Pharma Focus Asia - Issue 33

ISSUE 33 2018

APAC CRO MARKET STEPPING INTO THE FUTURE

Speed, Quality and Cost Leveraging Australia to expedite clinical development New and Novel Drug Delivery Technologies Enhancing product lifecycle

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Foreword Clinical Trials Destination APAC! The global pharmaceutical industry is undergoing a transformation resulting in slowdown of growth due to factors such as launch of innovative specialty products, regulatory, and pricing pressure etc. In the last 2-3 decades, drug development has evolved into a global phenomenon, and organisations had to reinvent their business models to stay relevant in this highly regulated and competitive market.

Rising research costs coupled with loss of revenue due to blockbuster drugs going off patent and lack of abundant in-house Research & Development (R&D) talent pool have forced pharma companies to rely on Contract Research Organisations (CROs) for their clinical trials. Outsourcing has thus become an integral part of the value chain for the pharmaceutical industry, specifically for clinical trials.

According to a report by Frost & Sullivan, the global CRO market is expected to be US$64.58 billion by 2021, with a CAGR of 12.8 per cent from US$35.41 billion in 2017.

Americas leads the global CRO market thanks to a well-established healthcare sector, followed by Europe where growth is driven by favourable policies, rise in healthcare spend, and most importantly increase in funds for research. Interestingly, the CRO growth in Asia Pacific (APAC) has been the fastest with an expected CAGR of 20 per cent by 2021. In development phases, drug discovery is the dominant segment for the CRO market while oncology is the largest segment in the therapeutics category.

Factors contributing to this CRO market growth in APAC are the region’s growing pharma industry, access to large patient pool, favourable regulatory environment, strong Intellectual Property (IP) protection and low legal barriers, and abundance of talent. Quality of clinical data produced in the APAC region is comparable to global standards. Japan and Singapore are ranked in top 10 countries for stronger IP Intellectual Property rights protection and legal environment.

The global CRO market, which was historically fragmented, has shown signs of consolidation owing to an increased consolidation. Around five CROs control one-third of the global market. Key factors such as large treatment-naive population, availability of highly skilled resources, robust clinical infrastructure among others have put APAC as the most favoured destination for clinical trials.

The cover story of this issue features an article on analysis of Asia Pacific CRO market. In this article, the author outlines the factors that contributed to growth of CRO in this region while dissecting the market to highlight encouraging trends country wise.

Prasanthi Sadhu Editor

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CONTENTS COVER STORY

AN ASIA PACIFIC CRO MARKET ANALYSIS

Stepping into the futures

10

Anmol Limaye, Business Analyst Nymro Clinical Consulting Services

STRATEGY 06 Ways to Create More and More Consistent Performers

16 Elixir for Sourcing And Retaining Candidates

Srinivasan V, Consultant / Advisor, Pharma Business / Enterprise 20 Speed, Quality and Cost

Leveraging Australia to expedite clinical development

Frank Andrew, Clinical Business Development Manager PCI Pharma Services

RESEARCH & DEVELOPMENT 24 Advanced Modelling and Simulation

Helps prepare medical countermeasures and optimise response to public health emergencies

Leigh Farrell, Senior Vice President, Asia Pacific Commercial Certara USA, Inc.

28 New and Novel Drug Delivery Technologies

Enhancing product lifecycle

2

38 Pre-Clinical Assessment of Drug-Induced Hypersensitivity Reactions

Tools and challenges

Emanuela Corsini, Professor of Toxicology Laboratory of Toxicology, Department of Environmental Science and Policy Università degli Studi di Milano

Valentina Galbiati, Laboratory of Toxicology, School of Drug Safety, Università degli Studi di Milano

Srinivasan V, Consultant / Advisor for Pharma Business / Enterprise

CLINICAL TRIALS

Ambikanandan Misra, Professor of Pharmacy Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda

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43 Product Design & Delivery

Subhadra Dravida, Founder CEO, Transcell Biologics Pvt. Ltd

MANUFACTURING 46 Advances in Spray Drying for the Improved Delivery of Poorly Soluble Drugs

Mark Davis, Research Fellow, SSPC, The University of Limerick

Gavin Walker, Co-Director, SSPC, The University of Limerick

54 Clinical Manufacturing on Time and Within Budget

David Brett, Team Leader Product and Service Management Vetter

62 Dissolution Prediction of Polymer-Coated Multiparticulates using In-Line Process Analytical Technology

Chris O’Callaghan, Innopharma Technology

Piyush Patel, Colorcon

Edward Godek, Glatt Air Techniques

Dr. Ian JonesD, Innopharma College of Applied Sciences

Luke Kiernan, Innopharma College of Applied Sciences

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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 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 SUBSCRIPTIONS IN-CHARGE Vijay Kumar Gaddam

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

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

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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

WAYS TO CREATE MORE AND MORE CONSISTENT PERFORMERS

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STRATEGY

For all pharma businesses, it is a challenge to enable their field force—Sales and Marketing— to be consistent performers. The success or failure in this direction will accordingly decide the fate of the organisations. Even if an organisation has highly innovative molecules in its product basket, it is of no consequence if its field force are not consistently performing. The very fact that every pharma business is trying to achieve this with all its might shows how important this activity is in driving the business forward, though only some succeed. In the light of this, the topic that we are going to discuss in this article assumes great importance.

Srinivasan V, Consultant / Advisor for Pharma Business / Enterprise

I

n ethically promoting Pharma business, field force are the resources who generate prescriptions for the products being promoted, thus bring in revenue, therefore the figures at the top of the line always depend upon their contribution. However, not all members of the field force are consistently hitting the numbers. If we enable most of the field force to unlock their potential and hit the numbers consistently, then imagine its impact on the top of the line! That’s what every business is trying to do, though only some succeed. Let’s discuss below some ways and means of achieving this, not by doing things drastically and painfully, but by tweaking a bit of things that we have been doing all along.

First and foremost, there should be an unending appetite to succeed in the profession—like Sunil Gavaskar for runs in Cricket—earn well, grow in career, and stand tall in the society in the minds of the field force. However, if this is lacking in a few, it should be inculcated by the organisation and also by the lINE MANAGERS. I have seen people growing from Medical representatives to Zonal Sales managers, Brand/Product managers, Marketing managers, National Sales managers, Vice presidents sales & marketing, Managing directors, Chief Executive Officers, etc in a span of 10-15 years.

They have earned such positions due to their sincerity, hard work, and delivery of expected results consist-

ently in each position, despite odds.

If this is possible for them, then why not for others? A session on this can be thought of during the in-house training programmes to inspire and motivate newly joined Medical Representatives.

The HR team, in consultation with the sales &marketing team arrive at the criteria they expect for a frontline salesman (medical representative) with which hopefully he/she can perform well in the field, and ensure that it is well understood and implemented by all involved in the selection of candidates. For example, some of the criteria may be as under: a) Biology or Pharmacy graduate, b) Fresher or with only 1-2 years of experience in same line, c) good communication skill, and d) enjoys meeting highly qualified customers, outgoing type , and interacting with them, e) age group 20-25, and f ) reference check should be favourable. Well begun is like half the battle won!

However, we all know what has been happening in reality. In their eagerness to fill up vacancies, line managers often finalize candidates who may not fulfill some of the important criteria, that are also approved by Sales/Marketing and HR Heads at Head Office. I have seen many Medical Representatives working in the field with I.T. (Industrial Training like Welder, Fitter), 12th pass qualifications who struggle for words in front of the Doctors. They may end up spoiling their own image as well as the organisation too in front of the Doctors.

Once the selection process is over, the selected candidates are sent to Head Office for a comprehensive class room Training, and are deployed only after successful completion of the Training programme. Rarely the concerned line managers regularly follow up with the HR and Training Heads about the progress being made by candidates in the training programme whom they have selected and sent. At the end of the training programme, when the time comes to reject candidates who couldn’t come upto the company’s standards, we often see the interference by line www.pharmafocusasia.com

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STRATEGY

managers to get them cleared in the name of having to fill up long pending vacancies, as otherwise we shall lose business.

We learn to come out of this mindset, and both Sales & Marketing and HR heads, in consultation with the training head, should say a firm ‘no’ in unison instead of compromising to candidates who couldn’t come up to the Company’s standards , keeping in view the long term interest of the organisation.

The line managers, though most of them know about what exactly is their job responsibility, believe that it is enough if they work with each one in the team for a few days every month; and while leaving tell them strictly that “I don’t know what you will do, but you will have to achieve the numbers this month without fail, otherwise you will not be in my team”. If some one is not performing well, they tend to blame the training department. Things may not work out like this most of the times.

Line managers have to ensure that each and every one in the team implements the sales &marketing strategy in full in the field, provide on-the-job training, mentorship, and also act as an ‘enabler’ or ‘facilitator’ in enabling each one in the team to hit the numbers, and thereby his own numbers consistently. This will help them to retain full strength in the team as well.

The communication part or the ‘detailing’ plays a big role in deciding whether a medical representative is going to succeed or will he end up as another mediocre performer. We all know the detailing story is designed by the marketing/product management team, and has to be memorised and reproduced verbatim by the medical representative in front of the doctors, thus convincing them to prescribe the products detailed. Here, the product management team can play a vital role in ensuring that the detailing story for any product is crisp, to the point, and not too lengthy. Doctors are very busy these days, and don’t have time and interest to listen to long stories. The meaning and importance of every point discussed in the detailing story should be 8

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explained to the medical representatives during the launch/cycle meetings by the marketing/product management team, and thereafter by the line managers in the field. If they understand the meaning and importance, it will be that much easier for them to memorise and reproduce, thus create the desired impact, leading to better results.

Similarly while finalising products for marketing, marketing department should decide on products with a difference that can offer some benefits to the patients, that can be highlighted in the detailing stories, instead of just ‘me too’ products.

Organisations should encourage consistent performers by rewarding them handsomely, including career growth.

Policy should be to look within for higher positions. Only when we don’t find suitable candidates within, we should look outside. Some organisations have the habit of saying goodbye to field force who are unable to hit the numbers right away, thereby creating more and more vacancies and losing sales. If the candidate is sincerely trying, working habits are good, and the primary and secondary sales are on the rise, then we should give him/her a few months to settle down and hit the numbers regularly thereafter.

In-house publications at regular intervals highlighting the achievements of consistent performers, highest incentive earners, career growth of high performers, awards, medals, certificates earned, information about great detailers, details of conversion of important doctors, success on

establishing new products, etc. can be considered to spread the competitive spirits around and also to inspire and motivate for better performance.

Review/Audit of the Customers/ Coverage list must be carried out periodically (at least once in six months) to understand the extent of contribution by each customer for each production whom we have invested precious efforts and promotional inputs vis-à-vis his/her potential and our expectations. If the contribution is very poor or nil, despite our best efforts, the medical representative and his line managers need to take a call on whether to replace that non-performing customer with a new customer from the same speciality from whom we can expect to get meaningful contribution in the near future. The idea is to have lots of customers in the coverage list contributing to the business, and avoiding wastage of precious efforts and inputs on nonperforming customers. This will in turn ensure that the customer/coverage list of each Medical Representative is updated and active.

If we implement the above in all sincerity, it will get into the DNA of the organisation. Then it will greatly improve the number of consistent performers in the field, leading to a big leap for better in the top of the line figures. Since most of the field force are now consistently performing, it should give them a lot of confidence, better quality of life through better earnings including attractive incentives, and career growth, leading to more stability in the field.

AUTHOR BIO Mr. Srinivasan V has over 35 years of rich experience in Pharma Industry in HR, Sales Administration, and Training functions. He was conferred with the award “The Transformational Leader in Pharma Industry”. He has to his credit over 500 published articles in India and abroad. Author of the book “Reach For the Stars” which is like a Bible for aspiring and already working Medical Representatives. He can be reached at shridhar1956@rediffmail.com, Mobile:9972390513

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COVER STORY

STRATEGY

AN ASIA PACIFIC CRO MARKET ANALYSIS

STEPPING INTO THE FUTURES

The pharmaceutical industry is undergoing several changes that are affecting its growth on a global scale. Despite the fact that the Asia-Pac market has faced ongoing challenges associated with regulatory ambiguity, long-drawn approval timelines and evolving policies, an increased global focus on multi-regional clinical trials and real-world evidence, rapidly evolving capabilities in data analytics and AI, a significant focus on precision medicine, in addition to access to a genetically diverse and treatment naïve patient population, has made it the fastest growing market today.

Anmol Limaye, Business Analyst, Nymro Clinical Consulting Services

T

he increasing cost of research in the west, the ongoing tightening of regulations and pricing policies, and major funding cuts for biomedical research have led to an increased interest in the outsourcing of clinical trials. Not only is the APAC pharma market growing faster than the rest of the world, it has a large treatment naïve population, and has shown improvements in the regulatory environment, rapidly making it a preferred outsourcing destination for clinical trials. But are these factors enough to overcome the perceived chal-

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lenges associated with an unharmonised regulatory environment and problems with IP protection?

North America has the largest share of active clinical trials. While APAC accounts for about 19 per cent of the global clinical trial share, it is expected to reach 30 per cent in the next five years. The Compounded Annual Growth Rate (CAGR) for global CROs is 12.8 per cent. CROs in North America are expected to grow at 10.4 per cent, whereas CAGR for APAC CROs is over 20 per cent, making it the fastest growing CRO market in the world.

Key Challenges for Conducting Clinical Trials in the West High Costs

Cost predictions for conducting clinical trials have varied over the past several years from US$200 million to over US$2 billion and continue to escalate in the west. The average increase in the cost of conducting clinical trials is 7 per cent higher than the average rate of inflation over the past 20 years (from 1989 to 2009). A few key trends have contributed significantly to the same.

• A shift in the biopharmaceutical industry towards creating drugs for degenerative and chronic diseases has necessitated larger patient pools and longer trials as extensive drug exposure and complex tests are required to observe long term effects • The productivity of the pharmaceutical industry has led to only incremental improvements in the efficacy/safety of drugs, needing extensive trials to conclusively demonstrate these improvements, while the introduction of novel therapies is rare.

Recruiting and retaining patients

57 per cent of clinical trials fail owing to challenges in recruiting patients.

With an increasing focus on chronic diseases, study sizes are growing,

STRATEGY

resulting in increasing challenges in recruiting patients. In the US, only 25 per cent of elderly cancer patients enroll in clinical trials while accounting for more than 60 per cent of new cancer cases. Low participation has encouraged companies to conduct trials beyond the US and Europe. According to the EMA, between 2005 and 2011, 62 per cent of patients were recruited outside of the EU. Longer timelines

Over a drug’s lifecycle, lengthy timelines lower revenues because of: • Shorter time under patent for the drug • Larger labor and infrastructure costs The ambiguity of regulations and pricing policies has only increased with the 2018 US fiscal budget indicating major cuts in funding for biomedical research. The average time for a drug

to go from discovery to approval takes 11-15 years in the US and Europe.

Proposals to repeal the Affordable Care Act and the individual mandate have repeatedly failed, keeping the future unclear and placing pressure on pharma companies in the US. Why Asia-Pac? Large treatment naïve population

One of the greatest assets of the Asia Pac CRO market is the access to a large treatment naïve population. Home to 53 per cent of the world’s urban population, and with an annual rate of urbanisation 3 times that of the West, Asia’s emerging middle class, acts as a growth engine for clinical trials in Asia-Pac. China, Philippines and Malaysia, all have less than 10 clinical trial recruitment centres per million people, while India has 0.5, as compared to over 150 in the US. The lower density of recruitment centres indicates greater patient access for pharma companies.

trials prove to be a more cost-effective way to get access to innovative treatments.

Similar disease patterns to the West

Disease patterns in Asia are increasingly mirroring those of the west; with some diseases once prevalent in the West, showing greater occurrence in Asia than the west. Examples include stroke, ischemic heart disease, gastric and lung cancers in China, liver and lung cancers, and chronic, geriatric diseases in South Korea, cervical and gastric cancers in India,providing an opportunity for pharma companies to conduct clinical trials in these countries.

Government spending and out-of-pocket costs

The per-capita healthcare spend in the US is 3 times (Japan) to over 100 times (China) greater than that of Asia (2014). Moreover, patients in Asia pay a far greater percentage of the costs for treatment out of pocket: Out of pocket costs in the US in 2015 were 11 per cent, while those for most Asian countries ranged from 30-60 per cent.

With a higher proportion of costs for novel therapies borne by patients, clinical

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STRATEGY

Comparative Analysis of the Clinical Trial Business in APAC

Table 1

Country

Therapeutic Indications

Phase

Market Opportunity

2

+++

+++++

9 months (CFDA)

3 months (DCGI)

0,2

India

1

HNC, gastric and lung and cervical cancers; vaccines; pregnant women

0.5

+++

+++

Japan

3

Geriatric; pediatric; digestive; autoimmune

51.2

+++++

++

Australia

3

Geriatric; pediatric

88.3

++

+++

Gastric, liver and lung cancers; geriatric

62.6

++++

++++

1,2,4

Strengthening infrastructure

APAC KOLs and Leading CROs

Not only is the number of highly skilled workers in Asia-Pac and citable articles coming out of these geographies rapidly increasing, expertise in various therapeutic areas, the establishment of specialised clinical trial centres hosting thousands of beds and hospitals with de-identified clinical trial databases is putting APAC at the forefront of the CRO industry.

Over 80 per cent of tertiary hospitals in South Korea have adopted EHRs, with China aiming to reach 80 per cent EHR adoption by 2020.

Most countries in APAC show great fragmentation of market share. IQVIA is the largest CRO with a 15.6 per cent share of the global CRO market (global or AsiaPac). Other major global players with a great influence on the Asia Pac include, PPD (8.4 per cent), PAREXEL (7.6 per cent), Covance (6.5 per cent) and ICON (6.1 per cent). On segmentation by trial phase, Charles River Laboratories has 17 per cent of the marker for pre-clinical studies.

Amongst APAC CRO countries, Japan would be considered tier 1, Taiwan, Singapore, Korea and Australia tier 2, and India and China tier 3, based on quality.

High quality data and low legal liabilities

EMA Good Clinical Practice (GCP) inspections (2000-2012) have revealed a smaller percentage of critical findings (4.9 per cent) in APAC as compared to the US (15.9 per cent) and the EU (9.1 per cent). In fact, only 1.3 per cent of findings necessitated that official action was indicated (OAI), which was much lower than in the US (9.3 per cent).

While there undoubtedly have been ups and downs in the recent past, these low numbers of critical findings indicate high regulatory compliance.

APAC countries have an added benefit over the US in terms of having much lower legal liabilities. A potential lawsuit targeting healthcare providers substantially increases legal liabilities in the US as compared to APAC, slowing down the recruitment process.

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Cost

China

South Korea

HNC, lung, gastric, liver cancers; pediatric

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Regulatory Approval Timelines

*Trial Density (Patient Access)

Dissecting the APAC Market China

China is rapidly catching up with the US and EU in terms of expenditure on R&D with more than US$206.5 billion (US$408 billion using purchasing power parity exchange rates) as of 2015, and US$278 billion as of 2017. It boasts a developing but sturdy research infrastructure and has over 30 regenerative medicine centres and at least 16 public hospitals with more than 3,000 beds each. Regulatory approval in China for clinical trial initiation involves passage through six regulatory bodies contributing to unpredictability as delays can

9-11 months (PMDA)

2 months (TGA) 1-2 months (MFDS)

occur at any of these steps. This necessitates partnership with a CRO that can navigate local regulatory requirements that can overcome the language barrier.

China hosts several global pharma players such as Merck, Sanofi and Bayer.

However, it has increasingly demonstrated a trend indicating closure of these R&D locations and increased dependence on CROs. The Chinese CRO market still demonstrates a high level of fragmentation, with WuXi AppTec and Tigermed Consulting being the leaders All other players account for less than 1 per cent of the market.

India

India boasts a highly qualified medical population experienced in conducting clinical trials. The turbulent regulatory system is gradually streamlining, with median approval times falling to 10 weeks. Several multinational CROs in India have end-to-end development capabilities, for which there has been an increasing demand. Another factor influencing partnerships with CROs in India is that there is no language barrier, facilitating partnerships even with local players.

Digital initiatives such as the launch of the SUGAM, the online portal for clinical trial applications, the revision of Indian GCP, the notification of 2017 Medical Device Rules, the drafting of the New Drugs and Clinical Trial Rules

STRATEGY

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STRATEGY

Japan

The Japanese CRO market has been expanding for the past 10 years, reaching $1.5 billion by 2016. It has made strides in lowering regulatory timelines and increasing harmonisation. The Pharmaceuticals and Medical Devices Agency (PMDA) in Japan has made concerted efforts for the standardisation of regulatory processes. Japan’s Sakigake route provides priority review to rare/ life-threatening disease drugs or worldfirst drugs and aims to complete the review within 6 months. It also provides a conditional marketing approval option for regenerative medicines. Singapore and Japan are consistently ranked among the 10 most secure countries in the world in terms of IP rights. The United Kingdom and United States are 14th and 15th, respectively.

The market has been largely occupied by large multinational CROs; EPS, CMIC, Quintiles and Parexel are offering full-stack capabilities.

South Korea

South Korea has developed a robust research infrastructure, conducive to running clinical trials, including specialised disease centres such as Woodirul Spine Hospital, a top global spinal treatment hub, with more than 1,130 neurospinal specialists. South Korea’s National Enterprise for Clinical Trials (KoNECT), South Korea’s SCI-Consortium, which includes 4 leading hospitals, 1,545 investigators, and 30,000 active patients enrolled in clinical studies, hospitals maintaining a de-identified patient and trial database and EHR adoption by more than 80 per cent of tertiary hospitals, has spearheaded clinical trial growth. Seoul National University Bundang Hospital was the first non-US hospital to achieve the HIMSS Analytics Stage 7 standard for highest EMR adoption. The KFDA 14

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has streamlined regulatory approvals, approving trials within 30 days, with parallel IRB approval.

Asia collaboration initiatives

China, Japan, and South Korea’s Tripartite Cooperation on Clinical Research allows trial data generated in one country to be accepted for drug registration in the other.

The ASEAN countries’ harmonisation initiative, AFTA (ASEAN Free Trade Area), has improved harmonisation of regulatory policies, ASEAN Common Technical Documents (ACTD) and ASEAN Common Technical Requirements (ACTR). ACTD gives information on the format, while ACTR acts as a guide for applicants to prepare an application that is consistent with the expectations of all ASEAN drug regulatory authorities.

Australia

Clarification of the regulatory environment over the last few years have set Australia up for a 15 per cent annual growth in trials. Companies are increasingly looking to invest in Australia due to favourable R&D tax incentives, as well as cash rebates such as a 43.5 per cent refundable cash benefit for eligible R&D activities in Australia. Asian countries on an average can provide cost savings to the tune of 30 per cent as against 40 per cent in Australia, as compared to the US. The market is expected to reach USD 600 million by the end of 2019, with a CAGR of 12 per cent with an emphasis on early phase clinical trials.

Some of the leading players in Australia include Novotech and George Clinical.

An increasingly streamlined regulatory atmosphere and favourable costs are making Australia the leading clinical trial destinations in the word.

Navigating the APAC Roadmap

APAC is continuing its path to becoming a clinical trial powerhouse. Industry experts foresee major growth in the APAC region. Large patient populations and maturing healthcare systems in India and Australia are demonstrating a huge potential for clinical trial outsourcing. China, South Korea and Japan are strengthening their infrastructure and demonstrating equivalence to the West in terms of quality of clinical trials.

Pharma companies have demonstrated that maintaining quality is more important to them than cost savings and that they would prefer to partner with CROs providing end-to-end services and that would help them navigate local regulatory bodies and that can help address local language barriers, such as those in China.

Although sponsors face significant challenges navigating APAC’s IP, regulatory and language barriers, it is unlikely that a large number of trials will move back to the West. The cost incentives, shorter timelines, lower legal liabilities and strengthening infrastructure tip the scales in favour of investing in APAC. As mentioned, patient recruitment is the number one driving factor for strategic clinical trial outsourcing decisions. The presence of large patient naïve populations and greater recruitment success at APAC sites as opposed to the West makes APAC an integral part of the clinical trial ecosystem of the future.

References are available at www.pharmafocusasia.com AUTHOR BIO

2018 (enabling accelerated approvals for life-threatening or rare diseases, and diseases of special relevance to India ) are expected to drive robust growth of research in India. Thus, there has been a change in how India is being perceived, from skepticism to acceptance.

Anmol Limaye, a biotechnologist, is serving as a Business Analyst at Nymro Clinical Consulting Services, where he has contributed to business strategy, competitive intelligence and pricing strategy. He has gained research experience at Tuft’s University School of Medicine and the Advanced Centre for the Treatment, Research and Education in Cancer.

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CLINICAL TRIALS

ELIXIR FOR SOURCING AND RETAINING CANDIDATES

Many pharma companies have been suffering silently from shortage of suitable candidates to fill up vacancies in the field, and also of high attrition rate, leading to terrible but avoidable loss of business due to vacancies. In this article, let’s discuss about various avenues available for sourcing of candidates, ways to retain them, and also how to enable them to contribute their best to the organisations.

Srinivasan V, Consultant / Advisor, Pharma Business / Enterprise

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isit the science, and pharmacy colleges in the vicinity where the vacancies exist, talk to the Placement Cell, and then finalise a date which is convenient both for the final year students who are awaiting results, and also for the Human Resource (HR) teams and the line managers concerned.

The HR Department and the line managers concerned should prepare well for the campus interview, which should include

CLINICAL TRIALS

introduction about the organisation, its promoters, its other businesses, if any, product profile, what exactly is the job requirement, career growth in the job for consistent performers, salary range for the job, scope for earning incentives, answers to questions if any from the students, etc. through a powerful power point presentation. Language of presentation should be ideally English, local language, and also Hindi. This is because now-a-days students from North come to South, and students from South go to the North to pursue studies of their choice. When I went for such a campus interview recently to a pharmacy college in Chennai, I used both English and Hindi, in addition to the local language (Tamil), which was appreciated by the principal and the students as well, because many of the students were from North, and they were quite comfortable listening to the presentation in Hindi. Such a professional presentation will make a good impact on the young minds and quite a number of them may show interest in the job. The organisation as well as the College must ensure that the occasion should not be simply used as a platform to collect resumes from students without any discussion and presentation.

In addition, we can also collect the mobile numbers of students of last year who had passed out, and get in touch with them to see if they are still available and are interested in our job.

bourhood (local) weeklies which have a wide coverage in specific localities.

The ad can be brief, but should contain vital information about the organisation, the job, ideal qualifications, skill sets required, range of compensation, career growth possibilities for consistent performers, etc.

Field force like medical reps, area/ district managers, normally keep their retailers and stockists informed if they are looking around for a change.

Therefore it will also help if we seek their assistance in filling up of vacancies.

Besides they also act as reference givers for selected candidates with local work experience. If they help the companies in getting good candidates, they also get rewarded through better business, and therefore, better earnings.

Line managers can seek help from their friends in other companies, and also from their own team members for suitable candidates to fill up vacancies.

While waiting in the Clinics, they can also pick up conversations with medical reps of other companies to see if any of the mare looking for a change. Medical reps in the team can chip in with their help like if any of their batch mates are still looking around for a job who may be suitable for the job, or any of their relatives or friends with necessary

qualifications and skill sets are available for the job, etc. Employees can be rewarded for suitable candidates referred by them and were selected.

HR along with the line managers concerned can organise ‘walk-ins’ to fill up vacancies. Release an ad as discussed above on the ideal day and call for ‘walk ins’ in a decent hotel in the town on a holiday so that the candidates don’t have to take leave from work, therefore better response to the Ad. Help of manpower suppliers/recruiters can be availed where and when necessary. Ads can also be released on reputed ‘online’ platforms such as Naukri.com.

Ads can be released on ‘social media’ apps like Whatsapp, Linkedin, etc.

Companies can also participate in job fairs if conducted in places where we have vacancies.

Normally resumes/applications for jobs are received by many companies through post, e-mail, online, etc.

However, these are not taken seriously or discarded often. If such applications are organised and kept properly, in times of need, these can be a source for candidates.

Interviews must be conducted in a professional manner by evaluating candidates on important parameters like education (science/pharmacy graduates), experience in similar lines

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Select popular newspapers — English as well as local language — which are the best in terms of circulation in places closer to where we have vacancies, and advertisements can be released on ideal dates and place in the newspapers. For example, if you decide to release the ad in Times of India, then Wednesday is the ideal day to release the ad in the specific pages meant for job advertisements. If the vacancies are in the state og Rajasthan, then one can prefer Rajasthan Patrika for Hindi (a local newspaper with a wide reach) and Times of India for English. Besides these, one can also release the same ad in any reputed neighwww.pharmafocusasia.com

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for a few years, whether they enjoy talking to people (outgoing) or are reserved, communication (detailing) skills, feedback from references, etc. and then the right candidates are selected. Now-a-days HR people in some companies also go through the social media pages if any of selected candidates before finalising. Once the selection is made, the selection/offer letter confirming the selection, position, headquarters, details of compensation, date of joining duty, etc. should be issued to the selected candidates, and their signatures obtained in the duplicate copy as a token of having accepted the offer. The line manager concerned should confirm to the HR at the head office if the selected candidates have reported for work at the as per the offer letter issued.

Your responsibility doesn’t end after having selected the candidates .You need to nurture them properly, to ensure that each candidate contributes to the organisation to the best of their potential. Detailed class room training, covering topics such as pharma industry, job responsibilities, career growth for consistent performers, etiquettes, product knowledge (indications for each product, the right customer(s), composition, etc. must be covered in detail. At the end of the training programme, those who have done well and come upto the standards of the organisation only are finally cleared.

No compromise should be made to accommodate below par candidates to somehow fill up vacancies which may be damaging in the long run.

Once the detailed training is over, then the line managers concerned should take care of On the Job Training for their team members regularly and nurture them properly. They should act as their guide, mentor, and developer, thus earning their respect. Once in a while people from Head Office like product/brand manager, national sales manager, etc. can also join them so that the candidates can learn many things for improvement.

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Field force like medical reps, area/district managers, normally keep their retailers and stockists informed if they are looking around for a change.

The line managers need to sit with candidates who are struggling to hit the numbers, identify reasons for the same product-wise,explain action plan to correct the same, and ensure that it is implemented by the candidates properly while working in the field, thus they are able to overcome the problems and hit the numbers consistently. Such line managers will be highly regarded by their team members, and they may not leave the team that easily even if lured by attractive offers. A few candidates may struggle initially for a few months before settling down.

If their working habits are good, and primary and secondary sales are growing gradually, even though falling short of the numbers, it is worth giving them a few months’ time and guide them to hit the numbers soon, rather than rushing to dump them in the dustbin.

AUTHOR BIO Srinivasan V has over 35 years of rich experience in Pharma Industry in HR, Sales Administration, and Training functions.

He was conferred with the award “The Transformational Leader for Pharma Industry”. He has to his credit over 500 published articles in India and abroad.

Author of the book “Reach For the Stars” which is like a Bible for aspiring and already working Medical Representatives.

However, you should not waste time and resources with people whose work ethics are questionable, and are hard to change for positive and productive.

Disbursement of salary, incentives, reimbursement of expenses, confirmation or otherwise of employees, yearly increments, samples, promotional inputs, etc. on time will help in keeping the employees morale high, and also in retaining them.

It is the responsibility of the organisation to take care of consistent performers by giving them good increments, attractive incentives linked to performance, promotions for higher responsibilities, sharing their success stories in the in-house magazines/ publications thus appreciating them for the job well done.

If any one leaves the organisation, exit interviews must be conducted in all sincerity without any cover-up, and action taken where necessary so that others do not leave for the same reason again. If ex-employees complete the necessary formalities, their full and final accounts should be settled promptly.

If the things discussed above get implemented in an organisation regularly in all sincerity, I am sure human resources will be very happy to work with in such organisations, and will not like to leave them that easily. No vacancies in the field means no sales lost due to vacancies. People will be very happy to join and work with such organisations. It is a win-win situation for both.

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Speed, Quality and Cost Leveraging Australia to expedite clinical development

Within the Asia-Pacific region, Australia is one of the most mature clinical trials markets and of increasing global significance—with many advantages that help make it a destination of choice for the conduct of early phase clinical studies, including robust government support to ensure speed-to-market and swifter outcomes for patient populations.

Frank Andrew, Clinical Business Development Manager PCI Pharma Services 20

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n recent years, the pharmaceutical industry has seen tremendous changes in the way it is expected to deliver new drugs to market: being under increasing pressure to expedite the development of new therapies, to decrease clinical study duration, and to drive new treatments through their clinical phases as quickly, safely and cost-efficiently as possible.

CLINICAL TRIALS

Such changes have required the industry to re-evaluate and rethink longstanding approaches to drug development and commercialisation, with attention being recalibrated on the ultimate goal; making it easier for the patient to reach improved health outcomes. Supporting this perspective is the understanding that optimal patient focus will be beneficial in turn for other stakeholders involved, such as the pharmaceutical company and healthcare provider, as well as the supporting community of associated service providers.

This rapidly developing environment means innovation and cost-efficiency in drug development is crucial; costs of research and development (R&D) are growing aggressively with an average investment of US$1.7 billion required to successfully initiate a new drug to market1 and an average 12 years to bring a new molecule from laboratory to approval.

Furthermore, approximately only 1 in 5,000 candidates entering preclinical testing make it to market2.

Specifically for progression of pipeline candidates entering Phase I Clinical study, a recent study from the Biotechnology Innovation Organization (BIO) noted that from 2006 to 2015, the overall likelihood of approval from Phase 1 for all drug candidates was 9.6 per cent, and 11.9 per cent for all indications other than cancer. AstraZeneca reported a success rate closer to five per cent. In the highly desired oncology space, the success rate is a striking, with an abysmal 3.4 per cent success rate3. Recent success with immune-oncology therapies has increased the prospects for oncology specifically.

The inefficiencies of drug development and pipeline success, coupled with incentives for special designations from FDA and EMEA, have driven the pharmaceutical industry to focus on 1 Forbes 2nd Oct 2012: Matthew Herpers 2012 ’The truly staggering cost of inventing new drugs.’

2 www.medicinenet.com-Drug Approvals - From Invention to Market ... A 12- Year Trip 3 https://biopharmconsortium.com/2018/03/14/mit-studyfinds-that-the-probability-of-clinical-trial-success-is-nearly40-higher-than-previously-thought/

The Australian Therapeutical Drugs Act 1989 dictates that all trials conducted in Australia must be carried out in accordance with the International Standards of Conduct for clinical trials developed by the ICH and the ISO.

rare diseases and unmet needs, thereby increasing success factors. Rare diseases are defined as affecting less than 200,000 patients in the US at any given time.

The same BIO study identified a success rate of 25.3 per cent of candidates for rare disease drug candidates4. In 2016, rare disease indications accounted for 41 per cent of FDA approvals. Many have argued that this rare disease focus is not a sustainable model for the industry, both for the overall number of target diseases as well as sustaining an economic model of commercial revenue driving R&D expenditures.

The overall impact of increasing drug development costs, continually lengthening development timelines, and trend towards low probabilities for success has fostered an industry strategy of ‘kill it fast’. Speed is essential in establishing feedback for in-human studies, quickly identifying critical and measurable factors that help provide a framework for either advancing or ‘killing’ viable drug candidates in human treatment, thereby minimising total cost and resource expenditures and advancing only the most viable treatments.

Product innovation is one area that drug companies have competed strongly 4 http://www.raredr.com/news/orphan-approval; Clinical Development Success Rates 2006-2015, BIO

against one another in, impacting on and leading to higher R&D costs. Such rises in R&D costs, combined with increasing pressure economically and politically for keener pricing of end product, mean that it is ever more critical to find ways of minimising overall costs. But costs are not the only issue facing the drug development industry: further pressure to speed up the development process comes from the scale, timing and complexity of clinical trials.

The care of patients across a broad variety of diseases could be transformed by industry R&D and use of the growing range of New Chemical Entities (NCEs), which are high value by nature. These increased costs therefore make it more imperative to accelerate drug product supply into clinic for the early phase, first-in-man clinical trials.

These changes have shifted the industry’s focus towards developing quality drug candidates and supporting them through clinical development as quickly, efficiently, and cost-effectively as possible, delivering unparalleled speed-to-study for their compounds. As such pharmaceutical companies are continually looking for alternative and innovative treatment methods and new markets to support these requirements.

According to a Frost & Sullivan report5, Asia-Pacific offers an attractive market for clinical trials, with more than 50 per cent of global clinical trials having treatment sites in the region. Sponsor companies are attracted to Asia-Pacific because of the vast availability of trial participants, offering a pool of about four billion people, with more than 1.8 billion in easily accessible urban areas.

Within the region, Australia is one of the most mature markets in AsiaPacific for conducting clinical trials.

The country’s drug sector’s R&D investment exceeds AUD$1 billion annually.

Investment in Phase I studies alone in Australia conservatively estimated at

5 Australia: Preferred Destination for Early Phase Clinical Trials, A Frost & Sullivan White Paper, https://ww2.frost. com/files/6514/7374/3781/Novotech_WP_20160701_ v2.1.pdf www.pharmafocusasia.com

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AUD$50 million 6. Phase I Clinical trial activity in the country recorded a 17.2 per cent growth in volume from 2012-2015, compared with 1.8 per cent globally7.

Australia also has many advantages that help make it a destination of choice for the conduct of early phase clinical trials, which should be taken into consideration.

Well-regarded internationally for its world-class infrastructure and medical facilities, highly skilled healthcare professionals and leading research institutes, Australia is also recognised increasingly as the Phase I destination of choice, with more than 50 per cent growth in First in Human Trials (FIHT) between 2010 and 2015, and more than 1,500 clinical trials of all phases carried out each year.

This upsurge is a true reflection of the proven excellence and performance of the clinical trial institutions in Australia which are greatly supported by the highly favourable regulatory and business environment. The Australian Government demonstrates its commitment to support and improve the clinical trial environment with considerable investment to ensure Australia remains a key contributor to trial success for global pharmaceutical companies.

Before commencing a trial in Australia, it is important to note that all trials must have an Australian ‘local sponsor’ whose role is to ensure that the clinical trial is being conducted in accordance with internationally recognised standards of Good Clinical Practice (GCP). The local sponsor is also responsible for liaising with Australian governance bodies in relation to the trial. This sponsor can be an individual, an organisation or a pharmaceutical company but they must reside in Australia and be willing to take on this role for the duration of the clinical trial.

Once a local sponsor is assigned there are a number of key advantages 6 https://australianclinicaltrials.com/the-australian-tourphase-i-clinical-trial-units/ 7 https://www.austrade.gov.au/.../2814/Clincal-TrialsCapability-Report.pdf.aspx

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in considering Australia as part of your clinical trial: • Speed • Highly efficient regulatory and ethical pathway • Quality • Internationally recognised standards • Diverse, willing and informed participants • Cost • Savings in time and cost • Government investment and support (R&D tax incentives) Speed Highly efficient regulatory and ethical pathway

Australia has an extremely pragmatic approach to the regulatory pathway for its clinical trials. Most trials in Australia are conducted under the Clinical Trial Notification (CTN) Scheme. Under this scheme, research proposals are submitted to Human Research Ethics Committees (HREC) and not directly to the Therapeutic Goods Regulator (TGA), which is simply notified of the trial. The HREC will then assume the primary review responsibility for the ethical and scientific review.

This process significantly reduces the regulatory challenges associated with the trial application and approval and the usual review cycle will usually take only four to eight weeks. This is based on the submission of a protocol, investigator brochure and if required the submission of an independent toxicology report. This expedited process is fast and efficient, reduces unnecessary duplication of data and costly preparation of

extensive applications, ensuring research can commence much sooner than in other jurisdictions.

Quality Internationally-recognised standards

Australia adheres to the highest level of Good Clinical Practice (GCP) and has a strong reputation for the quality of its medical research and trained clinical workforce. The Australian Therapeutical Drugs Act 1989 dictates that all trials conducted in Australia must be carried out in accordance with the International Standards of Conduct for clinical trials developed by the International Conference on Healthcare (ICH) and the International Organisation for Standardisation (ISO). As a result of these guidelines, Australian clinical research quality can be wholly relied upon and are viewed with confidence by international regulatory authorities including the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

Diverse, willing and informed participants

Australia is a multicultural country with a diverse population – which is ideal for meeting the varying recruitment needs for a wide variety of trial indications. An Australian national survey conducted in 2012 investigated proposed candidates’ attitude towards clinical trials and revealed that the vast majority of survey respondents were fully aware of the concept of clinical trials and that there was a significant willingness to participate in them8.

8 Five reasons to conduct clinical trials in Australia, http://www.corrs.com.au/thinking/insights/five-reasons-to-

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Cost Savings in time and cost (including R&D tax incentives)

The Australian Government is committed to supporting the growth and development of clinical trials in the country. The Government is continually assessing and conducting a number of significant projects which will address barriers to conducting trials in Australia and continue to encourage population involvement.

The Government’s R&D tax incentive scheme is a self-assessment program is jointly managed by the Australian Taxation Office (ATO) and Aus Industry.

This system provides a globally competitive tax incentive for conducting R&D activities in Australia and effectively functions as a government award.

The incentive is generous, enabling those companies that conduct certain ‘core’ R&D initiatives in Australia to qualify for a refundable tax credit of between 38.5 per cent and 43.5 per cent on eligible expenditure (according to their aggregated turnover). ‘Core’ R&D activities typically include early phase Clinical trials (Phase I/II and III) and are therefore covered by the R&D incentive.

Other benefits of which include: • Provision for access by international companies – indeed, there is no requirement for the company conducting the trial to be resident or hold intellectual property in Australia • Domestic tax exemption – there is no requirement for the company to pay any net Australian tax to be eligible for the credit • Expenditure support – companies may be able to obtain an advanced overseas

finding which allows them to claim expenditure on R&D activities which are conducted overseas but which have a significant scientific link to Australian activities.

Alongside the R&D incentive program the Australian Government has also introduced a number of other initiatives to support clinical trials in their country and ultimately encourage patient recruitment.

The creation of a dedicated website and information guides provide a comprehensive overview of the clinical trial process—content is designed to aid potential participants understand the risks as well as benefits of participating in a clinical trial in Australia, ultimately raising consumer awareness and helping to increase enrolment.

The recent introduction of a legislative scheme which allows for accelerated access to new medicines, prior to the completion of the clinical trials data collection, has seen significant results.

This initiative can be applied where clinical trial evidence has demonstrated likelihood that the recipient will receive substantial benefit from treatment with the drug, ensuring speed-to-treatment and swifter outcomes for its patient populations.

Further initiatives include the desire to remove uncertainty in costs of conducting clinical trials in Australia.

The Australian Office of the National Health along with the National Health and Medical Research Council (NHMRC) has set out the typical costs involved in the activities of a clinical trial in order to provide and authorita-

AUTHOR BIO

Australian treatment process and regimes are also extremely similar to those of other developed populations such as the US, Canada and a number of European countries. This, coupled with the country’s population diversity, enables recruitment of similar patient populations ensuring similar treatment groups.

tive reference for trial companies and the health provider conducting the trial providing assistance to overseas companies in negotiations with Australian clinical trial providers.

Reasons to outsource to Australia vary by country and by company. Some companies are driven by fast approval times with lower costs and comparable quality; others seek quicker and more transparent approval processes, with results that will be acceptable to internationally regulatory authorities; while for smaller biotech companies, the refundable R&D tax incentive is lucrative by world standards and may play a significant part in lowering their cost of innovation and R&D. Australia’s clinical trial process enables flexibility without impacting on quality; avoids process duplication; and ultimately saves trial sponsors ever-critical time and money. This all combined with the superior scientific talent and excellent medical infrastructure will continue to make Australia a preferred destination for early phase clinical trials.

With an established presence in Australia, PCI Clinical Services has extensive experience in executing effective clinical studies in the country. As a leading global biopharmaceutical outsourcing services provider, PCI has developed specialist knowledge of the regulatory and investigational product management requirements alongside the specific requirements for importing, manufacturing, compounding and labelling product for Australian clinical studies, compared to US and EU requirements.

Frank joined PCI in 2018 as a Business Development Manager, with responsibility for supporting clients in the Asia-Pacific region to ensure continued growth and success in this expanding market. Frank has an extensive background in business development within the pharmaceutical sector with varying roles at international businesses spanning more than 35 years.

Frank joined PCI from another leading outsourced clinical services provider, where he worked as a Senior Global Account Manager.

conduct-clinical-trials-in-australia/ www.pharmafocusasia.com

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ADVANCED MODELLING AND SIMULATION Helps prepare medical countermeasures and optimise response to public health emergencies

Careful preparation is key to success in any crisis. But how can a country ensure that it is ready to respond rapidly, effectively and cost efficiently to a naturally-occurring or manmade public health emergency? Value-focused Model-Informed Drug Discovery and Development (MID3) and precision public health models are being employed to prepare Medical Countermeasures (MCMs), determine the most appropriate MCM dosing, and support pandemic planning and response decisions.

Leigh Farrell, Senior Vice President, Asia Pacific Commercial, Certara USA, Inc.

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hat are MCMs? MCMs are regulated products that can be used in a public health emergency. The emergency could be due to a terrorist attack with Chemical, Biological, Radiological, Or Nuclear (CBRN) material, a naturally-occurring emerging disease, or a natural disaster.

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MCMs can be used to prevent, diagnose or treat conditions resulting from those natural or manmade threats. MCMs can include biological agents, such as vaccines, blood products and antibodies; therapeutic, antimicrobial and antiviral drugs; and a broad range of devices, for example diagnostic tests to identify threat

agents, and personal protective equipment, such as gloves, face masks, and ventilators.

By way of context, the US Food and Drug Administration (FDA) has approved, licensed or, cleared more than 120 MCMs (including supplemental changes to already approved applications and modifications to diagnostic devices) since 2012, for a diverse array of threats including anthrax, smallpox, botulinum toxin, plague, and pandemic influenza.

To protect their citizens from these potential threats, many countries have created MCM programs, which are public-private partnerships focusing on the development of advanced technologies to support their national preparedness strategy. In this way, bespoke virtual advanced MCM product development teams are formed with partners for each MCM technology. Such collaborations are usually between the country’s national departments of health and defence and various industry and academic partners. The most effective MCM programs harness expertise and resources from across civil and military domains, academia and industry to maximise in-country capabilities. Often advanced MCM technology projects also leverage the capability and capacity of international collaborators.

Growing Global Threat

With the dramatic growth in global travel comes a similarly dramatic increase in the risk of naturally-occurring or manmade public health emergencies. It now takes only hours for an infectious disease to travel between continents. Furthermore,

RESEARCH & DEVELOPMENT

as citizens grow older, their immune system gradually deteriorates and become less effective. This process, known as immunosenescence, means that older populations are less well equipped to mount a defence against, and as such are at much greater risk from, an influx of infectious diseases to which they have not been previously exposed.

That effect is of particular concern in Japan where more than 26 per cent of the population is older than 65 years of age, and that percentage is expected to rise to 45 per cent by 2050. Furthermore, Japan is preparing to receive a massive influx of international visitors when it hosts the Rugby World Cup in 2019 and the Tokyo Olympic and Paralympic Games in 2020.

Protecting Against Smallpox

Further illustrating the need for ongoing MCM research, and the importance assigned to it by global regulatory agencies, the US FDA approved TPOXX (tecovirimat), the first drug with an indication for treatment of smallpox on July 13, 2018.

“To address the risk of bioterrorism, Congress has taken steps to enable the development and approval of countermeasures to thwart pathogens that could be employed as weapons. Today’s approval provides an important milestone in these efforts. This new treatment affords us an additional option should smallpox ever be used as a bioweapon,” said FDA Commissioner Dr. Scott Gottlieb. “Today’s action reflects the FDA’s commitment to ensuring that the U.S. is prepared for any public health emergency with timely, safe and effective medical products.”

Although the World Health Organization (WHO) declared naturallyoccurring smallpox eradicated in 1980, following an extensive global immunisation campaign, small amounts of the virus remain in research labs and there have been concerns expressed for many years that it could be used as a bioweapon.

Since routine vaccination against smallpox was discontinued in the 1970s, many

people would be at high risk of getting very ill or dying if they were exposed to this highly contagious virus.

Smallpox is caused by the variola virus and spread by direct contact between people. Symptoms include fever, exhaustion, headache and backache. A rash initially consisting of small, pink bumps progresses to pus-filled sores before finally crusting over and scarring. Smallpox complications can include encephalitis, corneal ulcerations, and blindness.

TPOXX was developed by SIGA Technologies Inc. together with the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA).

The FDA granted TPOXX Orphan Drug status and both Fast Track and Priority Review. In addition, TPOXX was awarded the first Material Threat Medical Countermeasure Priority Review Voucher. This voucher program was established under the 21st Century Cures Act to incentivise the development of certain MCMs against some of the most serious threat agents.

Establishing an MCM Programme

The establishment of MCM programmes in particular countries often begins with a capability and capacity audit, during which an independent, experienced third-party assesses the country’s MCM preparedness. This assessment includes an evaluation of the country’s MCMs on market and under development, and a review of its national MCM stockpile and deployment strategies. It also features an evaluation of the country’s manufacturing capability and capacity for advanced MCM product development.

The auditing company can also examine and pressure-test the country’s emergency response strategies. For example, it can review questions such as: How would the government respond if the only potential treatment or protective vaccine available during a public health emergency had not yet received regulatory approval? What would the accelerated approval process look like? How would medical personnel be trained to adminis-

ter the new product? What would be the most appropriate dose to use? And how would the new product be distributed efficiently to the citizens who need it?

MCM experts generally recommend the development of virtual R&D teams, which can quickly leverage pertinent strengths and experience irrespective of the experts’ geographical location. For example, Medicines Development for Global Health (MDGH), an Australian not-for-profit bio pharmaceutical company, successfully employed a virtual R&D team to develop moxidectin for onchocerciasis (river blindness). Drug development was driven by a small, core in-house MDGH team that served as project leader/project manager. Certara contributed drug development expertise in clinical pharmacology, translational medicine, and regulatory science to the program. When the US FDA approved moxidectin as an oral treatment for river blindness on June 13, 2018, it was the first new drug approved for that disease in 20 years. In the process, MDGH became the first not-for-profit company to achieve FDA approval of a drug as a sole sponsor, and the first not for profit to be awarded a priority review voucher by the FDA. It also created a new model for developing medicines for neglected tropical diseases.

This virtual R&D team approach has proven to be the most efficient way to develop advanced MCM products identified as requirements during the audit.

It is also critically important that each country develops an agile, sovereign, advanced MCM manufacturing

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With the dramatic growth in global travel comes a similarly dramatic increase in the risk of naturally-occurring or manmade public health emergencies.

Departments of Health and Defence MCM policy.

The Australian Departments of Health and Defense have also used MID3 and deep knowledge of drug and vaccine development to develop an evaluation process for including experimental drugs and vaccines in the national stockpile prior to regulatory approval, and create co-development strategies to combat specific threats.

Establishing Appropriate Dosing Strategies

capability. It is not practical or prudent to rely on MCM supplies from allies during an international health crisis during which their primary focus will be on protecting their own citizens.

Developing Precision Public Health Strategies

Value-focused model-informed drug discovery and development (MID3) and agent-based modelling – which combine computer modelling and simulation with deep drug development expertise and real-world data – have been used effectively for assessing, developing and deploying MCMs in countries around the world. We call this MID3-Precision Public Health or MID3-PPH. MID3-PPH provides a quantitative decision support framework for public health officials and other stakeholders to discuss and evaluate the impact of potential pandemic scenarios, evaluate various response scenarios, review the country’s stockpiling strategies for pertinent vaccines and medications, and inform supply logistics decisions for the deployment of MCMs. The Australian Defence Science and Technology Group commissioned national MCM capability and capacity audits in 2012 and 2017. Those audits employed the quantitative Technology Readiness Level (TRL) system used

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Among the more difficult decisions to make during a public health emergency involve determining the most appropriate dosing regimen to use for a new MCM. MID3, especially physiologicallybased pharmacokinetic (PBPK) modelling, can be an enormous help in this regard. It can be used to determine firstin-human dose selection and evaluate new drug formulations.

In fact, MID3 is used extensively to evaluate drug safety and efficacy for different patient populations. It has the advantage that only a small amount of clinical data is required for the PBPK model to be able to accurately predict a drug’s impact across different patient populations.

MID3 can accurately determine a drug’s effectiveness in virtual patient populations in instances where it is not possible to recruit patients for clinical trials. MID3 is invaluable, for example, when researchers need to accurately bridge from adult clinical trial data to determine paediatric drug dosing.

This is a difficult exercise because paediatric patients are not simply small adults. There are numerous physiological changes that occur in children, such as maturation of metabolic capacity, immune system, and renal and hepatic function, which can have an impact on drug disposition, especially in those under two years of age. Changes in body composition can alter distribution volumes, and changes in gastrointestinal function can impact absorption. Furthermore, the number and quality of drug-related

receptors present as a function of age can also be important.

Fortunately, MID3 is able to take all those factors into account. In fact, Certara has a paediatric PBPK simulator that was specifically developed to inform on drug performance for children (and neonates) from 28 weeks through to two years of age.

MID3 using this paediatric simulator helped the developer of Tamiflu (oseltamivir), an antiviral used to treat and prevent influenza, to obtain dosing approval from both the US FDA and European Medicines Agency (EMA) for treating infants as young as two weeks.

MID3 can also be used to test new drug combinations, and predict drugdrug interactions (DDIs) in virtual patient populations.

This is particularly important for elderly people, who tend to have a higher incidence of comorbidities, often requiring polypharmacy, which can result in DDIs and potential adverse reactions.

Certara also has a simulator that models elderly populations, ensuring that health authorities can develop PPH strategies tailored to meet the needs of its senior citizens, too.

MID3 can similarly be used to determine the most appropriate drug dose for other vulnerable patient populations such as pregnant women, and patients with impaired liver or kidney function in realworld situations. This in silicomodelling and simulation approach allows many more drug combinations to be tested than could ever be achieved using real patients in clinical trials. It also spares patients and animals from unnecessary exposure to experimental drugs.

Furthermore, MID3 is already accepted by all major health authorities. These include Japan’s Pharmaceuticals and Medical Devices Agency, the Australian Therapeutic Goods Administration, the US FDA, EMA, and the China National Drug Administration.

“FDA’s Center for Drug Evaluation and Research (CDER) is currently using modelling and simulation to predict clini-

RESEARCH & DEVELOPMENT

Supporting Pandemic Planning

Pandemic influenza represents a significant seasonal threat globally. Government policy makers and pandemic planners wrestle with forecasting the influenza season every year. They never know how an emerging virus’ features may change during a pandemic, altering the optimal antiviral, its dose and deployment strategy.

Pandemic influenza is difficult for health authorities to manage for the aforementioned reasons. In addition, while it is spread by direct contact between individuals, there are a number of variables that affect its population impact — its degree of infectivity and virulence, patient resistance, the antiviral, dose and timing used, and preventative measures taken such as closing schools or wearing face masks.

Oseltamivir (Tamiflu) is a major component of national stockpiles and pandemic influenza planning worldwide.

By coupling MID3 methodology with epidemiology, viral characteristic and healthcare utilisation measures, an agent-based model has now been developed that can show officials how an influenza virus infection can propagate through a community and nation.

This model can demonstrate how a drug can influence an individual’s disease burden directly or a population’s disease burden indirectly via a reduction in viral shedding which can lead to decreased virus transmission. The proof-ofconcept model was based on oseltamivir.

Such an approach can be used to develop a PPH model for any infectious disease.

This model also provides a quantitative framework that enables public health officials, physicians, pharmacologists, pharmacometricians, epidemiologists and health economists to all speak the same language and engage in meaningful dialogue with industry regulators and payers.

As a result, this type of model allows health authorities to make informed realtime decisions when responding to a public health emergency.

Conclusion

MID3 provides valuable insights that allow governments and public health authorities to be appropriately prepared and enables them to make objective, informed decisions when faced with manmade and naturally-occurring public health emergencies.

AUTHOR BIO

References are available at www.pharmafocusasia.com Farrell has more than 20 years’ experience in the biopharmaceutical industry. He has served as Vice President of Business Development at Biota Pharmaceuticals, Associate Director at GBS Venture Partners, Research Manager at Johnson & Johnson Research, and CEO of Gene Shears.

He is a Fellow of the Australian Institute of Company Directors, a Non-executive Director of Pro Medicus Limited, and a member of the Walter & Eliza Hall Institute Board Commercialization Committee.

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In fact, 95 per cent of novel new drug approvals by the US FDA in the first half of 2018 were supported by Certara software or services. This approach has also led to new regulatory precedents and policies being defined.

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RESEARCH & DEVELOPMENT

New and Novel Drug Delivery Technologies Enhancing product lifecycle By infusing drugs with new and innovative therapeutic benefits, drug delivery systems extend products’ profitable lifecycle, giving pharmaceutical companies competitive and financial advantages, and providing patients with improved medications.

Formulation development is being used in the creation of new dosage forms for existing products, which not only reduces the cost and time of new drug development, but also helps with patent protection and bypassing existing patents.

Ambikanandan Misra, Professor of Pharmacy, Faculty of Pharmacy, Kalabhavan Campus The Maharaja Sayajirao University of Baroda

I

n the recent decades, most of the pharmaceutical companies often look for extensions for their patented product to enhance the product’s life cycle by means of various approaches like a) Drug repurposing i.e. new indication of existing drug, b) Using different formulation i.e. by means of using new and novel drug delivery technologies and c) Use of new combinations of drugs. A successful enhancement in life cycle of pharmaceutical product also involves the redefining R&D, establishing marketing and regulatory strategies, technology upgrading which ultimately extends the lifespan of products. Many pharmaceutical companies target on the middle period of the life cycle of pharmaceutical products which includes regulatory approval of product from expiration of exclusive right on product. Drug repurposing opportunities can be identified through variety of processes or resources including

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knowledge mining of existing scientific databases, in-silico approaches, in vitro and in vivo experiments, clinical observations, epidemiology and post-hoc analysis.

Reformulating already approved and patented medications is one of the key strategies for surviving the patent cliff.

However, for an application of extension of market exclusivity, the reformulated drug product must not only meet all criteria aimed at protecting patients, but the new substance/product must also improve upon the original purpose of the drug. Reformulation is a most promising approach as it allows the drug manufacturer to expand its offerings in a given market while targeting a new, potentially larger demographic that may not have been able to use the medication in its original dosage form.

Formulation development is being used in the creation of new dosage forms for existing products, which not only

reduces the cost and time of new drug development, but also helps with patent protection and bypassing existing patents. However, the goal for any new formulation development should be to make a better product rather than patent protection. Table 1 describes some of the drug reformulating approaches used till date.

Novel Drug Delivery Systems and ANDA

United States Foods and Drug Administration (USFDA) finds the importance of novelty in pharmaceutical formulations and offers shortened regulatory assessment options for the research focused on repositioning of existing drug, unlike NCE application which required detailed assessment. Two routes are well known for filing the variation from the approved reference listed drug as a generic player in the US market that is, filing an Abbreviated New

RESEARCH & DEVELOPMENT

Drug Application (ANDA) following the approval of Suitability Petition (SP) filing and another is filing New Drug Application (NDA) in-line with 505(b) (2) of the act.

FDA requirements should be fulfilled by a complex generic formulation manufacturer to be intended for administration. As per section (a) (3) a drug product that may have used for parenteral administration must contain the same active ingredients and inactive ingredient for FDA approval. However, an applicant may seek approval for the formulation that differ in buffer solution, solvent systems, or preservative, antioxidants if applicant are justify its used and proved bioequivalence of product with reference listed product. Patents for complex formulation have much more detailed and greater importance compare to conventional dosage form patents. A generic version of nanosystems should have same polymer and lipids with exact

quantity of encapsulated drug along with lots of parameters which make it harder to copying and manufacturer enjoys a loyalty market even on generic products.

Thus, the combination of even a very narrow composition or process patent claim with the FDA’s general requirements for parenteral drug products and the heightened requirements for advanced or complex delivery systems can result in a significant and long exclusivity period (Figure 1).

Moreover, in detail, exclusivities for a newly formulated drug, including new dosage form or new use exclusivity is granted for three years as defined in 21 CFR 314.108- – new drug product exclusivity. This is granted to drug when application or supplement contains reports of new clinical investigations (not bioavailability studies) conducted or sponsored by applicant and essential for approval. In addition, paediatric exclusivity is granted for 6 months

added to existing Patents/Exclusivity as an additional 6 months of market protection at the end of listed patents and/or exclusivity for sponsor’s drug products containing the active moiety, when the sponsor has conducted and submitted paediatric studies on the active moiety in response to a Written Request from FDA. Note also that under the Generating Antibiotic Incentives Now, Title VIII of the FDA Safety and Innovation Act, additional 5 years exclusivity for products that have been granted a Qualified Infectious Disease Product designation with some exceptions can be granted.

Many new drug delivery systems and methods have been developed that offer better efficacy, cost-effectiveness, and reduce side effects which ultimately leads to better therapy. Though there are many diseases and circumstances that have benefited from the reformulated drugs, there are many areas in which www.pharmafocusasia.com

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RESEARCH & DEVELOPMENT

Reformulation approaches by means of using new and novel drug delivery systems Route of administration

Reformulation approaches

Drug

Indication

Doxorubicin hydrochloride

Chemotherapy

Paclitaxel

Chemotherapy

Intravenous

Albumin nanoparticles

Propofol

Preoperative anesthesia

Intravenous

Propofol nanoemulsion

Cyclosporin A

Prevent Organ rejection

Topical

Cyclosporin A nanoemulsion

Sirolimus

Prevent organ rejection

Oral

Sirolimus nanocrystals

Megestrol

Breast cancer and endometrial cancer

Oral

Megestrol nanocrystals

Liposomes

HER2-positive breast cancer

Intravenous

IV administration for 30-90 min per dose,

First generic versions of liposomes were approved by FDA to overcome shortage of doxil which is liposomal product of doxorubicin in 2013. After that FDA issued guidelines for bioequivalence study on daunorubicin citrate, verteporfin, amphotericin B, and doxorubicin hydrochloride.

Trastuzumab

Intravenous

Doxorubicin liposomes (Doxil)

While subcutaneous (SC) formulation can be administered 2-5 min

by SC. Neupogen (Filgrastim)

Cancer chemotherapyinduced neutropenia

Intravenous

Neulasta (Pegfilgrastim), a PEGylated recombinant methionyl human GC-SF, can improve physical properties of the molecule, such as solubility, thermal stability, and immunogenicity

Table 1

there are significant unmet patient needs that reformulated drugs have the potential to address. Foremost potential areas for reformulating drugs are discussed in the following section.

Controlled/Sustained Release Medications

Controlled/sustained release oral dosage forms had an extensive history and established record of influence to increase in patient compliance and effective drug usage.

Actually, formulation and development has been a chief contributor to growth in the product life-cycle extension of innovator products for many pharmaceutical companies.

Moreover, the general dosing modification involves the formulation development of modified release products i.e. controlled or extended release and fixed-dose combination — versions of the patented product. For example, numerous antipsychotic products have become existing as new drug formulations including an inhalation powder (ADASUVEŽ (loxapine)) and long-acting intramuscular depot formula30

tions (paliperidone palmitate, olanzapine pamoate and aripiprazole) thought to be particularly beneficial for the patients with history of severe relapse due to medication discontinuation.

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Nanotechnology and Nanobiotechnology

Nanotechnology can be referred as the multidisciplinary approach has revolutionised the medicine in the recent decades. They have an enormous potential and choice to fundamentally advance the treatment and prevention in many chronic disease conditions like cancer, HIV/AIDS, asthma, arthritis, etc. Major potential areas for reformulating drugs by means of using nanotechnology are discussed herewith.

Polymeric nanoparticles

First approved product for polymeric nanoparticles by FDA was paclitaxel albumin nanoparticles (Abraxane) in 2005. Though FDA provides guidelines for studies and data requirements to facilitate research but there are no generic products available in market till day. There are large scopes to enhance life cycle of paclitaxel molecule with nanomedicines.

Nanoemulsion

Propofol and cyclosporine A are the nanoemulsions which are approved by FDA. In vitro comparison must require acceptable comparative physicochemical properties between test product and reference product. globule size distribution, viscosity profile as a function of applied shear, pH, zeta potential, osmolality, surface tension, in vitro drug release rate and drug distribution in different phases of cyclosporine nanoemulsions. As per FDA guidelines propofol nanoemulsions should meet

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RESEARCH & DEVELOPMENT

Market exclusivity: Complex formulation versus convectional dosage form

Novel Drug Formulations • High competition • Low margin • Easy to copying

Convectional Product

• Formulation strategy • Intellectual property complexity

• Lower competitions

• Lack of clarity on bio equivalence study

• High price margin

• Measurement of Pka at site of action may difficult

• Enjoys loyalty on market

Complex Generic Product

Figure 1

Supramganetic Iron Oxide and Colloidal Iron

Supra magnetic iron oxides or colloidal iron oxides are iron products which are approved for iron deficient anaemia.

Polyglucose sorbitol carboxymethylether are used to coat an iron oxide nanosized particle which makes it vulnerable and stabilise it. Colloidal iron oxide contains iron oxyhydroxide which is stabilised by sugars like glucose and sucrose.

Till date FDA has approved only one generic product Sodium Ferric Gluconate 32

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Complex in Sucrose for iron deficient anaemia. These nano formulations narrowing the gap between patents and generic formulation for pharmaceutical industries to enhance life cycle of product by complexing it in nanosized formulation.

Biologics

Biologics are becoming more dominant in the current pharmaceutical market.

Moreover, there are currently more than 150 Biologic License Applications approved in the United States. Biologics are typically manufactured in living systems that may produce similar, but not necessarily identical products.

System contaminants and structural alterations like changes in glycosylation can lead to immunogenicity problems

AUTHOR BIO

globule size distribution, viscosity profile as a function of applied shear, pH, zeta potential, osmolality, free acid concentration, amount of propofol partitioned in the aqueous and oil phases, nanoemulsions stability and compatibility with 5 per cent dextrose injection USP, lactated ringers’ injection, USP and 5 per cent dextrose and 0.45 per cent sodium chloride injection, USP intravenous fluids and in vitro drug release rate. Bioequivalence study should perform for both formulation to FDA approval. Generic products for propofol are available, while FDA have not approved generics for Cyclosporine A nanoemulsions.

which may not associated with the original ones. Therefore, there are both prospects and challenges for pharmaceutical companies interested in reformulating the biological products.

Under the Biologics Price Competition and Innovation Act (BPCIA), a biologic product can be a “biosimilar” if there are no clinically differences like in terms of purity, safety, and potency) as in comparison with the reference product. Moreover, a biosimilar product approval will only be granted for a previously approved condition of use and indication. An example of strategically reformulating a biologic product is the conversion of Hoffmann-La Roche's Herceptin (trastuzumab) IV infusion formulation to a subcutaneous formulation.

Ambikanandan Misra is currently Professor of Pharmacy at Faculty of Pharmacy, and former Dean, Faculty of Technology & Engineering (August 2011 to December 2015) & Head, Department of Pharmacy (July 2003- October 2008) at The Maharaja Sayajirao University of Baroda. He has been associated with the field of pharmaceutical sciences for more than 39 years.

45 Ph.D. and 136 Master students have completed their dissertation under his guidance. He has 8 books, 43 book chapters and 167 peerreviewed publications in reputed journals. He has filed 29 national and international patents out of which 9 have been granted so far.

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33

HOW CAN I USE IBCS IN A PHARMACEUTICAL FACILITY?

During the planning stage of a new pharmaceutical facility, you have a blank sheet of paper; anything is possible. You have time to carefully consider the layout of your facility, time to ensure it has the leanest manufacturing processes, using space in the most efficient way. You also have the opportunity to ensure the new facility meets all GMP standards and will yield efficient OSD manufacturing cycles, which will in turn positively impact the profitability of your business.

One of the biggest considerations during this planning process is whether to build a single or multifloor pharmaceutical facility (where material handling is split across 2 floors separated by a technical area).

When space is at a premium and budgets are tight, it is important that the decisions you make are the right ones as they have far reaching implications. Even if budget and space are not constraining factors, being informed now will help you to make better decisions later. In this article, we explore the advantages and disadvantages of single versus multi-floor facilities and what each offers your business.

Single Floor Facilities When planning a single floor facility, the primary advantage is cost. Typically, a single floor facility is less expensive to build/rent than a multi-floor building. But with less cost there is also less space so you need to plan how to use the space effectively.

A particular disadvantage in single floor facilities is in the GMP production area where space is often limited. A solution we frequently recommend is the 34

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installation of a pillar lift if there is sufficient ceiling height available. This is a prime example of why you need to consider your processing system choice and the industrial equipment you will be installing, before you commission your building; it’s difficult to increase a ceiling height after construction.

Single floor facilities are also great for improving productivity, especially with the implementation of IBCs where batch transfers can be closed. But for all the advantages there is one primary disadvantage to only having one floor and that is production capacity.

While you can achieve multiple batches on a single floor, it’s not as efficient due to the limited amount of space. Scaling up from a single floor facility to meet increased demand can also be costly and quite an upheaval. It is worth considering planning for growth now and building in that extra capacity in readiness for the future.

Multi-Floor Facilities Although construction or rental costs of a multi-floor facility are often higher than smaller (single floor) facilities, the overall gain in ‘lean’ efficiency can potentially be much greater, especially if you use IBCs. With production split over two-floors, you can use a multi-batch production process, which offers greater potential for scalability and ultimately profitability. The upper floor can be dedicated to powder & granule handling and the lower floor to tablets & capsules. With the benefit of increased space, production areas donot get as crowded as in single floor facilities.

ingredients from their delivery containers, to the blender and further processes.

Using a Matcon IBC, ingredients can be discharged directly into the receptor, this is also the blending vessel, and thus it eliminates an unnecessary step.

What’s more, with closed connections before, during and after IBC discharge, it will ensure a dust-tight transfer, and avoid the risk of contamination and cross-contamination.

With two floors, vertical transfer is a definite possibility, so you can let gravity do the hard work of moving materials between processes. As the IBCs are located on a single floor, it is even possible to remove manual IBC handling and automate these movements using an AGV for example.

Lower Floor – Pressed tablet or capsule packing processes The greatest benefit of a multi-floor pharmaceutical facility is the ability to separate processes by using the divide between the two floors. ‘Clean’ processes can be kept physically separate from ‘unclean’ areas, eliminating possible sources of contamination that might otherwise cause a company to fail regulatory inspections. This is a particular benefit for pharmaceutical manufacturers, where adherence to GMP regulations means that it is essential to isolate potential sources of contamination to generate safe, high quality OSDs. Having two floors available also means there is no need for mezzanine levels, or pillar lifts required to load IBCs onto equipment. Compared to a singlefloor facility, where everything is made on one level, using the space effectively in a multi-floor facility may mean you coulddesign a smaller building footprint, with smaller yet less crowded rooms that need minimal cleaning, incur fewer health and safety hazards, and are cheaper to buy/rent. Alternatively, the additional space afforded by a multi-floor facility means you can think bigger: achieving larger batch sizes without the extra costs associated with cleaning and storage space.

An example of a multi-floor building layout making the best use of height and space could be…

Upper Floor – Raw material handling and mixing of ingredients When handling powdered ingredients, a major source of waste is often product lost when transferring raw

As they can handle solid granules or particles of any size, including pressed tablets and capsules, Matcon IBCs make handling your intermediate and end-stage products easy and efficient, eliminating the waste often caused by manual processing methods.

Whether you choose to design your pharmaceutical facility on a single or multi-floor layout very much depends on your budget, the space available and your aspirations for business growth. The key to getting it right is planning and designing early before a building is commissioned. Whichever route you take, using an IBC-based production system is the most flexible and efficient way of using the space available while achieving GMP regulations.

Why IBCs? Flexible, cost-effective, and one of the ‘leanest’ types of materials handling system around, Intermediate Bulk Containers (IBCs) make perfect sense for any manufacturing industry that needs to move powders, granules or tablets between processes.

When it comes to the manufacture of pharmaceutical oral solid dosage (OSD) products, three things are of the utmost concern: quality, safety, and profitability.

This is especially true in the manufacture of generic OSD products, where quality and safety demands are stringent, but lower profit margins mean that high volumes must be sold to get a sound return on investment. www.pharmafocusasia.com

35

Powder Handling Process

Using Intermediate Bulk Containers (IBCs) in a pharmaceutical facility producing generic oral solid dosage (OSD) products is one way to trim production costs without compromising on the products themselves.

Once you have decided that you wish to use an IBC system for your material handling, consideration should be given to the type as not all IBCs are equal in functionality, manageability and performance. Understanding the benefits and limitations of the different types of IBC valve outlet makes for valuable research to give you an informed choice saving you costs in the long term.

A simple butterfly valve IBC might be satisfactory for your current range of products, but as Scientists and R&D develop new therapies and molecules, you may soon find out the limits of a butterfly valve system.

Investing today in a robust, flexible IBC System with proven ability to handle even the most difficult products sets you and your facility up to deal with whatever the future holds. This is where Matcon Cone Valve IBCs can help. In the short term, you can enjoy efficiency benefits over butterfly valve IBCs but in the longer term, you can be confident that your powder handling system will continue to deliver the same performance with more difficult flowing powders or those prone to segregation, without the need to manually intervene or scrap batches.

Who are Matcon?

Established in 1980, Matcon invented the first, unique valve which was game-changing technology.

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It was designed to control the flow of discharged materials. Matcon went on to create Cone Valve IBCs which have transformed the applications for IBCs compared to traditional methods and are the ultimate ‘lean’ solution for handling powders, granules or tablets.

The ‘lean’ philosophy is all about eliminating waste, because waste – whether that is lost ingredients, spoiled batches, or unnecessarily spent time or effort – all amounts to wasted money.

Using an IBC-based production system is cleaner, more efficient and more flexible than other types of traditional manufacturing lines and Matcon strives to support you with a system that brings you the maximum profitability and product quality.

Not just selling you a commodity bin, but taking a full look at what your manufacturing needs are and designing a flexible manufacturing system to match those needs, ensuring you are making the right investment.

Can I integrate IBCs into my existing pharmaceutical facility?

Absolutely! IBCs can be seamlessly integrated into almost any size or shape manufacturing space, with significant efficiency savings.

Where can I learn more?

For more information about planning pharmaceutical production lines or the best way to shape the space you currently have, please contact us at www.matconibc.com Advertorial

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RESEARCH & DEVELOPMENT

Pre-Clinical Assessment of Drug-Induced Hypersensitivity Reactions

Tools and challenges 38

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In the pre-clinical phase of drug development, no in vivo or in vitro methods to screen the hypersensitivity potential of drugs are performed on routine base.

Our improved understanding of molecular mechanisms underlying drug-induced inappropriate immune activation that could be used to assess allergenic potential of drugs will be discussed.

Emanuela Corsini, Professor of Toxicology Laboratory of Toxicology, Department of Environmental Science and Policy UniversitĂ degli Studi di Milano Valentina Galbiati, Laboratory of Toxicology School of Drug Safety, UniversitĂ degli Studi di Milano

RESEARCH & DEVELOPMENT

D

rug Hypersensitivity Reactions (DHRs) belong to type B adverse drug reactions, defined by the World Health Organisation (WHO) as dose-independent, unpredictable, noxious, and unintended response to a drug at dose normally used in humans.

They include drug intolerance, drug idiosyncrasy, drug allergy and non-allergic anaphylactic reaction. Most of type B reactions have an immunological basis, including idiosyncratic liver injury, often resembling hypersensitivity reactions.

Gomes et al. reported that DHRs represent about one third of adverse drug reactions, overall, affecting 7 per cent of the general population and up to 20 per cent of hospitalised patients. The incidence of drug-induced anaphylaxis has been estimated to range from 0.04 to 3.1 per cent, with an increased rate by 150 per cent from 1997 to 2005.

DHRs are responsible for significant morbidity, mortality and socioeconomic costs. Therefore, it will be extremely

important to have tools in the preclinical phase to identify potential drugs having the intrinsic ability to activate an inappropriate immune response to have proper risk management measures in place.

Despite the important adverse reactions linked to hypersensitivity, currently in the pre-clinical phase, there are no validated or requested in vivo/in vitro tests to assess the sensitising potential of a drug.

This article will focus on low molecular weight drugs, discussing available in vitro tools and challenges in the pre-clinical safety assessment of drug-inducing hypersensitivity reactions. Different it is the case with therapeutic proteins, which possess the structural complexity sufficient to induce a specific immune response, or drug-inducing pseudo-allergic reactions, in which adaptive immune response is not involved. Readers are referred to a recently published article by the same authors on the same topic.

Mechanistic Understanding

Hypersensitivity reactions can be divided in non-allergic (pseudo-anaphylaxis) or allergic when mediated by a specific adaptive immune response. In the latter case, they can be defined as an excessive humoral or cellular immune response to an antigen which can lead to tissue damage or systemic effects.

Examples of drug that can induce DHRs include penicillins, cephalosporins, diclofenac, neuromuscular blocking agents, hydralazine, methyldopa, sulphonamides, hydralazine, procainamide, neomycin, carbamazepine, allopurinol, benzocaine, and several biologicals (e.g. rituximab, naglazyme, infliximab).

Besides the Gell and Coombs’ classification of hypersensitivity reactions, a simpler classification, very useful in the context of preclinical safety assessment, is to divide drug hypersensitivities in drug allergies with primarily antibodymediated reactions or cell-mediated

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RESEARCH & DEVELOPMENT

Figure 1 Schematic representation of DHR induction and in vitro opportunities.

reactions, and pseudo-allergic reactions not involving the activation of a specific immune response.

Although the underlying mechanisms of drug-induced hypersensitivity are not completely understood, the creation of neo-antigens and/or the provision of adjuvant-like effects, together with danger signals resulting from cell or 40

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tissue damage, are considered important elements.

Central to all immune-mediated hypersensitivity reactions are helper T cells (Th). Th cells are an essential component in the pathogenesis of both antibody-mediated or cell-mediated hypersensitivity reactions to drugs or chemicals. These cells only see the

antigen if associated with MHC class II expressed on antigen presenting cells, such as Dendritic Cells (DC). DC are central in the initiation and regulation of any adaptive immune responses. Following the contact with antigens, DC undergo a process of maturation associated with the expression on the membrane of several co-stimulatory molecules (e.g. CD80,

RESEARCH & DEVELOPMENT

CD86 and CD40), various adhesion molecules (e.g. CD54, CD58), and secrete different cytokines (e.g. IL-1β, IL-12, IL-18). Thereafter, DCs migrate in the draining lymph node or in the spleen, where antigens are presented to specific T lymphocytes, through DC-bearing MHC class II molecules and co-stimulatory adhesion molecules expressed on both DC (i.e. CD86) and T cell (i.e. CD28) necessary to ensure full T-cell activation.

Traditional drugs have low molecular weights (< 500 Da) and as a such they are too small to be â&#x20AC;&#x153;seenâ&#x20AC;? by T cells, which do respond only to MHC/HLA-peptide complexes typically consisting of 8-12 amino acids in length. Immune-mediated drug hypersensitivity primarily results from immune-sensitisation to a druginduced neo-antigen. Therefore, low molecular weight drugs have first to bind to a larger peptide or protein before they can be recognised T cells or in some cases the drug may bind directly to HLA molecules and /or T cell receptors to initiate a T-cell response. In addition, drugs may alter protein structure, the process of antigen presentation, or by causing cellular or organ damage may induce the release of previously hidden auto-antigens (e.g. DNA or histones) for which no tolerance exists, favouring the development of hypersensitivity and autoimmune reactions.

While the complexity of the immune system cannot be easily duplicated in vitro, if we agree on the hapten hypothesis as the main mechanism together with the centrality of DC in the activation of specific immune response, where the adaptive immune response leading to severe DHRs are presumably preceded by an innate immune response, we could imagine to be exploit these two aspects in the screening of drugs that could induce unintended immune activation for hazard identification. Keeping in mind of course, that the effective risk of a hypersensitivity reaction in the patient will also depend on other factors, including formulation, dose, route of administration, genetic predisposition, disease conditions, etc..

Preclinical in vitro tools to investigate drug-hypersensitivity

As the use of animals in toxicology is gradually and globally being phase out, also for drugs, efforts should be devoted to develop reliable in vitro assays and integrated testing strategies.

In past decades, an incredible progress has been made in the development and validation of non-animal test methods for skin sensitisation assessment.

Methods based on keratinocyte activation maybe useful for topically applied drugs, for drugs inducing photo-allergic reactions or for medical devices contacting the skin. While these methods are probably of limited interest for drugs systemically administered, the DPRA (Direct Peptide Reactivity Assay) and the ADRA (Amino acid Derivative Reactivity Assay) for assessing haptenisation, and methods based on dendritic cells are potentially useful and relevant for systemically administered drugs (8).

Among the validated DC-based methods, I can mention the human cell line activation tests (h-CLAT), which quantifies changes in CD86 and CD54 expression in the human THP-1 cell line following 24 h exposure to the test chemical; the myeloid U937 skin sensitisation test (MUSST), which measures the induction of the expression of CD86 by flow cytometry after 48 h of chemical treatment; and the more recently validated IL-8 Luc assay, which measures the effects of chemicals on IL-8 promoter activity can be mentioned. Among the more than 145 substances in vitro tested and publicly available, few drugs associated with UDRs, including benzocaine, hydroquinone, p-benzoquinone and diphenylclopropenone were tested and correctly classified.

We developed a strategy based on IL-8 production, CD86 and /or CD54 expression in THP-1 cells useful for the in vitro identification of drug sensitisers. The test we developed allowed the correct identification of all the selected drugs tested, including penicillin G, sulfamethoxazole, probenecid and procainamide for which metabolism is needed. www.pharmafocusasia.com

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RESEARCH & DEVELOPMENT

AUTHOR BIO

There have been many efforts to develop integrated approaches to testing and assessment of skin sensitisers.

For drugs as a possible strategy, as initial screening the ADRA / DPRA should be performed and if positive, classify the drug as sensitiser, while if negative, h-CLAT or any other DC-based methods or keratinocyte-based assay for topically applied drugs should follow - a positive outcome denotes a sensitiser, a negative, a non-sensitiser. The choice of using different assays depends on how they compensate for each other's in terms of technical limitations and applicability domain.

Besides, in vitro methods to assess T cell activation are also available.

Information on this event could provide additional evidence to support a safety assessment approach: if the test substance is unable to induce a T cell response, it may be possible to conclude that it does not cause sensitisation, provided the T cell assay is sufficiently sensitive which is still and issue to resolve. The T cell priming assay may offer promises for the in vitro assessment of chemicals inducing a primary immune response if a T-cell repertoire is present in the donor cells.

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Emanuela Corsini has been working in immunotoxicology and immunopharmacology for over 25 years. Research has been moving in the context of immunotoxicology and immunopharmacology with the study of substances having allergenic/irritating and immunomodulatory effects including drugs, pesticides, endocrine disruptors and nanoparticles. She has authored over 170 publications with an H index of 41.

ORCID ID: 0000-0002-6927-5956

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The assessment of immunogenic potential using the T cell priming assay based on blood samples from human donors (>50) may generate information on the frequency, variability and magnitude of responding donors towards a given compound. T cell-based assays could also provide detailed mechanistic information (e.g. T cell receptor repertoire, HLA type, presented peptide by DCs, T cell subset activation and whether the response is CD8+ or CD4+ T cell mediated) on the antigen-specific T cell response. Not least, the other reason for performing the T cell priming assay is related to drugs inducing hypersensitivity by hapten/carrierindependent mechanisms resulting in direct T cell activation. In vitro T cell assays still represents a challenge but it holds high promises. Further investment and collaboration are required to simplify assays, optimise sensitivity, better define human donor-to-donor variability and evaluate the value to predict sensitiser potential of drugs.

One of the challenge is the metabolic capacity of the test system, as in many cases are drug metabolites the culprits rather than the parent compound. Lack of metabolic activity is one of the bottle-

Valentina Galbiati 4 years ago obtained the PhD in Pharmacological Sciences and from 2015 she holds a PostDoc fellowship in the Laboratory of Toxicology at the University of Milan. Starting from 2010, she has been working on non-animal methods for chemicalinduced hypersensitivity. She has authored 36 publications with an H index of 14. ORCID ID: 0000-00033380-1501.

neck of many in vitro methods. We know from chemical allergens that pro-haptens are negative in the DPRA, while they can still be identified in several of the other assays, but of course this requires a special attention In Figure 1, a schematic view of DHRs and in vitro methods is presented.

Conclusions

The problem of the pre-clinical identification of immunologically-based DHRs is related to the lack of appropriate experimental models but also to the insufficient use of what is available. We should try to make the best use of our knowledge to identify drugs potentially able to induced hypersensitivity reactions in the preclinical phase.

The number of drugs tested in the currently validated or published methods for the in vitro identification of skin sensitisers of chemicals is overall limited, no more than 15. Currently, there is too little data to know how accurately these assays might be for the prediction of DHR risk. However, additional efforts and extensive resources are necessary to improve preclinical testing methodologies, including optimisation, better design and interpretation of data.

The knowledge that allergenic drugs share with chemical allergens common mechanisms, could enhance targeting toxicity testing in drug development and hazard assessment of hypersensitivity. It is possible to speculate for drugs, as it has been done for chemicals, the possibility of tracking human drug allergens from identification of peptide-bound reactive small chemicals to chemical-specific naive human T-cell activation.

Abbreviations: ADRA, amino acid derivative reactivity assay; DPRA, direct peptide reactivity assay; h-CLAT, human cell line activation tests; GARD, genomic allergen rapid detection; MUSST, myeloid U937 skin sensitization test; Th, T helper cells.

For Bibliography, please visit www. pharmafocusasia.com

RESEARCH & DEVELOPMENT

PRODUCT DESIGN & DELIVERY

Product design and delivery is the ultimate interest of biotech industry with recent years witnessing the market opportunity for first-in-class, all new products grow rapidly. The meaning of product can be redefined with set delivery characteristics providing opportunity to the innovators to think smart and different at various stages of development. For instance, in drug discovery and development process, there can be more than 20 different points where each of these spots can be productised with commercial value. In 2016, the total global drug discovery market was valued around US$35.2 billion and it is estimated that the market will grow to some US$71 billion by 2025 indicating the chances on designing and delivering the market needs.

Subhadra Dravida, Founder CEO, Transcell Biologics Pvt. Ltd

B

y definition, biology is the natural science while biotechnology utilises biological systems, and living organisms to develop different products. A product could be an article or substance or technology that is manufactured or refined or developed for sale for sure. The list of biotechnological products broadly includes medicines, medical devices, diagnostics, healthcare apps, biofuels, biochips, biomaterials, equipment. An orthodox product in life sciences / biotechnology is a good or offering, the development of which requires the use of unique technical knowhow or techniques that are not obvious to common man and generated from Research & Development (R&D). Any product is expected to have commercial value while the application should be well defined.

All the sectors in the life sciences / biotechnology are assembled around a www.pharmafocusasia.com

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core set of activities that are allied to the process of either discovering, developing or commercialising covering product life cycle including: Pre-discovery stage includes an idea, plan, hypothesis, and framework. The end result of this stage could be a design patent, intellectual property that is worth finding a buyer or collaborator involving trade, agreements, commercials etc.

It could start as provisional patent and progress with productisation plan. Due to advancements in science and technology, pre-discovery phase is now more founding and sophisticated than ever with highest thrust on technical knowledge, rationale, requirement, and market opportunity with entire globe as the battle field to prepare for. Sometimes, unmet needs could be the starting point while delivery is localised. If in pre-discovery phase of pharmaceutical research, in-depth literature to assist in formulating a new hypothesis or to improvise on the existing solution available is quintessential.

Innovators must be able to ascertain connections to their idea from various pieces of literature to throw light on the significance of prior art. Also, typically, prior art does not need to be present physically or be commercially available while settling to the description available somewhere or shown or made something that contains a use of technology that is very similar to one’s new idea.

The discovery stage may include basic or translational research. The end result could be product, such a ‘druggable or undruggable’ target(s) inside the body that affect that mechanism of action, a class of molecule(s) that might be able to affect that target, a new class of molecule with known function, known class of molecule with new function, novel equipment to perform a special function, device to function, device in new integration, or biomaterial composition prototype. This stage is the logical and follow up on determined pre-discovery phase. The design of the ultimate product becomes more structured in this stage to strengthen commercials envisioned with broad emphasis on features of the 44

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product. The biopharmaceuticals industry has undergone series of revolutions in the past while discovery stage has been the most innovative space with scope on developing new features, improvising on old ones, deeper characterisations linking to the functions being hunted at small scale. Strong academic liaisons, partnerships in this stage add value to the offerings that are being productised. In India, the discovery phase is either completely non-existent or is weak when it comes to Biopharmaceutical sector contrary to the western scenario. The strongest of the alma maters have been successful in commercialising at the discovery stage of the product life cycle with heavy recognition of the innovative minds and applications in life sciences.

Pre-clinical stage is stereotypically looked at as the start of commercialisation, when a product prototype crosses discovery phase. A product in pre-clinical phase is ready to be trialed with humans, but needs to be established on lower species models. This is an age old ethical practice imposed with good intent on products’ intended applications.

Design and impact of pre-clinical studies is strongly felt through the product development and commercialisation process. Classically, pre-clinical studies support biotech entities to accurately and

An orthodox product in life sciences/ biotechnology is a good or offering, the development of which requires the use of unique technical knowhow or techniques that are not obvious to common man and generated from R&D.

efficiently evaluate prototypes to an optimal and final product model. During this pre-clinical stage, product performance as proposed to comply with regulatory authority standards such as safety and efficacy is demonstrated with an intent to align with global framework. Smart product designs would go through trials of prospective data collection anticipating global commercialisation markets during this phase. Each of these intermittent steps could be productised with deliverable end points designed commanding commercial value during pre-clinical stage in life sciences track. Additionally, cross-functional features like reimbursement plan and marketing collaterals of the products at the late stage application phase could derive support data from pre-clinical validations.

Between product design and delivery comes product packaging covering features, advantages, and benefits.

All of these characteristics have to be fixed during pre-clinical stage itself to be demonstrated while conducting in clinics before reaching markets. Product features typically speak on composition, source details, phenotype, quality, function. In the same context, product technical data sheets offer material on the core applications, areas of use, physicochemical, biological properties attributed with a note on personal safety and environment impact. Likewise, product safety data sheets communicate on potential hazards, recommendations for care, handling and use. The additional specifications for product storage is an important data point disclosed in the same product specific data sheet. Details on transport conditions and measures for first aid, accidental spillage, contact control and personal protection are the other key product relevant exhaustive information section in the data sheets. A designated product brochure will capture advantageous traits for the benefit of the user. Advantages of function, characteristics, ease of use are some of the highlighted product collaterals decided in the pre-clinical stage that comes handy in marketing and branding stage.

RESEARCH & DEVELOPMENT

and for dynamic industry in particular.

Irrespective of innovative level, any new product development is considered to be a high-risk and expensive process while success factors are industry specific.

In the midst of technology, patents, and products designed to deliver, there is an interesting element of productisation of services to the process. Typically, Contract Research Organisations (CROs) undertake contract of third-party R&D requirement to provide their services.

Even for these service providers in life sciences/biotechnology, there is scope to productise their services. The perceived advantages of productising services are to automate, outsource non-core things; and to invest in getting faster and better in delivering. These benefits would in turn trickle down to improving the top line and enabling higher quality delivery. This productised service with improved outcome and deliverables would command more in value chain automatically.

The new drug discovery market has seen rapid progress in the recent past with the potential to reach US$71 billion in 2025 itself, which is not too far to witness. The industry is focusing on first-in-class technologies, products, and approaches to come up with cure for debilitating diseases.

AUTHOR BIO

Product labelling is written information on the product and part of packaging. These labels cover vital information which has to be communicated to the user. Labelling requirements come from the country specific regulatory bodies. USFDA (USA), MHRA(UK), TGA (Australia), CDSCO (India), HEALTH CANADA (CANADA), MCC (South Africa), ANVISA (Brazil), EMEA (European Union), SFDA (China), NAFDAC (Nigeria), MEDSAFE (NewZeeland), MHLW (Japan), MCAZ (Zimbabwe), SWISSMEDIC(Switzerland), KFDA(Korea), MoH (Sri Lanka) are some pharma-specific regulatory agencies in respective countries typically deciding product-specific labelling requirements.

Any new product to be released in the market has to abide by specific labelling guidelines of geography/market specific regulatory bodies. The development of biologic drugs and patient-friendly delivery methods necessitate innovative packaging material. The need for novel, discreet, no pain, easy to apply like delivery platforms that could be productised is forecast to expand as the demand for biologic therapies is anticipated to grow throughout the next decade.

Product quality control documentation and implementation of set methods aims to assure quality at every production stage. This practice essentially avoids product recalls, anticipate any produc-

tion specific delays and majorly improve quality control budget. All the relevant quality control and assurance templates have to be designed and validated during pre-clinical stage of the product life cycle.

There are many methodologies to track product quality control in biopharmaceutical processes. The most basic one is through checklists to check off items that are vital to produce and sell products. Control chart is a dynamic tool that can predict outcomes, analyse variations to correct problems in quality as they happen. Histogram and pareto chart are few other product quality control tools that are products themselves within the process.

Testing or applying the product in humans is the most decisive phase of the product life cycle. This clinical stage typically happens in four distinct phases.

There are significant regulatory essentials to pass before entering each new phase: phase I generally tests for the safety of the product by evaluating tolerance, generally in healthy volunteers. Phase II tests for efficacy and side-effects in a predetermined product application specific sample size. Phase III is for safety and efficacy determination of the product in bigger populations. After this phase, if safety and efficacy data is shown to meet standards set, the regulatory agencies will approve the product for sale and general use. Ninety-five per cent of the products at this stage would command the rightful valuation and stand big for acquisitions.

Factors such as globalised market, competitive environment, disruptive technological changes, and shorter product lifecycles have made first-in-class product development in biotechnology an important strategy for companies in general A Scientist by profession, Subhadra Dravida led global stem cell research and commercialisation initiatives in regenerative medicine and drug discovery domains for over 12 years. She holds over two dozen patents in the field of regenerative medicine and has significant expertise in converting promising research into business opportunities.

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ADVANCES IN SPRAY DRYING FOR THE IMPROVED DELIVERY OF POORLY SOLUBLE DRUGS In recent years there have been more and more publications featuring spray drying to improve the bioavailability of drugs. Up to 70 per cent of pipeline drugs are poorly soluble, so use of the process is expected to increase. An overview of spray drying, including the latest advances and future prospects, is discussed herein.

Mark Davis, Research Fellow, SSPC, The University of Limerick Gavin Walker, Co-Director, SSPC, The University of Limerick

S

pray drying is an important unit operation, first patented in 1872.

Essentially, the technique involves the pumping of a solution through a nozzle into a drying chamber, where the solvent is rapidly removed by hot gas to yield a dry powder. Over the past couple of decades, research has become more sophisticated, and publications citing enhanced formulation bioavailability (relative to unprocessed drugs) have increased significantly (Figure 1). This was driven by the high proportion of poorly soluble drugs in the market.

In this article, the importance of formulation, process optimisation, downstream processing and the mechanism of dissolution enhancement are discussed. In addition, comparisons with other preparation techniques, novel analytical methods and future prospects are evaluated. It is concluded that spray drying is likely to increasingly feature 46

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in future drug product development, due to the requirement for bioavailability enhancement and the versatility of the method.

Poorly Water-soluble Drugs

It is currently estimated that 40 per cent of commercial API and up to 70 per cent of new chemical entities are poorly water soluble. Such compounds belong to BCS class II (high permeability, low solubility) and class IV (low permeability, low solubility). In particular, there is an opportunity to increase the bioavailability of BCS class II drugs by improving their solubility.

An Overview of Spray Drying

The spray drying apparatus consists of a heating element, fan, nozzle, drying chamber and cyclone (Figure 2). Liquid is pumped through the nozzle into the drying chamber. The most common nozzle types are rotary, pressure or 2-fluid and nozzle type and geometry affects particle engineering greatly. The liquid is sprayed into the drying chamber where it comes into contact with a hot gas. Heat exchange takes place, whereby the liquid droplets rapidly evaporate and dry solid particles are formed. The

particles and gas pass into a cyclone and/or bag filter, separating the dry solid powder product from wet gas. If the solvent is flammable, the drier is operated in a closed loop with nitrogen and a condenser to trap solvent. If the solvent is mostly water then the drier can be operated in open mode with air as drying gas.

Formulation

A wide variety of formulation types can be prepared using the spray drying process (Figure 3). It is important to carefully choose an appropriate excipient for the dispersion. In many examples, a polymeric excipient, such as HPMC-AS (hydroxypropyl methylcellulose acetate succinate) is selected. This excipient has performed well in many cases and been tested against many different drugs(Friesen et al., 2008). However, due to the variety in API structure and the differing requirements of formulations, excipient selection is often on a case-by-case basis, to achieve optimal performance.

Pre-formulation

Pre-formulation is useful to minimise the risks and costs associated with product

The increasing trend of publications featuring spray drying for delivery of drugs and poorly soluble drugs since 1998; source Scopus.

development. A variety of experimental, mathematical and computational approaches are available. Solvent casting is a quick and relatively inexpensive experimental method used to check the compatibility of solvents, polymers and drugs during amorphous solid dispersion development (Davis et al., 2016). The levitated single droplet method can be used to mimic the effect of formulation and process parameters on an individual particle. Mathematical models such as the Arrhenius equation have been adapted to measure the degradation rate of amorphous dispersions and predict stability. Computerised screening involving a series of partial differential equations comprising thermodynamic, kinetic and process data has also been employed to provide information on drug loading of API like itraconazole.

The Effect of Polymer Structure on Formulation Performance

The molecular structure of the polymer will have a profound influence on the stability and performance of the resulting formulation. This is due to the intermolecular forces between polymer and drug, such as hydrogen bonding. Ting and co-workers explored this by making analogues of HPMC-AS with differing levels of side groups(Ting et al., 2014).

The performance of the polymers with BCS II drugs was then tested in spray dried dispersions.

Formulation Optimisation

Formulations can be optimised by changing one variable at a time in a systematic way. This is particularly useful when focusing on a Critical Quality Attribute (CQA). Statistical methods such as Design of Experiment (DoE), response surface methodology and Artificial Neural Networks (ANN) are popular for optimisation.

Ternary Spray Dried Dispersions

Figure 1

The requirements of formulations are many-fold: good solubility, stability during storage and in vivo, good www.pharmafocusasia.com

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Figure 2 Schematic of a spray drying system, set-up in closed mode to handle poorly-soluble, lipophilic drugs

powder flow and compression properties, etc. As it can be difficult to satisfy all needs with one excipient, multiple component dispersions (such as ternary) have become more prevalent, because they increase the chance of meeting these many demands (Davis et al., 2017).

Miscibility of Components

Intimately mixed formulations are less likely to separate or recrystallise during processing, storage and dissolution. Solubility parameter differences (â&#x2C6;&#x2020;δ) can be calculated for polymers and drugs to predict miscibility before mixing. This is likewise related to polymer and drug structure. Drug loading, heat, moisture and preparation technique also affect miscibility.

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Fixed Dose Combinations Prepared

by Spray Drying

Using two or more combined drugs in a single dosage can reduce the number of tablets a patient must consume per day and this can improve patient outcomes.

The desirable physical properties of one drug can also be used to improve the properties of the other in such dispersions.

Solubility Enhancement Through Nanotechnology

Nanoparticles can be directly prepared by spray drying. Such systems are expected to have a significant influence on drug delivery methods, such as improved solubility, protection from degradation, targeted delivery and reduced side effects. The latest publications have included Solid Lipid Nanoparticles (SLN), Nanostructure

Lipid Carriers (NLC), Nano-Crystalline Powders, Nanocomposite Microparticles (NCMP), nanocapsules and nanosuspensions.

Preparation of Self-emulsifying Delivery Systems via Spray Drying

Self-emulsifying Drug Delivery Systems (SEDDS) are combinations of drug with oils, surfactant and solvent, that form oil-in-water emulsions in the body after ingestion. Recently, spray drying has been used to improve the oral bioavailability of lipophilic drugs such as erlotinib, valsartan and itraconazole using this method.

The Impact of Surfactants on the Physical Stability of SDD

Surfactants are generally included in formulations to enhance to solubility of

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drugs, but recent studies have shown that careful selection is essential. Taylor et al reported that nucleation from dispersions of celecoxib and HPMC-AS in acidic media was promoted by sodium dodecyl sulfate, but suppressed by sodium taurocholate(Chen et al., 2015).

Selecting an Appropriate Aolvent and Monitoring Residual Solvent Levels

A less toxic solvent such as ethanol or water is favoured, although stronger solvents like dichloromethane are often required in order to dissolve lipophilic drugs. Gas chromatography can be used to measure residual solvent levels and secondary drying is common to reduce levels to below ICH guidelines. Research into cleaner solvents, like super critical CO2, is ongoing despite solubility limitations.

Process optimisation

It is currently estimated that 40 per cent of commercial API and up to 70 per cent of new chemical entities are poorly water soluble.

ing gas rate, liquid feed concentration and pump speed all significantly influence particle properties and yield. In particular the outlet temperature, nozzle type and liquid feed concentration influence the outcome. As with formulation, optimisation is often accomplished using Design of Experiments (DoE), Response Surface Methodology (RSM), Analysis of Variance (ANOVA) and Artificial Neural Networks (ANN).

Nozzle Modifications

For high volume commercial processes the drier itself is designed around the product. With lab scale research equipment, versatility is more important, although optimisation of temperature, nozzle selection, drying gas rate, atomis-

The two-fluid (or pneumatic) nozzle is most common in pharmaceutical formulation, using gas (nitrogen or air) to shear the liquid into small droplets. However recent developments have seen the patenting of the pressure nozzle (Beyerinck et al., 2004), to improve powder flow properties. Vibrational nozzles have also been employed at research level to increase particle size.

Downstream Processing

Efficient downstream processing is a critical part of drug product manufacturing. The flow of powder into a tablet press die, or from a storage hopper can suffer from bridging and arching. This can lead to improper tablet weights or production delays.

To improve flow, larger more spherical particles are required, although this is sometimes countermanded by the need for smaller particles with better dissolution properties. Powder flow can be measured using a rheometer to design a hopper or determine how dispersions will process. Furthermore, optimising formulation and process parameters can alter flow properties. Alternative preparation techniques, such as hot melt extrusion, will deliver formulations with different flow characteristics (Davis et al., 2018).

Mechanistic studies of supersaturation or recrystallisation

Figure 3 Spray drying is versatile enough to produce several drug delivery systems

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Computer simulations, spectroscopy, imaging techniques and mathematical modelling have been used to deepen understanding of the mechanism of drug supersaturation in solution.

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AUTHOR BIO

It is hoped that these insights can lead to improved bioavailability outcomes.

Comparisons with other preparation techniques

Significant research has investigated the impact of preparation techniques on the properties (CQA) of formulations. Hot melt extrusion, milling, electro spinning, electro spraying, precipitation, film casting, freeze drying and rotary evaporation processes are regularly compared to spray drying processes in research literature.

Novel analytical techniques Mark Davis is a Research Fellow at The Synthesis and Solid State Pharmaceutical Centre (SSPC) based at The University of Limerick in Ireland. He has published multiple scientific papers concerning novel oral solid dosage formulations.

Mark has previously worked for Pfizer and completed his PhD in 2002 at the University of Edinburgh.

The standard analytical techniques are Powdered X-ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM) and polarised light microscopy (PLM). Fresh methods to obtain complimentary information include fluorescence, X-ray microtomography, atomic force microscopy, transmission electron microscopy, solid state fluorine nuclear magnetic resonance and static image analysis.

Novel dissolution techniques

Microcentrifuge dissolution has been examined as a technique to quickly gauge the performance of SDD. Moreover, an in vitro dissolution technique capable of discriminating between crystalline and amorphous drug has been reported.

Improvements on commercial dosage forms

Walker holds the Bernal Chair in Pharmaceutical Powder Engineering at UL and is a Visiting Research Professor at QUB. His interests include pharmaceutical engineering, process engineering and mathematical aspects for materials processing. He has been awarded >â&#x201A;Ź26m as Principal Investigator, published 178 articles and is a co-director of SSPC.

Several publications have mentioned SDD dissolution enhancement greater than existing commercial products; examples include valsartan and ziprasidone.

Other oral delivery technologies

Cubosomes of docetaxel with a cumulative release of 96 per cent after 2 hours have been prepared by spray drying. Bioadhesive drug delivery ASDs of metformin hydrochloride for the oral cavity have also been made with this technique.

Conclusions and Future Prospects

Spray drying is a versatile and important tool in the drive to improve the bioavailability of poorly soluble drugs.

There has been a large and steady increase in publications in this area over the last decade and this trend is likely to continue. Improvements in materials science and commercial technology will impact future possibilities. Advanced rotary atomisers are now available that are not susceptible to high maintenance costs.

A pressure nozzle has been patented

by Bend Research that can produce larger particles with better flow. A direct drive Magnetic Spray Machine (MSM) with no bearing lubrication requirements and low maintenance costs is in production. Hovione have patented technology based on continuous production capabilities. Process Analytical Technologies (PAT) such as FBRM, laser diffraction, NIR, turbidimetry and mass spectrometry could lead to more streamlined automated processes.

Regulatory pressures will likely continue to reduce the pervasiveness of toxic solvents such as dichloromethane in favour of ethanol or water. Although super critical CO2 is a potential solution, further research is required to improve the ability of this solvent to dissolve lipophilic drugs. With the rise of information technology and an increasingly informed consumer, greener and cleaner technology is also likely to be a marketing advantage.

Further innovation is likely to come from industry-academia collaboration, or from other sectors such as personal care, detergents or food/agri. Spray drying is common in these other industries and the regulation constraints are also different. The process has a bright future in pharmaceutical drug product development, thanks to its versatility and the ongoing problem of poorly soluble drugs.

References are available at www.pharmafocusasia.com www.pharmafocusasia.com

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Advertorial

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CLINICAL MANUFACTURING ON TIME AND WITHIN BUDGET In 2017, a record 46 submitted drugs received approval from the American regulatory agency FDA. One of the reasons for this success is the reciprocal commitment between the sponsor and regulatory bodies to maintain a high quality of applications. Both entities focus on reaching clinical end points as well as compliance with good and high-quality manufacturing practice. One way to help your company engage in good cGMP manufacturing and avoid common manufacturing issues is through the use of a thorough checklist for the clinical phases. This list can be used when discussing potential projects with partners or key stakeholders.

David Brett, Team Leader Product and Service Management, Vetter

T

he key to successfully developing and shepherding a drug to the approval stage and beyond lies in careful planning right from the start of development. Any and all issues that may arise during the process should be considered during this planning phase.

For gaining competitive advantages, it is crucial to make the right decisions early.

In this regard, ideally a company will have a checklist to keep track of the different phases and actions that need to be taken.

The effort put into this planning leads to the avoidance of costs and delays during the whole process. As we will learn, it is a 54

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way to streamline the entire process and enable product quality, compliance with budgets and schedules, and even its later success on the market. Here is a helpful checklist when developing a drug product and designing a manufacturing strategy.

Preliminary Planning: Be Realistic

Developing a drug and preparing it for approval is a complex process requiring the cooperation of many different organisations, companies and individuals.

This means first and foremost, setting a realistic timeline that seriously takes all critical points of the process into consid-

eration. Thus, an important first step then is to consult with your CRO (Clinical Research Organisation) to check that all relevant milestone dates are viable.

When discussing the project with the partner responsible for performing the clinical studies and manufacturing, knowing the unique API properties in depth is important. This includes ingredients used to manufacture the product such as organic solvents or nitrogen overlays, and, of course, the processes involved,

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like to manufacture in another country which entails understanding of local regulations and, most certainly, generates accurate documentation.

Besides the partners and suppliers, the company planning a submission for first-in-human studies should contact regulatory authorities as soon as possible to inform them about the molecule, its dosage form and the packaging being submitted. In return, they should receive advice for submittal.

Another aspect that must be included in early planning stages is the actual complexity of the manufacturing process.

A question to challenge the organisation with isâ&#x20AC;&#x2DC; whether it is more efficient to outsource manufacturing to a CDMO that can handle a complex process and guide it to the end?â&#x20AC;&#x2122; Primary Packaging, API and Materials: The Deep View

particularly if there are any special ones involved such as suspension filling. A partner must also be able to manufacture enough of the API for an effective trial run that is on time.

Looking ahead, a biopharmaceutical company must have deep manufacturing knowledge as well. The company or the Contract Development and Manufacturing Organisation (CDMO) contracted to do the work must be able to handle an active substance safely

and have the infrastructure for proper containment. It must also know how the API and excipients will react in a cGMP clinical manufacturing setting.

Such chemicals will have to be sourced in increasing larger quantities depending on the phase of the study. The supplier also needs to provide GMP grade material with auditable certificates of quality. It is not uncommon to encounter issues when trying to find a supplier that produces beyond lab grade. Some companies would

Primary packaging, while having impact on a later stage of manufacturing, is one of the leading issues in preparing a drug for market supply. Thus, it needs to be addressed thoroughly and with care. There are two aspects that need attention. First is the manufacturing itself. The biopharmaceutical sponsor will have to audit the partner or CDMO to be certain that all components and excipients are cGMP-quality and can be sourced in time. This is also the case for the API. The second is that the packaging can be divided into two chapters: in standard and nonstandard packaging issues. With nonstandard packaging the quantity and quality of sourceable materials becomes even more urgent.

A drug might require a cartridge for self-administration, or even a syringe with a dual chamber system for freeze dried APIâ&#x20AC;&#x2122;s. In such cases, only handfilling may be possible. Consulting a device developer at this stage can help determine whether an injection system is adapted to a specific drug.

Note: Even with standard packaging, companies must think ahead given vials, for example, come in different sizes throughout the world and with www.pharmafocusasia.com

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Milestones in a typical clinical manufacturing project

Source: Vetter

Figure 1 Milestones in a typical clinical manufacturing project

different neck sizes. Therefore, if a company is planning to scale up its product, it must be certain that the vial will fit the manufacturer's filling lines.

While considering primary packaging, it is also important to plan for laterstage injection device design. Typically, in early clinical phases, a drug is released in a vial which provides more flexibility for experimentation with dosing regimens. Considering early syringe clinical development, however, has several important benefits such as shorter time to market, reduced API loss and increased attractiveness for patients. Competitors may have already marketed a similar product in syringe form and keeping abreast of the market is, therefore, crucial. The use of a platform approach to development could gain an average of 18-month head start.

There are also concrete economic reasons for envisaging syringes as a packaging. Vial losses of API through manual overfill can accumulate to considerable sums. In one case, a yield increase of 2 per cent per batch of a protein worth â&#x201A;Ź0.89 per gram resulted in savings of â&#x201A;Ź650,000 per year when the drug was manufactured in a

pre-filled syringe as compared to a vial.1 Additionally, a parallel development strategy in a syringe can increase the value of a license to another partner.

This is especially true if the packaging selection, feasibility studies, lab studies, tech runs, stability and clinical batches, followed by validation and registration batches have all been done.

A final point to consider is whether the API will be imported or exported for manufacturing and trials. The target country may have special regulations and the API will have to pass through customs smoothly. A good idea is to discuss the matter with a consultant or a CDMO.

also involves "soft" topics like intellectual property rights which can have important repercussions.

In order to meet cGMP quality requirements, a company must understand what is required when the process moves from the lab to the clinical cGMP manufacture. Time and resources have to be invested into a formal audit of the company's quality standards which can cost a little extra time if the manufacturing is entrusted to a manufacturing partner. Finding and agreeing on an efficient path forward is not always a simple matter.

Good Contracts, Good Partners

Regulatory authorities have established stringent standards for risk management based on ISO standards, including cGMP. They are numbered ICH Q8/Q9/Q10 and cover Pharmaceutical Development, Risk Management and Pharmaceutical Quality System. Essentially, they include the overall manufacturing space and look at critical aspects of the entire supply chain and process parameters.

The authorities generally demand that Quality by Design methodology be applied to define and measure those

Before the clinical manufacturing can start, companies must discuss, verify, and sign legal quality and supply agreements with partners. Because this can involve multiple partners, it is worth encumbering extra time to make sure everything can be fully settled. Legal standards cover a wide range of topics such as jurisdiction in case of a court case. One must remember that manufacturing a drug 1 Vetter Internal Data. 2017

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Good Development Practice and Analytics

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The Big Moment â&#x20AC;&#x201C; Starting cGMP Clinical Manufacture

Once the clinical manufacturing process begins, interruptions for overlooked details can become extremely costly.

The pharmaceutical sponsor needs to ensure that the API amount is sufficient to cover all process steps in the scale-up. For example, the cGMP scaleup process may cause some API line losses from longer tubing and in-line filters. Destructive sampling and the additional API that may be needed for further stability or holding time testing should also be considered. Catching any issues at this stage can save a great deal of time and expense later on.

Technical runs with placebos should be made to determine fill volume specification and to see if there are any problems, e.g., filter clearance, air bubbles,

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P H A RM A F O C U S A S I A

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or standing times that need resolving.

While highly recommended, some companies might choose to avoid this step.

The time used for visual inspections and labelling should also be measured prior to starting, particularly if the product requires special labelling. The length of time a product stands between process steps could require more stability testing or refreezing. A pharma sponsor company should request from a manufacturing partner the time required to complete release testing to determine the time it will take to get a formal batch release.

Finally, if a company is considering a later lyophilisation of the product, the time to start some primary freezedried stability studies is now. Frozen formulations are often used to extend the time of unstable biologics such as large proteins. However, freeze thawing may not be practicable in commercial settings and, thus, the need for freeze drying. If a company is considering this approach, then planning at an early stage is important, especially when it comes to the choice of a manufacturing partner.

Another aspect to consider is automation: The global drive towards greater automation includes the pharmaceutical industry. However, there are some exceptions that need to be taken into account. For example, early phase toxicity studies or filling small batches i.e.

under five-hundred unitsâ&#x20AC;&#x201C; can be done by hand. For larger volumes, however, automation does offer many advantages, notably speed and safety since automated lines tend to reduce human error. Of course, filling machines are different.

It is always important to know what systems a manufacturing partner has in place and what their capacity is in terms of speed and formats. By factoring in the size of vials or lyophilisation where appropriate, a company can get an accurate estimate of how much time will be required to get all the batches manufactured and ready for submission.

Choosing the Right Partner

Manufacturing a drug and submitting it for approval is a complex and expensive process. That is why many companies choose to outsource to a partner that can take charge of a number of stages in the process. The over arching question that needs to be answered before any signing of agreements is whether the candidate partner actually has an available filling slot for the drug and can do the work within the schedule and budgetary limits?

Here again, being realistic about timeline estimates is of utmost importance.

The chosen manufacturing partner must be able to handle the compound safely. At best, they will have had experience with a similar API. Quality assurance is another key criterion. The quality audit system should match the

Source: Vetter

aspects and parameters and deliver effective risk assessment. A manufacturing partner must be able to provide those figures. Even with standard operating procedures, certain parameters such as concentrations of one substance can change. Companies need to flag Critical Quality Attributes (CQA) and Critical Process Parameters (CPP)so that the CDMO is aware of them. This not only generates product quality, but also avoids time-costly events later on in the process implementation.

In the early stages, formulation and stability trials are done at lab scale.

However, it is a good time to think about scaling-up for later trial stages and market launch. This may not require greater amounts of data. The job of an effective manufacturing partner is to root out any issues that might crop up during that process and offer concrete approaches. This is particularly important if a company has been using external lab services for tests or components which is done quite frequently. The company itself must determine how data is shared. It must also have robust standard operating procedures for the transfer of analytical methods.

Figure 2 A typical timeline with process step for a phase I-II liquid vial or syringe development project

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contracting company's quality assurance expectations. One aspect of this is the ability to perform the necessary analytical tests. Further a CDMO needs to have the drug sponsor's packaging configuration or be able to source it in time. Finally, there are more intangible aspects to make for a successful project. Many of them include project management, customer service, and response time to communication.

AUTHOR BIO

David Brett is Team Leader Product and Service Management at Vetter Pharma International GmbH. Before joining the CDMO in 2010, he worked in the Siemens Healthcare strategy and innovation department. Dr. Brett studied Biological sciences (University of East Anglia) and holds a MBA (University of Bayreuth) as well as a Ph.D. in Biochemistry (Imperial College London).

Use of a checklist discussing potential projects with partners or key stakeholders

Source: Vetter

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59

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wide. All the flights are operated via ABC’s cargo hub in Moscow Sheremetyevo airport, featuring up-todate equipment and guaranteeing seamless connection throughout the airline’s expanded international network within a 48-hour delivery time, including handling, all managed by highly-skilled and qualified

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Dissolution Prediction of Polymer-Coated Multiparticulates using In-Line Process Analytical Technology The drug release rate of pharmaceutical drug products is critical for ensuring product effectiveness and patient safety. This is controlled by the thickness of the coating layer applied to drug product particles. This study demonstrated that in-line particle size analysis is a viable method to predict dissolution performance and thus can be used to control a coating process.

Chris Oâ&#x20AC;&#x2122;Callaghan, Innopharma Technology Piyush Patel, Colorcon Edward Godek, Glatt Air Techniques Dr. Ian JonesD, Innopharma College of Applied Sciences Luke Kiernan, Innopharma College of Applied Sciences

P

rocess Analytical Technology (PAT) is a mechanism for measuring and controlling process performance parameters and Critical Quality Attributes (CQAâ&#x20AC;&#x2122;s) with the goal of ensuring final product quality.

Comprehensive implementation of PAT can compensate for process variability within normal operating conditions to ensure process and product quality is managed. Off-line measurement to monitor and control processes introduces a delay between process sampling and the availability of results. In some traditional sampling approaches, the physical act of sampling introduces additional variations that may impact resulting data. In-line PAT facilitates immediate access to process data enabling rapid decision making to optimise process conditions during development and 62

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MANUFACTURING

manufacture. Additionally, the application of in-line PAT supports the automated collection of process data for continuous process verification. Using real time analysis, feedback control tools can be implemented to modify conditions for process optimisation.

Many PAT tools are currently available that support the real time measurement of critical quality attributes based on physical or chemical characteristics. Dissolution, a CQA that directly impacts the final drug product quality, cannot be directly measured in-line due to sampling time requirements of standardised dissolution testing. Many solid dosage forms, including pellets and multiparticulates, are coated for modified release. Enteric or delayed coatings can increase bioavailability and improve patient acceptance while sustained release coatings can increase patient compliance and enhance convenience. Fluid Bed or Wurster coating processes are routinely applied to a range of core materials to produce the required drug release profile. The correlation of dissolution performance to data currently measured with the implementation of PAT provides an opportunity to predict dissolution test results for a modified release product.

Presented here are several elements of a study to predict the dissolution performance of polymer-coated multiparticulates using in-line PAT.

EXPERIMENT

SUBSTRATE

In-line multiparticulate data is first assessed, and an in-line and off-line particle size measurement technique comparison is presented for a selection of substrates and functional coating processes. The correlation between multiparticulate film thickness and predicted weight gain is investigated and finally dissolution performance predictions and results are compared.

taken at 30 mins and 1 hour of curing.

In-line particle size data was collected at these intervals also for comparative studies. Collected samples were sent for analysis by Colorcon’s analytical lab to determine dissolution and separately measure off-line Particle Size Distribution (PSD) data using a Camsizer system.

Experimental Plan

Materials & Equipment Formulation

The experimental processes and associated formulations are presented in Table 1.

Chlorpheniramine Maleate (CPM) and Propranolol HCI (PRP) coated Colorcon Suglets® were coated with Surelease® and/ or Opadry® EC functional coatings.

CPM-SR-1 and CPM-SR-2 are identical with the intention of demonstrating repeatability of results and dissolution performance prediction.

Process settings for functional coating materials were based on recommendations

by Colorcon and applied for a predicted weight gain of 18-20 per cent. Colorcon also recommend a 1-hour cure time for the aqueous-based Surelease functional coating.

Based on the quantity of coating solution sprayed, samples were extracted from the process at points corresponding to a predicted weight gain of 2.5 per cent, 5 per cent, 7.5 per cent, 10 per cent, 12.5 per cent, 15 per cent, 17.5 per cent and 20 per cent. Surelease based samples were also

For process experiments CPM-SR-1 and CPM-SR-2, sugar spheres (Suglets®, Colorcon) mesh size 18/20 (850-1000μm) were layered with Chlorpheniramine maleate (CPM).

The CPM layered pellets were coated with Surelease aqueous ethylcellulose dispersion (E-7-19040, Colorcon) as a barrier membrane coating and Opadry Hypromellose based coating system (YS-1-19025-A, Colorcon) as a pore former at 80:20 ratios. Preparation of the coating dispersion solution comprised the dissolution of Opadry in deionized water. This was then added to Surelease to obtain total solid content of 15 per cent w/w.

In process experiments CPM-EC and PRP-EC,Opadry EC ethylcellulose organic coating system (505O190028, Colorcon) was used as an alternative fully formulated barrier membrane organic coating to evaluate the performance on CPM and PRP layered pellets respectively. Opadry EC coating

FUNCTIONAL COATING

BATCH SIZE

INLET AIR TEMP

PRODUCT TEMP

SPRAY RATE

PER CENT SOLIDS

CPM-SR-1

CPM-coated 18/20 mesh sugar spheres

Surelease / Opadry 80:20

2 kg

70°-75°C

44°-46°C

15-20 g/m

15

CPM-SR-2

CPM-coated 18/20 mesh sugar spheres

Surelease / Opadry 80:20

2 kg

70°-75°C

44°-46°C

15-20 g/m

15

CPM-EC

CPM-coated 18/20 mesh sugar spheres

Opadry EC

1.75 kg

40°-45°C

30°-32°C

20-25 g/m

8

PRP-EC

PRP-coated 20/25 mesh sugar spheres

Opadry EC

1.75 kg

40°-45°C

30°-32°C

20-25 g/m

8

PRP-SR

PRP-coated 20/25 mesh sugar spheres

Surelease / Opadry 80:20

1.75 kg

70°-75°C

44°-46°C

15-20 g/m

15

Table 1 List of Experiments www.pharmafocusasia.com

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solution was prepared in Ethanol and water at 90:10 ratios.

Sugar spheres (SugletsÂŽ, Colorcon) mesh size 20/25 (710-850 Îźm) were layered with propranolol HCl (PRP) for process experiment PRP-SR. The PRP layered pellets were coated with Surelease aqueous ethylcellulose dispersion (E-7-19040, Colorcon) and Opadry Hypromellose based coating system (YS-1-19025-A, Colorcon) as a pore form. er at 80:20 ratios as described previously in CPM-SR-1.

The targeted coating weight gain was 18-20 per cent for all experiments and samples were taken at every 2.5 per cent predicted weight gain (WG).

Coating system

The Wurster coating process is commonly used to apply coating films of high quality and uniformity. It can be applied to a wide range of base materials of varying particle size and shape. The use of differential air flow streams to create a cyclic flow of particulates inside a chamber with a spray nozzle located at the bottom of the fluidised bed ensures a uniform application of desired coating thickness. A diagram of the Wurster bowl and component parts is presented in Figure 1. Critical process parameters include Spray Rate, Atomizing Air Pressure, Air Volume, Product Temperature, Orifice Plate Configuration and Partition Height.

These require monitoring and control to ensure the process produces the desired quality.

A Glatt GPCG-2 lab system was deployed for this experiment. It is a lab scale unit commonly used for formulation and process development,

Figure 1

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P H A RM A F O C U S A S I A

Figure 2

offering flexibility for a range of fluid bed processes. Figure 2 shows the product container used for this study, including the SD-55windows added to accept non-product contact PAT. The Eyecon2 device was installed on the lowest positioned window of the product container to deliver optimal measurement of particulates during Wurster processing. In general, the application of in-line PAT to capture data such as PSD or moisture content during fluid bed coating processes allows for greater process understanding and control from product design through to commercialisation.

Figure 3

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Analytical instrument

The Eyecon2 from Innopharma Technology was used to measure in-line particle size distribution data.

The Eyecon2 employs the principles of direct-imaging to capture images of flowing or static material and uses advanced digital image processing to provide data on the particle size and shape distribution. The Eyecon2 can be used at-line or in-line and has application in typical oral solid dose processes including granulation, milling and fluid bed coating. Implementation of the Eyecon2 can significantly reduce analytical time and increase process

MANUFACTURING

knowledge from development to commercial manufacturing.

Figure 3 shows the Eyecon2 mounted on the lower window of the Glatt GPCG-2 lab system to provide an in-line measurement device without the necessity of product contact. Such positioning offered the opportunity to capture dense images of the multiparticulates, maximising the number of particles captured per image, and therefore minimising the time required to obtain representative measurements.

An image captured by Eyecon2 of the CPM-coated multiparticulates partway through the Surelease / Opadry functional coating process is presented in Figure 4.

Graph 1 CPM-SR-1 Coating Process Profile

process experiments is identical and the resulting plots demonstrate little variation. Use of the Eyecon2 over time will facilitate the identification of control limits and the accepted variability of the process.

Graph 1 presents Eyecon2 in-line particle size data collected during experimental process CPM-SR-1 at the sample intervals of predicted weight gain discussed earlier i.e. at every 2.5 per cent

predicted weight gain up to a value of 20 per cent, plus two additional samples during the curing phase. The particle size distribution is defined at each sample interval using the Dv10, Dv50 and Dv90 values. Dv50 represents the median particle diameter for the volume distribution, while 10 per cent and 90 per cent of the population distribution lies below the Dv10 and Dv90 values respectively. These values confirm a steady rate of particle growth over time, with a negligible rate of growth during the curing step as expected.

Real-time on-screen images captured with the Eyecon2 during the start and end of the film coating process are presented in Figures 5 and 6 respectively.

In-line images can provide subjective supporting information for process understanding and performance investigation.

To demonstrate in-line process measurement repeatability, the Eyecon2 in-line particle Dv50 data collected during process experiments CPM-SR-1 and CPM-SR-2 is presented for comparison in Graph 2. The formulation for both

Figure 4

Figure 5

Figure 6

Colorcon lab analysis

An off-line instrument, Camsizer, using the principle of backlight imaging and digital processing was used as an alternative method to measure particle size distribution for comparison with the In-line data.

Drug release was measured using a UV spectrometer of 1 gram of CPM and PRP barrier membrane coated pellets in a dissolution bath using USP apparatus I (baskets) at 100 rpm. USP purified water was used as a dissolution media (1000 ml) at 37.0 ¹ 0.5 °C. Results & Discussion In-line multiparticulate analysis

Comparison of in-line & off-line results

A comparison of the particle analyser distribution data from the Eyecon2 and off-line Camsizer is presented in Graph 3. Reported are the Dv10, Dv50 and Dv50 values produced by each particle analyser instrument for process CPM-SR-1. Some variation is expected as different instruments can use different measuring techniques and hence yield marginally different results.

However, a strong correlation between the particle size distribution data for each method for the duration of the process is apparent.

The correlation of the on-line and off-line data is further explored in Graph 4 where a linear plot of the Eyecon2 in-line values against the equivalent Camsizer off-line values are presented.

The resulting trendline R-squared values for each data set i.e. Dv10, Dv50 and

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Dv90, indicate a high correlation particularly for Dv50 with a value over 0.98.

To further determine the correlation of the in-line and off-line measuring

techniques, all Dv50 data collected during the sample intervals of each of the five process experiments is presented in Graph 5. The resulting trendline r-squared value of 0.9895 offers a

high degree of confidence that the Eyecon2 particle analyser is consistently producing results comparable to the offline Camsizer system.

The data clustered around 850um on the X-axis represent the smaller, PRP-coated starting substrates while the data points clustered around 975um represent the larger CPM-coated substrates.

Coating Thickness Measurement

Graph 2 Particle Size Growth during CPM-SR process

Graph 3 Particle Size Data Comparison

Graph 4 Correlation of Eyecon and Camsizer Data 66

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Dissolution performance of multiparticulates is influenced by particle size. The thickness of applied functional coatings for multiparticulates will directly impact the dissolution process. For each of the five experimental processes, the functional coating was applied to achieve a predicted weight gain of 20 per cent.

As coating densities vary due to differences in functionality, variations in total film thickness are expected across the experimental processes to achieve the relevant predicted weight gain.

In-line PSD data from the Eyecon2 can be used to evaluate coating thickness and demonstrate the correlation between film thickness and predicted weight gain. The film thickness (f ) at a given sample interval can be defined as the increase in reported particle size diameter divided by two, as seen in Figure 7. As a range of PSD descriptive parameters are available from Eyecon2, three methods to calculate coating thickness are explored to determine the most suitable for dissolution predictions. These are the difference in Dv50 percentiles, the difference in the average of the most common percentiles of Dv10, Dv50 and Dv90, and the difference in the average of all the percentile data measured by the Eyecon2.

A comparative representation of the data collected in the experimental process CPM-SR-1 presented in Graph 6 indicates a close match between the three methods.

A good correlation for in-line and off-line Dv50 parameter measurements was previously demonstrated. Due to

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the similarities of the three coating thickness calculation methods, the difference in Dv50 values has been selected for coating thickness representation in the dissolution prediction element of this study. The relationship between calculated coating thickness and predicted weight gain for experiment CPM-EC is presented in Graph 7. Results confirm a similar trend to the CPM-SR-1 process however, the coating thickness is lower as expected due to the difference in the functional coating compositions.

Predicting Dissolution using Inline Measurement

Several factors affect drug dissolution rate. Prediction of the dissolution rate using in-line measurement techniques necessitates a formulation model specific to the coated multiparticulates under test. A dissolution prediction model was designed using the dissolution test results of experimental process CPM-SR-1. The formulation and process parameters were repeated in CPM-SR-2 and the dissolution prediction model was used to predict CPM-SR-2 dissolution performance and a comparison is made against actual results.

The dissolution rate data for the multiparticulate samples collected during experimental process CPM-SR-1 at the predicted weight gain intervals is presented in Graph 8. As previously discussed, each predicted weight gain sample correlates to an equivalent coating thickness.

The relationship between dissolution performance and equivalent film thickness calculated is presented in Graph 9.

Each best fit polynomial represents a specific time in the dissolution medium.

For example, a film thickness of 20um yields a much lower dissolution performance at 15 minutes compared with 240 mins as expected. These polynomials can be used to predict dissolution performance based on calculated film thickness as determined from in-line particle size measurements.

Graph 5 Correlation of Eyecon and Camsizer Experiemntal Dv50 Data

Graph 6 Film Thickness vs Predicted Weight Gain for CPM-SR-1

Graph 7 Film Thickness vs Predicted Weight Gain for CPM-EC

Using the polynomial equations displayed in Graph 10 and in-line particle distribution data collected in experimental process CPM-SR-2, dissolution performance is predicted.

The results are presented in Table 2.

A graphical representation of the data is presented in Graph 10.

To corroborate the validity of the prediction model, the predicted (P) and actual (A) dissolution data is presented in Graph 11. The close www.pharmafocusasia.com

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It is also noted that the application of PAT in this study facilitated real time process understanding with the support of in-line data and images. This has the potential to enhance process development, control, optimisation, investigation, scale up and transfer.

Using Colorcon products and process knowledge, multiple datasets are potentially available to develop robust predictive models for deployment.

The Glatt GPCG2 lab system unit offers flexibility to facilitate experimental requirements with different Wurster processing parameters.

Figure 7

overlay generally observed between the predicted and measured data shows the viability of the prediction model. To improve the accuracy of the dissolution prediction model for deployment, an expansion of the data set is recommended. Inclusion of CPM-SR-2 actual data in building the prediction model will further enhance the viability and value of the prediction model for subsequent repetition and dissolution prediction of the process.

Graph 8 CPM-SR-1 Dissolution Performance

Conclusions

• A strong correlation was demonstrated between in-line and off-line digital image analysis to measure particle size distribution • Data from the Eyecon2 demonstrated a direct relationship between predicted weight gain and functional coating thickness • A clear correlation was established between functional coating thickness and dissolution profile • It was established that in-line particle size data analysis is a viable method to predict dissolution performance using formulation specific models.

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Graph 9 Film Thickness vs Dissolution

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SR2

Predicted Dissolution @ (minutes)

Sample Point

Film Thickness

0

15

30

60

120

240

480

600

720

0 per cent WG

0.00

0 per cent

99 per cent

100 per cent

100 per cent

100 per cent

100 per cent

100 per cent

100 per cent

100 per cent

5 per cent WG

6.36

0 per cent

72 per cent

84 per cent

91 per cent

97 per cent

98 per cent

100 per cent

100 per cent

100 per cent

10 per cent WG

16.34

0 per cent

39 per cent

59 per cent

73 per cent

88 per cent

95 per cent

99 per cent

99 per cent

100 per cent

15 per cent WG

26.19

0 per cent

17 per cent

36 per cent

57 per cent

77 per cent

90 per cent

98 per cent

99 per cent

100 per cent

20 per cent WG

36.50

0 per cent

4 per cent

14 per cent

39 per cent

61 per cent

83 per cent

96 per cent

98 per cent

100 per cent

30 min cured

38.81

0 per cent

3 per cent

9 per cent

35 per cent

57 per cent

81 per cent

96 per cent

98 per cent

100 per cent

60 min cured

38.08

0 per cent

3 per cent

11 per cent

36 per cent

58 per cent

82 per cent

96 per cent

98 per cent

100 per cent

Table 2 CPM-SR-2 Predicted Dissolution

AUTHOR BIO

Graph 10 CPM-SR-2 Predicted Dissolution

Chris Oâ&#x20AC;&#x2122;Callaghan is a mechanical engineer who has been with Innopharma Technology for 6 years.

He is the Senior Product Manager responsible for the Eyecon particle sizing technologies, with a focus on hardware development and product applications research. He manages, custom engineering projects to interface PAT systems with new and existing product lines.

Graph 11 Comparison of CPM-SR-2 Predicted and Actual Dissolution

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®

FILE TRANSFER AND THE GDPR

File Transfer Features Needed for GDPR Compliance The General Data Protection Regulation (GDPR) encompasses 7 data protection principles that, together, assure the rights of the individual are central to the collection and processing of personal data.

File Transfer systems, fitting the definition of ‘processing’, must provide the following functionality in order to enable compliance.

PRINCIPLE 1

“Purpose Limitation”

PRINCIPLE 5

PRINCIPLE 4

PRINCIPLE 3

“Fair, lawful and transparent processing”

PRINCIPLE 2

THE 7 GDPR DATA PROTECTION PRINCIPLES

Personal data collected for one purpose should not be used for a new incompatible purpose.

“Data Minimisation” Collection and processing should be limited to the personal data needed to achieve the stated purpose.

Non-repudiation to validate that personal data is transferred only between authorised senders and receivers.

Centralised, fine grained access control to safeguard user credentials, permissions and personal data.

Cryptic scripts should be replaced with a forms-based solution that provides a standardised, secure and documented record of data transfer tasks.

Comprehensive analytics that provide the required insights into transfer activities to assure on-going compliance with GDPR’s data protection principles.

“Accuracy” All reasonable steps must be taken to ensure that personal data is accurate.

“Storage Limitation” Personal data should not be stored for longer than necessary for its stated purpose.

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Additional care must be used when designing and implementing personal information processing activities.

GDPR-REQUIRED FILE TRANSFER FUNCTIONALITY

“Integrity and Confidentiality”

Automatic file integrity checking to validate that a file has not been altered.

The system should allow the scheduling of common repetitive pre- and post-transfer tasks, including the scheduled deletion of personal data files.

ISSUE - 33 - 2018

Encryption of personal data in transit

P PRINCIPLE 6 PRINCIPLE 7

stated purpose.

“Integrity and Confidentiality” Personal data must be secure against internal and external threats, wrongful processing, damage, loss, and destruction.

“Accountability” Compliance with the Data Protection Principles must be documented.

personal data files.

Encryption of personal data in transit and at rest.

Integration with Data Loss Prevention and Anti-virus solutions.

Automatic collection and reporting on data transfer logs on one centralised consolidated location.

Audit logs should be tamper-evident in order to be trusted for accuracy.

The lowest risk, most cost-effective way to meet all 7 GDPR Data Protection Principles is a managed data transfer solution like Ipswitch MOVEit File Transfer.

MOVEit integrates secure data transfer with centralised workflows, access control, and audit logging. The result: fewer moving parts, which translates into lower risk to personal data, and less time and money spent managing and supporting data transfer processing activities. Learn more by trying a

FREE TRIAL OF MOVEit MANAGED FILE TRANSFER

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PRODUCTS & SERVICES Company........................................................................Page No.

Company........................................................................Page No.

STRATEGY Airbridgecargo........................................................................ 60-61

CLINICAL TRIALS Qatar Airways................................................................................19

Cantel Medical..............................................................................05

Syneos Health™..........................................................................IBC

Eva Air Cargo................................................................................13 Qatar Airways................................................................................19

MANUFACTURING Akzo Nobel Chemicals (India) Ltd.............................................. IFC

Swiss World Cargo.......................................................................09

Cantel Medical..............................................................................05

Turkish Cargo............................................................................OBC

Chemspeed Technologies AG......................................................33

Valsteam ADCA Engineering........................................................03

F. P. S. Food and Pharma Systems Srl.........................................27

Vetter Pharma-Fertigung GmbH & Co. KG...................................15

Lonza.............................................................................................49

maskargo.......................................................................... 59, 52-53

maskargo.......................................................................... 59, 52-53 RESEARCH & DEVELOPMENT Chemspeed Technologies AG......................................................33

Orient EuroPharma Co. Ltd..........................................................31

F. P. S. Food and Pharma Systems Srl.........................................27

Vetter Pharma-Fertigung GmbH & Co. KG...................................15

Turkish Cargo............................................................................OBC

Matcon.............................................................................. 37, 34-36 Optel India.....................................................................................41 Orient EuroPharma Co. Ltd..........................................................31

INFORMATION TECHNOLOGY RoundRobin Tech Services Pvt Ltd........................................ 70-71

Syneos Health™..........................................................................IBC

SUPPLIERS GUIDE Company........................................................................Page No.

Company........................................................................Page No.

Airbridgecargo........................................................................ 60-61 www.airbridgecargo.com

Optel India.....................................................................................41 www.optelgroup.com

Akzo Nobel Chemicals (India) Ltd.............................................. IFC www.kromasil.com

Orient EuroPharma Co. Ltd..........................................................31 www.oep.com.tw

Cantel Medical..............................................................................05 www.mcpur.com

Qatar Airways................................................................................19 www.qrcargo.com/qrpharma

Chemspeed Technologies AG......................................................33 www.chemspeed.com

RoundRobin Tech Services Pvt Ltd........................................ 70-71 www.roundrobintech.com

Eva Air Cargo................................................................................13 www.brcargo.com

Swiss World Cargo.......................................................................09 www.swissworldcargo.com

F. P. S. Food and Pharma Systems Srl.........................................27 www.foodpharmasystems.com

Syneos Health™..........................................................................IBC www.syneoshealth.com

Lonza.............................................................................................49 http://pharma.lonza.com/

Turkish Cargo............................................................................OBC www.turkishcargo.com

maskargo.......................................................................... 59, 52-53 www.maskargo.com

Valsteam ADCA Engineering........................................................03 www.valsteam.com

Matcon.............................................................................. 37, 34-36 www.matconibc.com

Vetter Pharma-Fertigung GmbH & Co. KG...................................15 www.vetter-pharma.com

To receive more information on products & services advertised in this issue, please fill up the "Info Request Form" provided with the magazine and fax it.

1.IFC: Inside Front Cover, 2.IBC: Inside Back Cover, 3.OBC: Outside Back Cover

syneoshealth.com

SHORTENING THE DISTANCE FROM LAB TO LIFE . ®

INC Research and inVentiv Health have become Syneos Health™, the only fully integrated biopharmaceutical solutions organization with a unique approach.

At Syneos Health, all the disciplines involved in bringing new therapies to market, from clinical to commercial, work together with a singular goal — greatly increasing the likelihood of customer success. We call our business model Biopharmaceutical Acceleration. You can call it the future. www.pharmafocusasia.com

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THE WORLD'S HEALTH IS IN THE SAFEHANDS OF TURKISH CARGO AS THE CARGO AIRLINE THAT FLIES TO MORE COUNTRIES THAN ANY OTHER, WE CARRY ALL YOUR HEALTH AND WELLNESS NEEDS, FROM PHARMACEUTICALS TO MEDICAL SUPPLIES WITHOUT EVER INTERRUPTING THE TEMPERATURE-CONTROLLED COLD CHAIN.

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www.pharmafocusasia.com

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