved check point inhibitor, ipilimumab improved the survival of advanced untreatable melanoma patients by 3.7 months as compared to conventional therapy.

However, adverse side effect associated with immune-Related Adverse Events (iRAE) and moderate response rates to patients of ipilimumab compromised its use. Successively, PD-1 was considered as a better target than CTLA-4 because pembrolizumab and nivolumab antibody blocked the PD-1 in tumour-infiltrating T cells in the tumour milieu that reduced the side effects and improved response rates. The PD-1 therapy is effective for the PDL-1 positive tumours. This observation led to development of PDL-1 inhibitors such as atezolizumab

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that has been approved for non-small cell lung cancer (NSCLC) and advanced urothelial carcinoma (including bladder cancer) with improvement of overall survival to 4.2 months as compared to docetaxel treatment for NSCLC. Several combination therapies, including antiCTLA-4 and anti-PD-1 have won the regulatory approval as early as 2014 for various types of cancers, such as stomach, breast, bladder, pancreatic, renal, lung and ovarian cancers. In 2017, 251 clinical trials were reported with combination immunotherapies. The reason for more effectiveness of combination therapy than the single therapy is due to their divergent mode of target. One such example is the combination of ipilimumab that target T-cell of lymphoid tissues and PD-1 inhibitor that target T-cell of tumour microenvironment. Although

a combination immunotherapies have resulted in better therapeutic outcome, 60 per cent of the patients have reported severe iRAE including colitis or diarrhoea.

Nanoparticle for Improving Check Point Inhibitory Effect

To address the adverse effect such as iRAE, several nanoparticle approaches have been utilised in cellular and preclinical setting. Lei, C. et al have reported that micron-sized mesoporous silica nanoparticle encapsulated with anti-CTLA-4 antibody had high loading efficiency and improved anti-melanoma efficacy as compared with soluble antibody and this result is attributed to controlled release of antibody from the microparticle. Kulkarni et al. reported a self-reporting nanoparticle system containing paclitaxel, PDL-1

targeting ligand, Fluorescence Resonance Energy Transfer (FRET) pair, DyLight 755 (fluorescent dye) and DyLight 766 (quencher) conjugated through caspase 3 cleavable linker. The novel design had a purpose to selectively target the PDL-1 positive infiltrating CD4+ and CD8+ T-cells that delivered the nanoparticle into the tumour environment, resulting in induction of paclitaxel mediated caspase 3 activation.

This led to separation of FRET pair yielding a fluorescent signal. The [18F] FDG-PET or CT imaging of this nanoparticle showed no reduction in tumour uptake even after 7 days post-treatment. One of the limitation of this nanoparticle is the inability of real time imaging of the infiltrating T cells in tumour microenvironment.

Delivery of siRNA against PD-L1, CTLA-4 has also been investigated using various types of nanoparticles such as polymeric and cationic lipoid nanoparticles. Teo PY. et al reported the delivery of PD-L1 siRNA encapsulated in polyethyleneimine (PEI) polymers decorated with folic acid (FA) for sensitisation of epithelial ovarian cancer (EOC) cells through T cell mediated killing. The conjugation of FA with the PEI nanoparticle had enhanced siRNA uptake into EOC cells through cell surfaced over-expressing folate receptors and the data demonstrated almost 50 per cent PD-L1 protein silencing in EOC cells. Chen M et al reported feasibility of biodegradable poly(DL-lactide-coglycolide) nanoparticle (PLGA-NP) loaded with anti-OX40 antibody to efficiently induce cytotoxic T lymphocyte (CTL) response. The nanoparticle was prepared by double emulsion method and demonstrated an average size of 86 nm with a loading efficiency of 25 per cent. OX40 loaded PLGA-NP produced CTL activation and cytotoxicity to cancer cell through production of cytokine as compared to free anti-OX40 antibody.

These results suggest that PLGAbased nanoparticle could be an efficient delivery system for cancer immunotherapy. www.pharmafocusasia.com

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Revolution of Cell-based Therapy with CAR T Cells

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In the not too distant future, nanoparticles are expected to play a significant role in improving the efficiency of disease therapy.

emerging role and few attempts have been adopted. In this regard, MT Huynh has developed clinically used calcium alginate nanoparticles (CANs) for delivery of vaccines and chemokines that improve the tumour homing of GD2. CAR T cells in neuroblastoma microenvironment. The ganglioside GD2 over-expressed on neuroblastoma and GD2 specific CAR T cells has been designed for tumour inhibition. As the insufficient migration of CAR T cells to solid tumours is one of the major problem of CAR T therapy, the author has used XCL1 chemokine to improve the diffusion of GD2. CAR T cells at the neuroblastoma site. Nanoparticles encapsulated with contrast agents have

AUTHOR BIO

Recently, several companies are developing and commercialising cell-based therapeutics including hematopoietic stem cell (HSC) transplants, and chimeric antigen receptors (CAR) T cell therapy. In 2017-18 FDA approval of Tisagenlecleucel (Kymriah™) for lymphoblastic leukaemia and Axicabtagene ciloleucel (YescartaTM) for large B-cell lymphoma have revolutionised the T cell therapy and the data of these CAR-T therapy demonstrated overall response rate of 70-80 per cent indicating sustainability of the anti-tumour response.

CAR is a engineered receptor that was designed to introduce the anti-tumour function of immune cells, such as T cell for killing cancer cells. Typically, these receptors graft the specificity of a monoclonal antibody onto a T cell. The chimeric receptors are the fused form of different sources, such as mouse and human. In CAR-T cell therapy, T cells were isolated from patients and then transfected with CAR vector containing tumour cell antigen recognising domain.

Thus, after intravenous infusion of engineered CAR-T cells back into patients they will be able to recognise cancer cells and selectively kill them. Although CAR-T therapeutics have demonstrated outstanding clinical outcome, their safety and production are major challenges.

Many patients experience the nonspecific cytokine storm effect. Alongside, individual T cell population has a unique cytokine profile and they can be identified either as a beneficial tumour-killing T cells or as detrimental counterparts.

Thus, identifying subsets of CAR-T cell with tumour killing phenotype is one of the most important features for clinical success. Thus new strategy is required for producing CAR-T cell with persistent in vivo proliferation and reproducible potency. It is evident that T-cell subset with the less differentiated and stem-cell-like property had better therapeutic efficacy. In order to improve the odds against these challenges nanotechnology is playing an

been used for tracking the biodistribution of CAR T cells. For instance, Super Paramagnetic Iron Oxide NanoparticlesCopper-64 (SPION-64Cu) nanoparticles have been developed for performing whole-body PET imaging to detect T cell accumulation in CD19+lymphoma.

This SPION-64Cu nanoparticle has been subjected to dual-modal imaging using high-resolution MRI to correlate biodistribution of CAR T cells with PET imagining. To reduce the cost of CAR T cell production, as well as restrictions on the number of genes that can be package, viral vectors are currently the most effective means to stably express these transgenes. To improve the transfection efficiency of CAR gene into T cell and to improve the scale up process in each patient, Dr. Smith et al., used synthetic DNA nanocarriers that can efficiently introduce leukaemia-targeting CAR genes into T-cell nuclei, resulting in long-term tumour remission.

Conclusion

Beside the CAR-T cell therapy, different sorts of cell therapy products are undergoing clinical evaluation for treating a variety of diseases, including autoimmunity, cancer, and infections. In the not too distant future, nanoparticles are expected to play a significant role in improving the efficiency of disease therapy.

References are available at www.pharmafocusasia.com

Samaresh Sau is a research associate at Department of Pharmaceutical Science in Wayne State University, USA. His research is focused on developing clinically translatable drug delivery system for imaging and chemo-immune therapy of cancer. He has 30 international publications, 2 US patents, and 2 Co-I or PI grants.

Arun Iyer is the Director of U-BiND Systems Laboratory and Assistant Professor of Pharmaceutical Sciences and at Wayne State University in Detroit, Michigan, USA. Iyer received the US DoD Early Career Investigator Award and the CRS T. Nagai Research Achievement Award for his outstanding contributions to controlled release science and technology. Iyer has authored close to 100 publications in peer reviewed International Journals and books of high repute.

MANIPAL HOSPITALS ENTRUSTS MOVEIT® WITH SECURE AND FULLY AUTOMATED SENSITIVE DATA TRANSFER hospital partners and patients was seamless and secure. These data transfers had to be reliable and easy to track so files could be accessed quickly and there would be no delay in the exchange of crucial information. Data security was also a key concern to protect patient privacy and ensure compliance with internal/external audits

The Solution- MOVEit File Transfer Results

Manipal Hospitals, part of the Manipal Education and Medical Group (MEMG), is the pioneer in the field of education and healthcare delivery in India. The third largest hospital in the country with multiple care facilities located across five states, it currently operates and manages 4,900 hospital beds and caters to around 2 million patients from India and overseas every year.

The Challenge • IT Team burdened with manual transfers of large volumes of data across hundreds of users • Process required extensive set-up each time • Users inconventiently sent to a specific web site to enter their information • Data involved is senstive and confidential patient information, so security is essential.

The Vision The IT department of the hospital needed to ensure that the flow of information between internal users,

• Greatly simplified process for the transfer of sensitive data • Fully automated, fully encrypted • Works seamlessly across departments • 100s of transfers per day, likely rising to more than 1000 • Easy to use, easy to implement • Administrative tasks around file transfer have been reduced by 85 per cent.

IT Department, Manipal Hospital “We estimate that we have reduced time spent on administrative tasks, such as creating individual users or ensuring transfers are running successfully, by as much as 85 per cent."

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RoundRobin Tech Services Pvt Ltd Distributor for Ipswitch Products in SAARC Countries To know more visit us at www.roundrobintech.com Email: sales@roundrobintech.com Ph: +91 9152813296 Advertorial www.pharmafocusasia.com

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USHERING IN THE FUTURE OF PHARMA

3D Printing opens the doors of possibility for pharmaceutical and medical device industries

3D manufacturing carves out a niche in the pharmaceutical industry While it’s hard to foresee the wholesale replacement of current tablet manufacturing processes, 3D technology creates the opportunity for precise deposition of niche medications and personalise tablets. This article will explore potential areas of application, including orphan drugs (those created for rare diseases), early phase drug development and testing. It will discuss the role of 3D manufacturing in moving treatment away from a one-size-fits-all approach and towards personalisation. It will also cover the different types of 3D printing technology and the benefits and limitations of each as they relate to pharmaceutical manufacturing.

Tom Egan, Vice President, Industry Services, PMMI

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harmaceutical manufacturers and consumers alike can look forward to a rapid evolution in the way medicine is manufactured and brought to market. New possibilities in 3D printing are opening doors for both pharmaceutical research and applications such as personalised drug dosing, complex drug release profiles and even bio printing. The implications are enormous: imagine an elderly relative being able to take a slew of medications in one personalised pill, or contemplate 3D printing a life-saving lung to be

used in a transplant for a cystic fibrosis patient.

While it is unlikely that current pharmaceutical manufacturing processes will ever be entirely replaced with 3D printing, the technology certainly has vast potential for application in both the pharmaceutical and medical device industries. In fact, research company MarketsandMarkets.com estimates that the use of 3D printing for medical devices alone could reach a market value of US$2.13 billion just two years from now.1 Fuelling this market is increasing global demand. The world’s quickly ageing population has drastically impacted both markets and the 1 https://www.marketsandmarkets.com/Market-Reports/3dprinting-medical-devices-market-90799911.html

industries in which they operate, presenting new challenges--and opportunities-for manufacturers.

Solutions fuelled by 3D printing and other innovations will be on display at Healthcare Packaging EXPO, co-located with PACK EXPO International (Oct. 14-17, 2018; McCormick Place, Chicago).

Back to Basics

3D printing technology has improved drastically over the past thirty years.

Its foundation, stereolithography, was invented in 1983 by Charles Hull2. The technology converts photopolymers from liquid to solid form following the introduction of ultraviolet light. This light, in the form of a laser, traces a defined area based on a design, creating a tangible, physical object. Stereolithography is the seed of 3D printing, but it has taken 2 https://www.asme.org/wwwasmeorg/media/ResourceFiles/ AboutASME/Who%20We%20Are/Engineering%20History/Landmarks/261-Stereolithography.pdf

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Considerations for 3D printing include regulation of the printer itself as a medical device, the person operating the machine and all distribution channels

decades to develop the technology as we know it today.

3D printing uses an additive process whereby successive layers are applied based on a three-dimensional digital model. Traditional methods of manufacturing rely on subtractive methods such as moulding and casting.

Today, new applications for 3D printing are rapidly emerging. The technology is already being used to manufacture artificial limbs, hearing aids, orthodontics and dental implants, and for pharmaceutical tablet manufacturing. As 3D printing continues to expand across both consumer and industrial sectors, regulations will need to be established, but the impact of this technology will be prolific across both the medical device and pharmaceutical industries.

First in Pharma

In 2015, Aprecia Pharmaceuticals achieved the first tablet manufactured through 3D printing to be approved by the U.S. Food & Drug Administration (FDA).The drug, called Spritam, is a reformulation of the anti-epileptic seizure medication levetriracetam. Using 3D printing technology, Aprecia created a highly porous structure for Spirtam,

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which could not be achieved with traditional manufacturing3. This structure causes the pill to dissolve in seconds upon contact with water, helping both elderly and young patients suffering with trouble swallowing pills, known at dysphagia.

This innovative development was achieved through a proprietary powder bed and inkjet 3D printing technology known as ZipDose. The process begins with a powdered layer that contains the drug. That first layer passes under an inkjet print head and a binding liquid is printed at specified locations along the powdered sheet. Successive layers are then printed up to 40 times, depending on the size of the tablet. Printing the layers allows the drug to be packed more tightly.

A single tablet that would normally hold 200 mg can be layered to hold 1,000 mg.

The result is a high-dose medicine that is easy to swallow for epileptic patients.

Personalised for Patients

As pharmaceuticals become more personalised, demand for patient-specific solutions is increasing. According to a whitepaper by PMMI, The Association for Packaging and Processing Technologies, 3 https://www.chemistryworld.com/feature/3d-printing-inpharma/3008804.article

the pharmaceutical industry is being transformed by a new emphasis on personalised care. The whitepaper, entitled The Top 5 ForcesShaping the Pharmaceutical and Medical Device Industries in 20174, notes the industry is witnessing a decline of blockbuster drugs, along with explosive growth in biologics and growing use of generics.

Vision for 3D printing in pharmaceuticals is that medication will be customised to an individual’s needs, increasing both safety and efficacy. The size, dose, appearance and rate of delivery of a drug can be designed for each patient. One can imagine a situation in which a tablet for a child is printed into the shape of a cartoon character with the dosage customised to the child’s specific biology. The possibility even exists of layering different medications into one pill to reduce confusion for elderly patients and those that may have to take numerous medications over the course of a day.

Pharmacogenetics

Today, once a drug has finished clinical trial requirements and met all regulatory approvals, the dosage options that are 4 The Top 5 ForcesShaping the Pharmaceutical and Medical Device Industriesin 2017

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brought to market are either one-sizefits-all, or based on key factors such as organ function, weight and age. However, by accounting for genetic variations, a practice called pharmacogenetics, doctors can avoid potential problems, including adverse reactions and lack of response by predicting an optimal dose for individual patients5.

Personalised medicine based on pharmacogenetics is already applied today— albeit on a limited basis. For example, HIV patients are now routinely tested for a genetic variant that would make them more likely to have an adverse reaction to the antiviral drug abacavir (Ziagen)6.

Patients with a trial fibrillation, or irregular heart rates, can also benefit from pharmacogenetics. A genetic test that identifies variations in two specific genes that affect the body’s ability to metabolise Warfarin can be easily administered. Combined with other factors, the test indicates a proper dosage range for the patient, avoiding adverse reactions including uncontrolled bleeding, lifethreatening blood clots, or a potential stroke.

With 3D printing, tablets may be designed to meet the needs of an individual patient identified by genetic testing and printed as needed. Unique drug doses, a combination of drugs and the release profile of the formulation can all be personalised.

and promise of an effective treatment is invaluable. Thankfully, regulations are in place across Asia, Europe and the U.S. to provide incentives for orphan drug research and development. These include tax exemptions, expedited approval and market exclusivity. Such incentives went into effect Japan and in Australia in 1993 and 1997 respectively.

Still, the need for innovation in this space is great, and the inherent flexibility of 3D printing holds tremendous potential for orphan drugs. Bringing a drug to market typically takes around ten to fifteen years and millions of dollars. This is not economically viable for medicines that treat rare diseases, as they only help a small percentage of the population.

3D printing’s ability to rapidly print small batches means that it could serve those who suffer from rare diseases as a means of rapid and more economical drug development.

Aprecia is already putting this concept to the test. In December 2017, the company announced a partnership with Cambridge, UK-based Cycle Pharmaceuticals to develop and commercialise 3D printed tablets for rare diseases8.

Drug Development

8 http://www.cambridgeindependent.co.uk/business/ business-news/cycle-pharmaceuticals-to-use-3d-printing-todevelop-orphan-drugs-1-5342956

9 https://www.medicalnewsbulletin.com/could-3d-printing-be-next-breakthrough-drug-development/

The current drug development process is cost-prohibitive and requires years of trial. Part of this is due to the initial stages of the process in which the therapeutic potential of a molecule and its level of toxicity are evaluated 9. The rate of failure during this initial stage is high, and therefore pharmaceutical companies must identify and test molecules as quickly and as cheaply as possible. 3D printing can help by expediting the process through speed and flexibility inherent in its ability to produce small batches of drugs with different compositions.

The potential for 3D printing in drug development and testing lies in the ability to rapidly iterate products using flexible, on-demand production for small batches of drugs. Variations in dosage, physical characteristics, and release profiles of drugs could be produced on a small scale for testing.

Made on Demand

We have explored the implications of 3D printing in drug trials and personalised medicine, but how might the technology impact the way consumers purchase medicine? The

Implications for Rare Diseases & Orphan Drugs

3D printing also holds tremendous promise for orphan drugs designed to treat rare diseases that are sometimes not developed by the pharmaceutical industry due to economic reasons. The number of such rare diseases is estimated to be between 4,000 and 5,000 worldwide 7. For those patients that are living with a rare disease, the hope 5 https://ghr.nlm.nih.gov/primer/genomicresearch/pharmacogenomics 6 https://www.genome.gov/27530645/faq-about-pharmacogenomics/ 7 https://www.orpha.net/consor/cgi-bin/Education_AboutOrphanDrugs.php?lng=EN

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pharmacy of the future could look quite different.

To accommodate an increasing demand for personalisation, pharma manufacturers are adjusting their operations with a focus on faster production speeds, shorter batch runs, specialised packaging and high-value items. As the demands of the market evolve, manufacturers are also evaluating the location of their operations, and many have decided to move production as close to the point of sale as possible.

At the next level, this would mean potentially decentralising pharmaceutical production. With 3D printing, medicines could conceivably be manufactured much closer to patients, perhaps directly in a pharmacy or even in a doctor’s office. On-site, a physician or pharmacist would be able to question the patient regarding factors that could influence dosage decisions.

Instead of storing medicine, pharmacists would simply have each drug’s base product and an encrypted blue print that could be adjusted to suit individual patients’ needs. Medicines could then be printed on the premises.

also exist. Could the ease of production with 3D printing lead to a proliferation of illegal drugs?

The nature of the pharmaceutical industry lends itself to complex regulations, and it will take time to find ways to safely bring advanced applications of 3D printing in this space to market. Still, the potential benefits of this technology are undeniable and the industry should move quickly and cautiously to recognise that potential.

Collaborate and Innovate at Healthcare Packaging EXPO

Healthcare Packaging EXPO (Oct. 14-17; McCormick Place, Chicago), co-located with PACK EXPO International, will provide a powerful opportunity for pharmaceutical and medical device manufacturers to converge and address evolving consumer and regulatory demands. Both owned and produced by PMMI, The Association for Packaging and Processing Technologies, the shows will also offer educational programming

and opportunities to cross-pollinate ideas among industries.

This year’s show is slated to attract more than 50,000 attendees, including 7,000 international visitors from more than 130 countries. Next generation technology will be on display from the 2,500-plus exhibiting companies spanning 1.2 million net square feet of exhibits.

Attendees across industries will benefit from the Innovation Stage, a series of 30-minute free seminars on technological breakthroughs. Industry specific innovations include updates on trends shaping pharma and medical device companies, coding and serialisation technology, and supply chain visibility among others.

Registration for Healthcare Packaging EXPO, $30 through September 28 and US$100 after, will also include admission to PACK EXPO International for all four days of the show. Register for Healthcare Packaging EXPO today at www.hcpechicago.com.

AUTHOR BIO

Regulatory Challenges

These developments would certainly amount to an unprecedented level of innovation within all parts of the pharmaceutical industry. Growth and potential at this level does not come without potential roadblocks. There are many questions that have yet to be resolved, but one major issue is the need for regulation.

From serialisation to track and trace technology, today’s pharmaceutical landscape is more heavily regulated than ever before. Considerations for 3D printing include regulation of the printer itself as a medical device, the person operating the machine and all distribution channels. If a drug were to cause an adverse reaction, who would be responsible in a decentralised system?

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Tom Egan serves as the Vice President of Industry Services for PMMI, the Association for Packaging and Processing Technologies. He joined the PMMI staff in 2003 following more than 20 years in the packaging industry during which he was also an active PMMI member. His time in the field included tenures at Barry-Wehmiller Design Group and as Vice President, Marketing & Sales, for Hoppmann Corporation. He has an MBA from Baldwin-Wallace College, and a BS in Electrical Engineering from Villanova University.

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Residence Time Distribution (RTD) Model Novel applications to continuous pharmaceutical manufacturing

The Residence Time Distribution (RTD) is a fundamental chemical engineering concept. By definition, it is the probability distribution of time that solid or fluid materials stay inside one or more unit operations in a continuous flow system. It can be used to characterise the mixing and flow behaviour of material within a unit operation. Currently, the pharmaceutical companies are going through a paradigm shift from conventional batch to Continuous Manufacturing (CM). RTD has been recognised as one of the most important tool that have several novel applications in continuous pharmaceutical manufacturing.

Ravendra Singh, C-SOPS, Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey

T

he Residence Time Distributions (RTD) can be determined experimentally through the injection of a tracer material into the process in the form of a pulse or a step. To achieve this, the outlet tracer concentration is measured until the effects of the injection settle down. A key aspect to be considered during the experimental determination of residence time distributions is the tracer selection. The addition of tracer should not influence the flow properties of the bulk powder while still being readily detectable through analytical techniques or any other methods. The RTD determination and its modelling is very useful for continuous pharmaceutical manufacturing. www.pharmafocusasia.com

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In this article, the development of RTD model and its applications for continuous pharmaceutical manufacturing process have been highlight. The real time product quality assurance and material traceability are some of main applications of RTD model, widely spreading across pharmaceutical industries. The RTD based control system, ensures the drug concentration in final tablets while the material traceability framework tracks the identity of batch and lots of the product produced. The materials need to be traced for regulatory perspectives and to recall a specific batch of the products if needed. RTD model has been also used to characterised the unit operations involved in CM as well as the integrated line.

1. Process Description

A continuous direct compaction tablet manufacturing pilot plant has been developed, situated at ERC-SOPS, Rutgers University. The snapshot of the pilot plant is previously reported.

The pilot plant is built in three levels at different heights to take advantage of gravitational material flow. The top level is used for feeder placement and powder storage, the middle level is used for delumping and blending, and the bottom level is used for compaction. There are three gravimetric feeders (K-Tron)-with the capability of adding more- that feed the various formulation components (API, excipient, lubricant etc.). A co-mill (Glatt) is also integrated after the feeder hopper primarily for de-lumping the powders and creating contact between components. These feed streams are then connected to a continuous blender (Glatt) within which a homogeneous powder mixture of all the ingredients is generated. The chute is placed in between blender and tablet press. The chute has interface to integrate the sensors. Finally, the outlet from the blender is fed to the tablet press via feed frame. The process flow sheet is previously reported.

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Axial dispersion model

The RTD model has potential to use for the prediction of drug concentration where the conventional sensing method is either not available or cannot be integrated with the plant.

2. Residence Time Distribution Model

There are two approaches commonly used for RTD modelling as discussed in following sections.

Tank in series model

The tank-in-series model approximates the RTD of a system as a series of equally sized CSTRs, resulting in a realistic mixing description. The number of tanks is an integer varying from 1 to infinity, and a larger number of tank results in a narrower RTD, tending to a Plug Flow Reactor with no axial mixing (PFR) as the number of tanks tends to infinity.

The tank in series model is represented by following mathematical equation:

Where Ď„, is the mean residence time and n is the number of Continuous Stirred Tank Reactors (CSTRs). E(t) is the residence time distribution. TIS means tank in series and PFR means plug flow reactor. The experimental RTD data can be used to fit into this equation by determining the number of tanks and mean residence time.

The axial dispersion model describes the RTD of the system as an ideal plug flow within a tube superimposed by a diffusion term resulting in a system characterised by back mixing. The dispersion RTD function for open-open boundaries is given below (Taylor, 1953).

where Ď„ is the mean residence time, Ď„PFR is the system dead time, and Pe is the Peclet number. As the Peclet number tends to infinity, the behavior of the system approaches an ideal plug flow reactor, where no axial dispersion is present. This model has a similar fitting procedure as the tank in series model with the only difference being the fact that the main fitted parameter of the dispersion model is the Peclet number (Pe), which represents the ratio between convective and diffuse transport.

Applications of Residence Time Distribution model

There could be several applications of the RTD model in continuous pharmaceutical manufacturing process. Some applications are highlighted in following sections.

Characterisation of unit operations of continuous pharmaceutical manufacturing plant

The RTD model can be used to characterised the unit operations involved in continuous pharmaceutical manufacturing plant. Specifically, it is very useful tool to understand the mixing inside a unit operation. For example, the RTD model can help to understand the mixing inside a feeder and thereby supports to establish the efficient feeder refill strategy. Similarly, the RTD model is useful to understand the mixing capacity of a blender and thereby to improve its performance. Wider RTD means more mixing. The blender operating condition and blade configuration can be adjusted

MANUFACTURING

to improve the mixing if needed. The mixing in continuous pharmaceutical manufacturing is happening till the powder/granules goes to the dies.

Therefore, the RTD model can also help to understand the mixing in feed frame and thereby the final uniformity of the blends/granules entering to the die.

Characterisation of integrated continuous pharmaceutical manufacturing plant

The RTD model of integrated continuous pharmaceutical manufacturing process is extremely important to characterise the line. It provides mean residence time of the powder particles entering the line. The overall mixing and segregation happening in the line can be also characterised by employing the RTD experiments and corresponding model.

RTD has been recognised as one of the important tool to model the intergraded continuous pharmaceutical manufacturing process.

Prediction of drug concentration

The RTD mode can predicts the drug concertation. So it can be used as an alternative measurement of drug concertation wherever the actual sensors are either not available for real time monitoring or cannot be integrated because of ‘sensor integration constraints’. Following are some of the possible scenarios where RTD model is useful: If the API (Active pharmaceutical ingredient) concentration in the formulation is too low, then it cannot be accurately detected by PAT (process analytical technology) sensor in real time.

However, there could be offline sensors to measure this variable. In that scenario, the RTD model can be used to predict the drug concertation. The predicted drug concertation can be used for real time monitoring, process control or diversion of out of spec products.

For continuous pharmaceutical manufacturing via wet granulation, the drug concertation need to be measured and assured at the outlet of wet granulator. If the drug concertation in granule cannot be measured in real time (may be because of low concentration), then RTD model can be used to predict it.

In case of continuous pharmaceutical manufacturing vid direct compaction, the RTD model can be used to predict the drug concentration at blender outlet, feed frame outlet and of final tablets. The real time monitoring technique of drug concentration of final tablet is currently not available and therefore, RTD model can play an important role here. The tablet potency is normally measured offline for example using Bruker MPA. The integration of Process Analytical Technology (PAT) sensor into feed frame for real time monitoring of drug concertation is still a challenging task. Therefore, RTD model can be used to predict the concentration of the drug just before entering to the die.

Feedback process control

The real time measurement of the control variable is an essential requirement for feedback control implementation.

As discussed in previous section, the RTD model can be used to predict the drug concentration and thereby it can enable the real time feedback control.

Any control algorithm such as classical Proportional Integral Derivative (PID) or advanced Model Predictive Control (MPC) can be used for feedback control.

One example, of RTD based feedback control is the continuous granulation process where drug concentration is too low to be detected by PAT. In this case, using the RTD model of granulator, the drug concertation at granulator outlet can be predicted. This signal then can be used to manipulate the upstream dilution feeder flow rate in order to get the consistent drug concentration in granules.

Feed forward process control

The real time prediction of the drug concentration using RTD model can also enable the feed forward control. The feed forward controller takes the proactive actions and therefore it can mitigate the effects of disturbances before it will propagate to the final product. Thereby, the feed forward controller can reduce the wastage of the final product significantly.

The feed forward controller is essentially a mathematical model derived in a very specific way that takes the measured

disturbance as the input and generate the corrective actions proactively in real time.

In this case, the predicted drug concentration using RTD model will be used as the input disturbance for the controller.

One example of RTD-based feed forward controller in continuous pharmaceutical manufacturing is discussed here. The RTD-based feed forward controller can be used to assure the desired tablet potency.

The drug concertation of powder blend measured by NIR is the input for this feed forward controller. The feed forward controller then manipulates the fill depth to keep the tablet potency at consistent level. Meaning that, if the drug concentration in blend detected by NIR is higher/ lower than desired value then the feed forward controller will reduce/increase the size of the tablet so that the total drug contents in the tablet is same. However, the change in tablet size should be within the permitted limits by regulator. There should be one additional controller to maintain the consistent hardness. This controller manipulates the tablet thickness to keep the tablet hardens at consistent level.

Real time granules diversion strategy to assure drug concertation

The continuous pharmaceutical tablet manufacturing process via Wet Granulation (WG) involves dryer and some hoppers (among other unit operations) which are not truly continuous and have larger dead time. Therefore, for continuous WG process, out of spec granules need to be diverted in order to avoid mixing bad granules with good granules. The RTD model can be used to divert the out of spec granules in real time. A PAT sensor can be used for real time monitoring of drug concentration of the blend entering the granulator.

This creates a real time availability of the inlet drug concentration data at the entry of the granulator. The diversion strategy then uses this inlet concentration to determine a signal for the diversion strategy that can accurately be used to reject granules that are out of tolerance limits at the outlet of the tablet press.

The RTD is used to predict the outlet www.pharmafocusasia.com

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Real time tablet diversion strategy to assure drug concertation

A drug concentration based diversion system is an intrinsic requirement for continuous pharmaceutical manufacturing. For the continuous manufacturing process, an upstream disturbance could propagate downstream if it has not been controlled locally or if the local control is not efficient causing overshoots.

Depending on the performance of downstream unit operations, this disturbance could amplify or diminish. Nonetheless, due to this disturbance propagation, there is a need to control or be able to mitigate situations that have the capacity to deteriorate end product quality. The drug concertation can be measured before tablet press using PAT. This creates a real time availability of the inlet drug concentration data at the entry of the tablet press. The diversion strategy then uses this inlet concentration to determine a signal for the diversion strategy that can accurately be used to reject tablets that are out of tolerance limits at the outlet of the tablet press. The RTD is used to predict the outlet concentration from the inlet concentration. The predicted signal is then used to initiate the diversion.

Material traceability

One area that is highly desired to be systematically investigated is material traceability in continuous manufacturing systems. The Residence Time Distribution (RTD) method can be used for material traceability in continuous 42

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AUTHOR BIO

concentration from the inlet concentration. The predicted signal is then used to initiate the diversion.

pharmaceutical tablet manufacturing process. By conducting tracer experiments using a pulse or step change of detectable material at the inlet, the response of the tracer at the outlet can be measured. The amount of time it takes for tracer to first be detected at the outlet, as well as the time it takes for clearance of the tracer material provide valuable information for material traceability. Utilising the minimum and maximum residence times for the continuous line pre-production, raw material batch changes that occur during feeder refill can be traced at the outlet of the process. In the case that one component of the formulation changes batch number, theoretically, the tablet quality should not change given that the process conditions are unchanged. However, for material traceability purposes, the tablets containing raw material from one batch and another need to be distinguished.

This raw material batch change occurs during a single manufacturing order and with no changes to the process conditions, therefore is still the same batch.

However, we can assign these tablets containing new raw material batch to a separate ‘lot’, within the current tablet batch. This would be a ‘specific identified portion of a batch’ in which the tablets contain material from a raw material batch different from the previous lot. The idea is that, when tablets are released, with a specific batch number and lot number, it exactly traces to what raw material batches may be present in the tablet. By changing the lot based on raw material batch composition in the tablets, it can be certain, if recall was required for specific raw material batch, which lot of tablets must be recalled as well, without recalling the entire batch, many of which tablets contain none of the recalled raw material batch.

Conclusions

The Residence Time Distribution (RTD) model is an important tool that has several applications in continuous pharmaceutical tablet manufacturing. In this article, some of those applications have been highlighted. The RTD has been extensively used for the characterisation of unit operations performance involved in continuous pharmaceutical manufacturing as well as the characterisation of whole line. The RTD model has potential to use for the prediction of drug concentration where the conventional sensing method is either not available or cannot be integrated with the plant.

Therefore, the RTD model can be also use for feedback and/or feed forward control.

Interestingly, the RTD model has been recognised as the essential tool to enable the diversion of out of spec intermediate granules and/or final tablets. The material traceability as required by regulator and essential for product re-call can be also achieved using RTD model. The RTD model enable the real time assurance of drug concentration and material traceability in continuous pharmaceutical manufacturing which is a significant advancement in pharmaceutical industry and is considered essential for real time release as well as patient safety.

Acknowledgements This work is supported by the US Food and Drug Administration (FDA), through grant 5U01FD005535, and National Science Foundation Engineering Research Center on Structured Organic Particulate Systems, through Grant NSF-ECC 0540855.

References are available at www.pharmafocusasia.com

Ravendra Singh is Research Assistant Professor at C-SOPS, Department of Chemical and Biochemical Engineering, Rutgers University, NJ, USA. He is the recipient of prestigious EFCE Excellence Award from European Federation of Chemical Engineering. He has published more than 55 papers, written12 book chapters, presented at over 95 conferences and edited pharmaceutical book.

INFORMATION TECHNOLOGY

Creating Better Clean Label Soft Gels Without Gelatin Crosslinking Modern manufacturers are facing to produce the perfect, clean label soft gel. Cross-linking is a common reaction in gelatin capsules, with a direct impact on APIs bio availability and opening time. Modern technology offers a number of solutions: Rousselot’s latest development for example, StabiCaps, has been specifically formulated for more stable capsules.

Claude Capdepon, EMEA-SEA Application Laboratory Manager Rousselot

S

oft gels, also known as soft capsules or soft caps, are a highly popular pharmaceutical and nutraceutical dosage form, with around 2,500 units consumed every second globally. A forecast by HJR Research predicts a CAGR of 5.5 per cent over the next decade, with the global market value expected to reach $756 billion by 2025. During the same period, the Asia-Pacific region is projected to be the fastest-growing market at a CAGR of 6 per cent, in terms of value.

Driven by the increasing popularity of nutraceuticals, where clean label and comfort in swallowing are key factors in customer buying decisions, soft gels have also proven to be the best option for recently-developed, www.pharmafocusasia.com

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the capsule’s overall effectiveness. It is essential therefore not only to use a specific and high-quality gelatin for the shell, but also to strictly control all steps of the production process to achieve the right level of moisture.

Optimising Gelatin for Manufacturing Performance

complex and poorly soluble fillings in pharmaceutical products.

In this article, Claude Capdepon describes the formulation challenges, particularly cross-linking, associated with soft gel manufacturing, and explains the results of Rousselot’s recent research on the behavioural patterns of cross-linking and the development of an advanced gelatin solution for stable capsules.

Gelatin - The Perfect Partner for Soft Gels

Robust functional properties, full compatibility with the human body and compliance with stringent regulatory requirements make gelatin the preferred excipient for soft gel applications. In addition, as the only clean label excipient, it provides an added appeal for conscious consumers. However, not all gelatins are equal. Soft gel manufacturing is a complex procedure that requires technical knowledge and excipients with specific characteristics, to avoid the following commonly encountered formulation pitfalls.

Optimising Gelatin for Maximum API Delivery

There are several factors that impact Active Pharmaceutical (API) ingredient delivery, including the capacity of the shell to dissolve fully and timely. One of 44

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the main requirements for soft gels is to protect the API against early degradation while in storage. However, soft gels are particularly sensitive to heat and moisture and loss in shell quality can prevent its proper dissolution. Another specific risk is the movement of components between shell and fill, as well as from the external environment into the shell. If either of both of these conditions occur, capsules are then at risk of becoming unstable and brittle, due to the reaction between the different ingredients. Without adequate protection, the risk of oxidation and recrystallisation increases, lowering

Selecting a gelatin with the right characteristics is particularly important for soft gel formulation in order to avoid any of the typical defects, which include poor encapsulation yield, twins and leakages.

The foaming and filming characteristics of the gel mass should be evaluated carefully to maintain high levels of production efficiency and performance. At the same time, when it comes to optimum manufacturing, gelatin must also be highly soluble, easy to use and should exhibit excellent mechanical strength and elasticity properties. Most importantly, the increasing number of APIs being developed means that manufacturers need to take into consideration the interactions that may occur between the shell and the fill when developing new formulations.

For soft gels to remain in perfect conditions throughout their shelf-life, they must undergo a drying process to prevent stickiness. For instance, a Rousselot study performed in 2013 on fish oil formulations demonstrated the

INFORMATION TECHNOLOGY

three alpha chains that cross together to form a triple helix. Along with its specific amino acid composition, this predisposes gelatin to crosslinking.

Of it 18 amino acids, lysine and arginine are the most reactive, and play a key role in the crosslinking reaction.

When manufacturing soft gel capsules, gelatin accounts for 40 to 47 per cent of the total gel mass composition, such a high proportion can bring gelatin’s crosslinking an important concern for soft caps manufacturers.

Key factors in crosslinking reactions

Figure 1 Reaction scheme between formaldehyde and gelatin, leading to cross-linking.

(Source Cross-linking of gelatin capsules and its relevance to in-vitro-in-vivo performance, Digenis et al., 1994)

effect of final moisture level on softgel capsules, and showed that a moisture level above 11 per cent significantly increases the risk of stickiness.

Safe, non-allergenic and fully compatible pharmaceutical gelatins are now available to help overcome such challenges meet the needs of soft gel manufacturers. Compliant with the highest safety, quality standards and practices, such as IFS, HACCP and GMP, specialised gelatins can help to minimise risk of soft gel defects during manufacture and maximise productivity and save costs, throughout the formulation process. The provision of certified Halal and Kosher gelatin options also creates additional appeal to a diverse range of consumers.

linkages between gelatin chains. It can cause the shell to become rubbery and insoluble, ultimately adversely affecting soft gel stability.

A purified, soluble protein, gelatin is a polydisperse polymer composed of

The main factors that are responsible for crosslinking can be grouped into three categories: storage conditions, complex fills and aldehydes.

Temperatures above 30°C and humidity above 60 per cent have been shown to create a chemical reaction called self-crosslinking, where the R chains of arginine and lysine create double covalent bonds between different chains, making the gelatin shell insoluble.

Crosslinking: Gelatin’s Soft Spot

Although essential to produce a high quality soft gel, attention towards all the factors mentioned above might not be enough. The complex nature of soft gel formulation creates some extra challenges even for the most careful of manufacturers, such as crosslinking.

But what exactly is it, and how can it be avoided?

Crosslinking is a term used to describe the formation of strong chemical Figure 2 Sensitivity of market gelatins in the presence of cross-linkers (Internal Rousselot study, EMEA Application laboratory, 2017) www.pharmafocusasia.com

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Complex fills, including multivitamins and multi-minerals, can trigger a chemical crosslinking reaction. Over time, crosslinkers tend to migrate towards the shell, forming an insoluble membrane between the fill and the shell. The most reactive components inducing crosslinking are aldehydes. In figure 1, formaldehyde reacts with the amino group of gelatin, forming an imine.

It’s important to mention that the reactions involved are often enhanced by the characteristics of the gelatin: viscosity in relation to molecular weight distribution and pH for example can play a key role when it comes to crosslinking.

For this reason, we can assume that by understanding gelatin’s behaviour under specific circumstances, it is possible to predict its resistance to crosslinking.

Rousselot, the leading producer of gelatin and collagen peptides, has developed a specific testing protocol that measures the increase of gelatin viscosity in the presence of crosslinkers. During this predictive test, a gelatin solution is mixed with a crosslinker in order to calculate the reaction time. This test highlights the time it takes the gelatin solution to reach maximum viscosity value and therefore potential to crosslink. The higher the reaction time, the lower its sensitivity to crosslinking. The reaction speed is an additional parameter used to measure sensitivity where a lower reaction speeds corresponds to lower sensitivity.

StabiCaps: Future-proofing Soft Gel’s Stability

Building on the extensive in-house research mentioned above, Rousselot has developed a range of gelatins with superior performance in terms of soft gel stability and resistance to crosslinking; this patented technology is commercialised under the name StabiCaps.

StabiCaps reaches specific low viscosity profiles and low Ph range in a clean label formulation, to ultimately reduce crosslinking. Additional salts have been added to StabiCaps Plus with the aim to fix any crosslinking residue and avoid the release of amino acid groups.

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To evaluate StabiCaps’ performance against other commercially available gelatins, Rousselot Application Lab team carried out a series of comparative tests on several different gelatin types to study their sensitivity in typical crosslinking situations such as the presence of aldehydes, high humidity or high temperature conditions.

Tested in the presence of crosslinkers (including vitamins and antioxidants), StabiCaps outperformed both standard gelatins and other reduced-crosslinking ranges available on the market and showed a significantly longer reaction time.

Stability has also been tested on soft gel films (or gelatin plasticized films) in specific temperature and humidity conditions (40° C and 75 per cent humidity) or in the presence on vitamins or antioxidants (at 30° C and 65 per cent humidity). All dissolution tests were conducted in water at 37° C in a dissolution vessel.

The Most Significant Results have been Described below.

Temperature and humidity: Tests carried out after six months of storage at 40 per cent and 75 per cent have tested the Maillard reaction and shown a significantly faster dissolution rate of StabiCaps compared to a standard gelatin. More specifically, 90 per cent of the capsule film was dissolved in 20 minutes.

The same results were confirmed by tests on StabiCaps and standard gelatin grade after 6 months storage in the presence of cranberry powder or vitamins, a powerful antioxidant, at 30° C and 65 per cent humidity.

In all cases, dissolution occurred at a faster pace than with standard gelatin showing the capacity of StabiCaps range to reduce cross-linking and to effectively enhance API bioavailability.

Regulatory Compliance

Rousselot StabiCaps comply with most international pharmaceutical and nutraceutical supplement regulations, including the US and

Figure Slope of the linear part. Measure of viscosity increase in %

the European pharmacopoeia and edible regulations.

Conclusion

As soft gel consumption grows in the nutra- and pharmaceutical industries, capsule manufacturers increasingly need to balance consumer demand for natural, clean label solutions with increasingly complex fillings and new API technologies. Among all excipients available, gelatin remains the preferred option due to its outstanding functional properties and clean labelling. Any formu-

lation challenges can more easily be overcome by using high quality and consistent gelatins and partnering with experienced suppliers who can provide in-depth technical expertise.

Tests show that best results can be obtained with the use of specific gelatins, optimised against crosslinking.

Among these, StabiCaps have demonstrated superior performance in terms of reaction, dissolution time and stability and so make the ideal choice for pharmaceutical soft gel products.

AUTHOR BIO

Claude Capdepon specialized in organic chemistry from the University of Montpellier. She started her career in organic chemistry research before moving into photographic and pharmaceutical gelatin developments. Since 2008, Claude has been Application Laboratory Manager at Rousselot overseeing operations in M.E.A., S.E Asia and Japan. She works on the development food, nutritional and pharmaceutical gelatins and collagen peptidesbased applications.

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The Pharmaceutical Supply Chain from a CDMO’s Perspective In the world of drug manufacturing, change is a constant. In order to be successful, Contract Development and Manufacturing Organisation’s (CDMO’s) must remain flexible, anticipating and adjusting to market dynamics as necessary. This ability to adapt is critical to establishing a successful and efficient supply chain. What are some of the key processes and individual demands that CDMO’s must take into consideration when addressing new markets while continuing to maintain high quality and safety standards?

Michael Schmitz, Vice President of Planning & Logistics at Vetter offers his insights.

Michael Schmitz, Vice President, Planning & Logistics, Vetter Pharma-Fertigung GmbH & Co. KG

1. What are the major changes you see affecting today’s pharmaceutical supply chain?

The primary change we see is that of market dynamics and rapid growth resulting in an increased complexity in the supply chain. In an era of globalisation, international pharmaceutical and biotech industries are faced with continuous market changes which include intensifying competition, higher complexity of compounds, rising costs, increasing regulatory requirements, and a steady growth in the number of products and customers. Continuous advances in research and development also drive specialisation. This differentiation of individual drugs has resulted in strong fluctuations in market demand and growing pressure on the pharmaceutical supply chain.

2. How will these changes affect the way contract manufacturers approach their business?

The fluctuations resulting from globalisation will have a challenging impact on the advance planning of contract

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manufacturers, especially when it affects drugs manufactured in smaller annual volumes, increasing customer service levels, and reduced lead times. To remain relevant and successful, drug manufacturers must have the flexibility to be able to react quickly to changes in demand while continuing to provide a secure supply chain and maintaining a high quality level. To adapt, service providers have to embrace market changes and react accordingly, particularly in regards to fluctuating demand as a natural market development. They must realise that the market dynamics are a form of “natural” conflict, filled with volatile and uncertain demands.

3. Given this complex scenario, how does a CDMO establish an efficient supply chain?

It is important to begin with the establishment of open communication between all stakeholders including the drug manufacturer, service provider and any suppliers.

By doing so, this coordination and cooperation will strengthen the relationships through a common understanding of

the other parties’ expectations, allowing for the overcoming of roadblocks and challenges that could disrupt both operations and the partnership. For example, processes such as demand exchange, or cut-off times for purchase orders can be handled through a supply agreement between the pharmaceutical company and the CDMO to help avoid misunderstandings of different targets. Ongoing consultations in the form of business review meetings, monthly reviews of supply and demand, or customer Sales and Operations Planning Process (S&OP) meetings allow for a highly focused view of the situation and early identification of changing circumstances. The internal target is high maximised machine utilisation, and the external target high customer service level. It is best to think in scenarios of minimum, base, and maximum when in defining capacities for upcoming months. Optimised planning processes demand certain preconditions in production in order to facilitate flexibility especially as it applies to areas of technology, processes, and human resources.

AUTHOR BIO

4. How does a CDMO adapt to these variable demands in the supply chain?

Adapting to the needs of the market is critical for success. It matters little whether it’s a sudden increase in demand or decrease in available API, a CDMO must stand ready to allocate resources according to real-time demands. For example, final planning for cleanroom capacity utilisation must be done weeks before production. To realise this level of high flexibility means a CDMO must have the use of multiproduct lines featuring modular equipment since it is essential to be able manufacture one product on different lines. A CDMO already having established and validated equipment and processes in place is a distinct advantage. Today, many biopharmaceutical companies prefer qualifying two different clean rooms at the same service provider when security of supply is absolutely crucial orif a second supply site does

not exist at all. Another area of great importance is human resources since employees cannot focus solely on one specific job and must be trained as well in handling different tasks within the manufacturing process. This flexibility of the workforce allows for the use of staff at short notice in other work areas where there may be a greater capacity gap.

5. Should issues regarding storage capacity and stock also be taken into consideration?

That is absolutely the case. The volatility of the market has a significant impact on storage capacities of CDMO’s, especially API, deep-frozen or finished products.

The shelf life of products is of critical importance to the customer. Thus, the cold chain must be maintained throughout the entire production process in order to uphold their quality. It is essential that provisions be made for providing comprehensive storage for these products in a

variety of different temperature needs. A CDMO can react to unforeseen demand changes only when inventory is available and accessible in the short term.

Any fluctuations in demand or increased regulatory requirements often challenge the proper adjustment of inventory for an in-time production process. At the end of the process, all products must be maintained and stored properly in the warehouse regardless of whether it is ambient or cold storage.

6. Do you have any final thoughts that you would like to share?

It is clear that globalisation of the drug industry and the market dynamics that define it will continue to lead to new markets. To be successful, it is essential that each new market be addressed and served according to its specific demands.

As the number of drugs continues to increase and supply chains become more complex, pharmaceutical companies and CDMO’s must be prepared to face the challenges that result. There is a clear need to further improve upon open communication in a sharing demanding scenario. It will take efficient processes to achieve the desired flexibility while maintaining high quality and safety standards for the products. The key to an agile CDMO supply chain is real-time planning with the possibility to adapt capacity to react flexibly to changes in demand.

Michael Schmitz is Vice President, Planning & Logistics of Vetter PharmaFertigung GmbH & Co. KG. In this position he is responsible for overseeing a staff of individuals focused on all logistic operations, as well as planning for all production resources and promoting OEE measures and customer service levels. He is also responsible for inventory management.

Schmitz joined Vetter in 2009 as Director of Logistics. At the time, he was responsible for leading the S&OP process and for heading up Logistics Operations, and was also site manager.

www.pharmafocusasia.com

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DEVICE

OWN

YOUR

BRING

IS IT A CREDIBLE OPTION FOR MY STUDY?

Firstly, why should sponsors consider adopting a BYOD approach over other tried and tested electronic approaches (i.e. provisioned eCOA)?

There is a drive towards greater patientcentricity in today’s clinical trials.

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Simplifying trial participation is a key element of this. Enabling patients to use their own mobile devices or computer hardware to provide patient-reported outcome data may make trial participation more convenient and reduce training requirements. In a BYOD study,

patients do not need to use, carry and keep charged a second handset while participating on the trial.

When it comes to reducing the time and cost associated with the traditional method of supplying patients with a dedicated handheld device, a BYOD

Traditionally, electronic Clinical Outcome Assessments (eCOA) data has been captured via provisioned devices, i.e., devices that have been provided to participants. The main reasons for this are to ensure that the patient-reported outcome instruments are displayed identically for all patients, and the desire not to exclude participation due to hardware ownership. However, over recent years there has been a noticeable rise in the number of sponsors and CROs looking to design their clinical trials around a Bring-YourOwn-Device (BYOD) strategy. This has ultimately been driven by the widespread availability of the technology that increasingly spans populations of different ages, geographic locations and economic backgrounds. BYOD allows participants in a clinical trial to provide study data using their own internet-enabled hardware. Not just restricted to smartphones, this could also be a tablet, desktop computer or laptop. The shift towards BYOD promises a transformation of how field-based Electronic Patient-Reported Outcome (ePRO) assessments are implemented in clinical trials, and while the approach has traditionally been used in late-phase studies or short studies collecting objective data not supporting a label claim, application has turned to its use in Phase II and III trials. Here, Bill Byrom from CRF Health, discusses the pros and cons of the approach with readers, and shares valuable insights for those considering adopting a BYOD approach within their studies.

Bill Byrom, VP, Product Strategy and Innovation at CRF Health

strategy is perceived to contribute significant advantages. By eliminating the need to source, provision and supply devices to the entire patient population, sponsors may be able to realise cost savings, particularly in large studies. Eliminating the need to store devices, as well as manage deliveries and returns may also reduce the burden on study sites.

And in a snap shot, what are the benefits to patients?

BYOD offers numerous benefits to patients — as previously mentioned, allowing them to use their own device provides optimal familiarity and reduces the perceived burden of having to carry around an additional device for the duration of the study. We have already seen that patients, when choosing a mobile

device for personal use, self-select a device that has good usability for their individual needs. For example, we observe that the proportion of patients using larger screen (tablet) devices is higher amongst elderly cohorts compared with other adult age groups. We believe this factor will improve usability and reduce training requirements when a patient collects ePRO data using their own mobile device. Having the ePRO solution on the device they routinely use throughout the day for other purposes may also mean that the trial can easily fit into their everyday schedule, improving the accessibility and usability, and making it simpler for them to meet the obligations of the trial. Coupled together, these factors may improve the patient’s overall experience and, in turn, boost compliance and improve the quality of data captured.

A major concern for sponsors and CROs is whether the data captured as evidence will be accepted by the regulatory bodies, who are as yet to issue any formal guidance on BYOD trials. What can sponsors do to ensure the data they capture in a BYOD trial will be accepted?

Although there is no official guidance from the regulatory bodies around BYOD trials, and we’re not aware of any new drug applications containing BYOD data yet, they have informally indicated they are open to the concept and recognise the benefits it might bring to patients in a clinical trial.

As with any approach to collection of patient-reported outcome data, there are a number of essential elements to consider. First, will the display of validated instruments on screens of different sizes ensure that the instrument’s measurement properties are unchanged when compared to the format it was originally developed in. While this may seem more complex to demonstrate in a BYOD setting, where the devices that patients will present with are unknown, there is a growing body of evidence

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supporting migration equivalence when instruments are implemented electronically on screen-based formats. Along with industry colleagues, I recently published the industry’s first formal equivalence study exploring the measurement equivalence of patient-reported outcome data collected using BYOD compared to paper and a provisioned device. 1 This study, published in Value in Health, provides reassuring results supporting the validity of instrument measurement properties using BYOD. A second consideration is mitigating the possible loss of data due to data plan restrictions, patients upgrading to new devices mid-study, turning off in-app diary reminders, or not having a suitable device to use. With all BYOD studies, we recommend allowing for a quantity of provisioned handsets to ensure that patients without a suitable device (or unwilling to use their own device), and those changing to a device that is unsuitable, can be provided with the means of collecting or continuing to collect their self-report data throughout the study. In addition, we also recommend that patients leverage Wi-Fi connections when available to limit data plan restrictions affecting data transmission. While the quantity of data transmitted using eCOA is typically very small, local storage of non-transmitted data is also important to ensure that data will be transmitted when a connection is made, or when a data plan renews for the following month. In our experience of running the industry’s largest phase III BYOD study, we observe that ePRO completion rates are at least as high amongst patients using their own handsets compared to those receiving provisioned phones.

This suggests that missing data is no greater in BYOD settings than when providing provisioned devices.

A third consideration is related to limitations in data security when operating with mobile devices owned by the patients themselves, where the vendor has less direct control. It is a myth that a well-designed app cannot enjoy the

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BYOD offers numerous benefits to patients allowing them to use their own device, provides optimal familiarity and reduces the perceived burden of having to carry around an additional device for the duration of the study.

same level of data security when downloaded onto a patient’s smartphone compared to the solution provided on a provisioned handset.

Finally, careful consideration of site and patient acceptance of the use of BYOD is a critical success factor for any study where BYOD is being considered.

Although smartphone penetration is increasing, not everyone owns one, and not everyone has access to technology, particularly in developing countries/regions.

How can sponsors address any issues surrounding device availability and reduce any bias due to technology ownership?

While global smartphone ownership is increasing — current figures suggesting that over a third of the adult global population own or have access to a smartphone 2— not all trial participants will have a smartphone, and not all may be willing to use their own device for the purposes of the trial. It is essential not to eliminate trial participation based on smartphone ownership. Study samples should be representative of the underlying patient population, and sample bias due may be introduced if samples are limited based on technology ownership.

To counteract this issue, sponsors should consider implementing a “partial

provisioning” strategy, where patients who own smartphones enter their data using the app or browser on their own device, and those who don’t have a suitable device (or are unwilling to use their own) are provided with a dedicated device to do so. Typically, these provisioned handheld devices are mobile phones which have had their texting, calling, and browsing functionality disabled and have been programmed to run only the dedicated eCOA software.

To improve BYOD uptake, solution providers should ensure that the app utilised within their study is designed to work across the most widely used operating systems (Android, iOS etc) or web browsers (Internet Explorer, Chrome, etc).

Some in the industry have raised concerns over the security of data with a BYOD approach. Can you ease these concerns?

Absolutely. There is a misplaced belief that the provisioned devices traditionally used with an eCOA approach are inherently more secure than a clinical app on a personal device. In fact, it is practical to build all necessary security and protection controls into the trial software, whether it is delivered through a personal or provisioned device. This will include password / PIN protection, session timeouts, data encryption during local storage and transmission, ensuring data is segregated from access by other apps, and ensuring the app cannot access other personal data on the smartphone.

With growing public concern for cyber security, it is also likely that some patients will be uncomfortable sharing health data via an app, so it is important that researchers are able to provide clear information to reassure participants that the software is secure and is only being used for the purpose of the collection of self-report data during the study. By providing training and a clearly-worded informed consent process, researchers can alleviate patient concerns and improve BYOD uptake.

provide advice to clients in selecting the optimal approach for individual studies.

We can also support Sponsor discussions with regulatory bodies where required.

AUTHOR BIO Bill has worked in the Pharmaceutical Industry for over 25 years, in clinical development and as an eClinical thought-leader and strategist. He has helped to develop and launch a range of innovative technology solutions and services across the industry, and has a rich, first-hand knowledge of clinical trial operation. Academically, Bill also has a strong track-record of contribution to the scientific advancement of the electronic clinical outcome assessments (eCOA) and the wearable technology disciplines.

How do sponsors know which modality is best for their study?

When considering a BYOD approach, it’s important to also decide whether to collect data through an app downloaded onto the patient’s smartphone or tablet, or to collect data through a web browser using a mobile device or PC/laptop computer.

Web provides easy access from multiple devices and may be superior for very long studies where technology and app-compatibility may change over time. It may also be preferable for studies requiring only infrequent completion (for example, quarterly completion as part of a long-term registry) where users may be less willing to retain a locally installed app that is only used occasionally. A

disadvantage of web is the requirement for connectivity to complete the COA instrument(s) and so it may be less suitable for certain types of eCOA application or for use in certain geographies.

Using an app provides the ability to enter data and complete COA instruments without a mobile connection. This may be important in studies requiring frequent completion, or studies in locations where connectivity may be limited.

A disadvantage of app is the need to download and to ensure its compatibility on patient devices for the duration of the study.

At CRF Health we have significant experience in delivering large BYOD studies using both app and web, and our operations and scientific experts can

Finally, bearing all of this in mind, what does the future hold for BYOD? BYOD has been somewhat of a hot topic in the industry for a few years now, with adoption continuing to grow. Despite many in the sector being hesitant to make their move due to scientific, technical, practical and regulatory concerns, the majority of these issues can be mitigated in studies where BYOD provides an appropriate option. We expect to see the use of BYOD continue to increase as we strive to make trial participation and the collection of robust clinical outcome data more convenient. In addition, we expect to see new drug applications containing patient-reported outcome data collected using BYOD to be submitted to regulatory bodies in the coming months, and this will provide a clear indication of the acceptability of submission data collected in this way. Despite this, we see that all BYOD studies will be supported by a partial provisioning strategy to overcome the unavailability of device ownership by all potential study participants.

While we see BYOD increasing, we believe that decisions between BYOD and full provisioning will be made on a studyby-study basis, taking into account study designs, patient populations, geographies and patient and site acceptance – and we expect to see both approaches being used for the foreseeable future.

References: 1. Byrom B, Doll H, Muehlhausen W et al. Measurement Equivalence of PatientReported Outcome Measure Response Scale Types Collected Using Bring Your Own Device Compared to Paper and a Provisioned Device: Results of a Randomized Equivalence Trial. Value in Health 21: 581-589, 2018.

2. https://www.emarketer.com/Article/ Worldwide-Smartphone-UsageGrow-25-2014/1010920 www.pharmafocusasia.com

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How SMEs Can Achieve Regulatory Compliance through a Risk-Based Approach Since the introduction of the ICH E6 (R2) addendum, the industry has seen a rise in the implementation of a variety of risk-based monitoring (RBM) methodologies and technologies. However, quite often, small and mediumsized enterprises (SMEs) are more reluctant to adopt such methods as they perceive these types of approaches to be expensive and complicated. Consequently, they are generally unsure of the steps they need to take to implement an RBM strategy. As the industry changes and evolves, it will be essential for SMEs to learn how the regulations will impact them, and to understand how an RBM approach can be implemented quickly and efficiently to suit their specific needs. There are solutions out there that facilitate ICH E6 (R2) compliance and can support SMEs from pre-study risk assessment through to database lock and submission. The key is to find an approach that offers both consultation services and technological software that addresses the challenges faced by small and mid-sized research organisations in effectively adopting RBM and ensuring compliance with ICH E6 (R2).

Patrick Hughes, CCO, CluePoints

1. What is the current consensus on the ICH E6 (R2) Addendum within SMEs? The complexity and size of clinical trials has intensified over recent years alongside mounting costs and escalating regulatory pressures. The introduction of the finalised ICH E6 (R2) means that organisations across the industry are now reviewing the update to grasp its implications, including evaluating the requirement for modified strategies and operating models. Watching and waiting

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is no longer an option when it comes to RBM. Those that had not previously prioritised an RBM implementation are now driven to more determinedly assess this concept and determine an effective roll-out strategy.

Many SMEs are unsure of how to embrace RBM and often how it might add significant value. Rather than fearing the change, organisations should see this as an opportunity to embrace improved and more efficient approaches to trial design, conduct, oversight, recording,

and reporting, while continuing to ensure human subject protection and the reliability of trial results. The most logical place to start is to find an expert who can provide consultation on the ICH E6 (R2) addendum and RBM methodology.

The aim of a good consultation is to help organisations fundamentally understand what the regulation wants. By demonstrating how a risk-based approach meets the compliance obligations, many SMEs will be reassured that they can implement an approach that not only achieves regulatory compliance but also improves both cost and resource efficiencies.

2. What should SMEs be looking for when trying to achieve regulatory compliance through a “riskbased” approach?

The ICH E6 (R2) guidance specifies that the execution of RBM, and more specifically using centralised statistical monitoring (CSM) as a core component of clinical trial execution, is recommended due to its ability to provide “additional monitoring capabilities that can complement and reduce the extent and/or frequency of on-site monitoring and help distinguish between reliable data and potentially unreliable data.”1 Ultimately, the responsibility for the quality and integrity of the trial data always resides with the sponsor although a sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO. Both the regulators and Good Clinical Practice (GCP) are making RBM an essential, and GCP compliance concern as well.

RBM and Quality by Design (QBD) have been intensely recommended not only in the updated ICH GCP guidance but in related guidance documents issued by the FDA and EMA over the past several years. QBD and RBM working hand-in-hand have the potential to yield higher quality, reduce time lines and drive greater operational efficiency in clinical research. QBD and RBM both necessitate ongoing assessment and mitigation of operational risk. QBD is conducted at the earliest stages of clinical research design to ensure that studies are optimised not just for scientific merit, but for operational success as well. Once a study protocol has been developed, QBD becomes RBM. Risk assessment is performed on completed designs by a cross-functional study team. Remaining operational risks are identified and prioritised, and risk mitigation and risk monitoring recommendations are established to guide all downstream operational study management plans.

Essentially an RBM approach includes the following: Critical process and data identification: processes and data that are critical to ensure human subject protection and the reliability of trial results should be identified during protocol development Risk identification: sponsors should identify risks - at both system and clinical trial level – critical to trial processes and data up front Risk evaluation: researchers must carry out risk assessment/critical data identification before the study to characterise risks through risk evaluation, looking at the likelihood, detectability and impact of those risks. They should then put together a quality oversight plan that is a targeted approach to operational quality management, specifically focused on the biggest risks to operations Risk control: the sponsor should decide up front which risks to reduce and/or to accept. Predefined ranges within which various quality measures

will be accepted should also be established, to identify issues that can impact subject safety or the reliability of trial results. Detection of deviations from these predefined limits should trigger an evaluation to determine if action is needed Risk communication: quality management activities should be documented and communicated, to facilitate risk review and continual improvement during study execution Risk review: risk control measures should be reviewed intermittently to check that the implemented quality management activities remain effective and relevant Risk reporting: reporting should include a description of the quality management approach taken and review key deviations from the predefined quality limits, and any remedial actions taken.

3. What are the benefits of adopting an RBM approach?

A successful RBM centralised monitoring implementation can provide three essential aspects of value. It will make a substantial positive impact on quality outcomes across a business, resulting in additional successful marketing submissions and faster time-to-market.

It also offers a practical opportunity to appraise on-site monitoring that can lead to considerable and direct savings in the

cost of clinical research and clinical trial budgets. Effective centralised monitoring can also result in shorter study time frames.

The implementation of a successful centralised monitoring plan will help SMEs manage the shift towards RBM, while achieving compliance with the new regulatory guidelines. By supporting organisations in bringing significant improvements to the quality of their data, and therefore the success rates of their trials, it will be a vital tool in optimising operational quality monitoring within this exciting new paradigm for clinical research.

4. What are the benefits of Centralised Statistical Monitoring (CSM)?

CSM uses statistical methods to identify unexpected or unusual patterns in clinical data. It not only drives significantly better-quality outcomes but offers greater operational resource efficiency, enabling a significant reduction in the reliance on source data verification (SDV) and related on-monitoring reviews. CSM is ideally composed of at least the following components: Statistical Data Monitoring (SDM): A well-designed, robust set of statistical tests to be run on all clinical data in the study, with the purpose of identifying atypical data patterns that may represent operational risks of various types including

AUTHOR BIO

Patrick holds a Marketing degree from the University of Newcastleupon-Tyne, UK, and a post-graduate Marketing diploma in Business-toBusiness Marketing Strategy from Northwestern University - Kellogg School of Management, Chicago, Illinois. Responsible for leading global sales, product, marketing, operational and technical teams throughout his career, Patrick is a Senior Executive with over eighteen years international commercial experience within life sciences, healthcare and telecommunications.

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RBM – Pre-Study Risk Planning

fraud, study equipment malfunction, site sloppiness and training issues.

Key Risk Indicators (KRIs): KRIs represent a set of metrics designed to help monitor for known operational risks across all sites in a study. A few examples of commonly-used KRIs include: i. The rate of protocol deviations ii. The rate of adverse event reporting iii. Timeliness of data entry iv. Rates of queries or data errors v. Screen failure rate and early termination rate vi. Rate of missed procedures – especially key efficacy or safety procedures.

Quality Tolerance Limits (QTLs): Similar to KRIs, QTLs represent metrics designed to monitor for specific operational risks. However, the focus is on more systematic issues, monitoring for specific thresholds beyond which the study would likely be considered an operational failure.

5. How can SMEs fast-track their ICH E6 (R2) Compliance?

As a starting point, SMEs should review the below pointers to fast-track their ICH E6 (R2) compliance and RBM adoption: Develop an understanding of the ICH E6 (R2) guidelines and the fundamentals of RBM methodology Establish an overview of the pre-study risk assessment and mitigation planning process

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Establish Key Risk Indicators (KRIs) – review their purpose, key considerations for optimal effectiveness and review a set of standard KRIs Develop a Data Quality Assessment (DQA) – this includes comprehensive statistical data monitoring as a next step in risk detection — evaluate what it comprises and its critical importance in surfacing operational risks that may not have been anticipated via pre-study risk planning.

When selecting a Risk-Based Monitoring solution, key software elements should be incorporated, providing the necessary tools for organisations to start implementing a risk-based approach without over complicating the process, giving users the freedom and opportunity to implement further RBM activities as and when required. This can include tools that facilitate the development of risk assessments, key risk indicators, patient profiles, tracking systems and training.

6. What can SMEs expect if they quickly and efficiently adopt a fitfor-purpose combination of technology and expert consultation?

While compliance is a justifiable motivator, a risk-based approach to clinical trial management should deliver much more value than simple compliance, including: Substantial reduction in the cost of clinical development, primarily due to

the reduced reliance on 100 per cent SDV and frequent on-site monitoring visits. By way of example, in a typical Phase III trial, over 30 per cent of the average US$100 million trial cost is spent on on-site monitoring. 50 per cent of this time is spent conducting Source Data Verification (SDV), amounting to an average cost of US$15 million per trial. Even reducing this by 20 per cent using CSM results in a saving of US$3 million.

Shorter study timelines –propelled by enhanced enrolment and retention rates, as well as more effective database lock processes Higher marketing approval rates, driven by significantly higher study and data quality.

Now is the time to investigate how a shift in mindset, from simply ensuring compliance towel coming valuable RBM, can offer these immense business opportunities. The ICH E6 (R2) addendum has the capacity to profoundly revise how clinical research is managed. Risk-based trial design and quality management will, undeniably, be a necessary element of the clinical research landscape for years to come.

References 1.https://www.ich.org/fileadmin/Public_ Web_Site/ICH_Products/Guidelines /Efficacy/E6/E6_R2__Addendum_ Step2.pdf

Books

Drug Delivery Nanosystems for Biomedical Applications (Micro and Nano Technologies) Author: Chandra P Sharma Year of Publishing: 2018 No. of Pages: 451 Description: Drug Delivery Nanosystems for Biomedical Application reviews some of the most challenging nanosystems with different routes of delivery that are useful for specific drugs, from both efficacy and bioavailability points-of-view. The chapters explore how this area is developing, the present state of the field, and future developments, in particular, inorganic, metallic, polymeric, composite and lipid nanosystems and their possible evolution to clinical applications.

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Description: This volume is a thorough presentation of the state-of-the-art research and developments in drug delivery systems using nanotechnology and its applications. The second of this two-volume set, it addresses the applications of nanotechnology or nanosized materials in the medical field and the real-world challenges and complexities of current drug delivery methodologies and techniques.

This volume includes 11 chapters that focus on the targeting facet of drug delivery systems. Targeting is a focused maneuver to achieve the specified goals, including achieving the desired result and reaching the specific location. Targeting has now been successfully achieved for several diseases/disorders; however, its role is noteworthy in cancer treatment where chemotherapy is a main course of approach. Nanotechnology-based products have great potential by virtue of their inherent features.

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