IPI - Volume 6 Issue 3 - Sept 2014

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Volume 6 Issue 3

Peer Reviewed

Regulatory Scenario of Herbal MedicinesA Global Review

Key Considerations for Conducting Clinical Trialsin Idiopathic Pulmonary Fibrosis

Device DesignIs Driving Innovation

Impact of Sterilisation MethodOn Packaging Component Machinability Performance

International Pharmaceutical Industry Supporting the industry through communication

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 1www.ipimedia.com

Contents

DIRECTORS: Martin Wright Mark A. Barker

EDITOR:Cecilia [email protected]

EDITORIAL ASSISTANTOrsolya [email protected]

BOOK MANAGER: Anthony Stewart [email protected]

BUSINESS DEVELOPMENT:John [email protected]

DESIGN DIRECTOR: Fiona Cleland

CIRCULATION MANAGER:Dorothy [email protected]

FINANCE DEPARTMENT: Martin [email protected]

RESEARCH & CIRCULATION:Heather [email protected]

COVER IMAGE: iStockphoto

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All rights reserved. No part of this publication may be reproduced, duplicated, stored in any retrieval system or transmitted in any form by any means without prior written permission of the Publishers.

The next issue of IPI will be published in December 2014. ISSN No. International Pharmaceutical Industry ISSN 1755-4578.

The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright.

2014 PHARMA PUBLICATIONSVolume 6 issue 3 - Autumn - 2014

International Pharmaceutical Industry Supporting the industry through communication

06 Editors Letter

REGULATORY & MARKETPLACE

08 Regulatory Scenario of Herbal Medicines: A Global ReviewIn the last few decades there has been exponential growth in the field of herbal medicine and regulation of herbal medicines has become key to ensuring the safety, efficacy and quality of herbal medicinal products. In their paper, Balamuralidhara V., Shilpi Khattri, Vandana K. and T. M. Pramod Kumar of JSS College of Pharmacy, JSS University, Mysore discuss in detail herbal drugs regulations in India, providing also an overview of the regulatory status of herbal medicine in the USA, Australia and Europe.

18 The Interim Exec Community calls for a Conscious Coupling of RPOs and Interims Specialists

Pharmaceutical companies have widely adopted strategies to outsource elements of their business operations, as part of an ongoing drive to deliver a more flexible model that unlocks cost efficiencies and alleviates some aspects of risk associated with drug development. As Dafydd Wright, Director of Interims of RSA, explains, recruiting talent is one such element. However, pharmaceutical companies should be wary of saving on recruitment at the risk of missing out on the best candidates, particularly when it comes to senior staff.

22 The 3E Principle: Key Considerations for Selecting and Outsourcing to a Vendor

Influenced by forces such as macroeconomics, politics, regulations, population growth and aging, there has been a major shift in the way biopharmaceutical companies conduct business. There is ever-increasing pressure to comply with evolving regulations along with cost reductions in order to grow business. Dr Chitra Lele of Sciformix Corporation outlines the 3E Principle of Effectiveness, Efficiency and Economics; key parameters organisations should consider when selecting an outsourcing partner to assist with knowledge-based activities in drug development and post-marketing stages of the product lifecycle.

28 Funding Options for R&D in the Life Sciences SectorTypically, funding for R&D and business growth has been hard to secure over previous years due to the financial crisis. However, now that the financial uncertainty is passing, there is a definite sense of increased confidence in the economy with funding options returning and becoming more readily available and accessible to life sciences businesses. Nigel Greenaway and Laura Herdman of Greenaway Scott discuss the various funding options available and the positive impacts and initiatives these bring to businesses in the life sciences industry.

34 Global Tracking Regulations Present Challenges and BenefitsLars Hoejberg of NNIT looks into serialisation, the foundation of any tracking system. Drug makers are facing an ever-increasing challenge as more countries implement serialisation and tracking regulations and set compliance deadlines, in an effort to ensure the safety and quality of prescription drugs being sold within their borders. Complying with regulations coming into effect will be a demanding task due to a lack of global harmonisation.

42 Get Ownership of your IP Right; Otherwise it can Turn into a Nightmare!

When filing a patent application, there are lots of things to consider. Most of the attention is directed towards getting the disclosure of the invention right and ensuring that you have adequately covered your commercial product/concept to prevent your competitors from entering the market space. Jenny Donald of Forresters warns that too often, little thought is given to who actually owns the invention. And if you get this wrong, it can be incredibly difficult to rectify the situation at a later stage.

2 INTERNATIONAL PHARMACEUTICAL INDUSTRY Autumn 2014 Volume 6 Issue 3

Contents

DRUG DISCOVERY, DEVELOPMENT & DELIVERY

48 The Respiratory Drug Delivery Asia 2014 A PreviewThe Respiratory Drug Delivery (RDD) Asia 2014 scientific conference will welcome pulmonary and nasal drug delivery experts from all over the world to Goa, India from November 12-14, 2014.

50 Device Design is Driving Innovation Devices are playing an increasingly important role in medicine. Medical devices offer innovative examination and treatment options and drug delivery devices permit precise, customised and intelligent therapies. New drugs with innovative active ingredients are being launched in conjunction with equally innovative delivery devices, and Peter Wallrabe of Gerresheimer Medical Plastic Systems tells us why the development of innovative drugs goes hand-in-hand with the development of equally innovative drug delivery devices that guarantee stability, optimise bioavailability and ensure the necessary precision of dosage.

54 Improving Study Design in Diabetes Drug Development using Predictive Analytics

Diabetes mellitus is a serious disease that arguably has reached global epidemic proportions. In their paper, Denise F. Messer, Claudia De Oliveira, Xiaoqiang Xue, Rick Turner and Erica Caveney of Quintiles scrutinise how predictive analytics can facilitate more efficient study designs in development programmes for new antidiabetic drugs for type 2 diabetes mellitus (T2DM), with

a brief recap of the essentials of the FDA and EMA guidelines and an account of how the drug development landscape has changed within the last decade or so.

66 How can Pharma Develop Paedriatic Medicine?In the evolving healthcare landscape, the key areas of patient engagement, education and empowerment are only just starting to be scrutinised in paediatric medicine. Dr Kate Hersov, UK CEO and Co-Founder of Medikidz discusses the many as-yet unexplored opportunities for the pharmaceutical industry to become established leaders in driving innovation in these areas. With a history of driving innovation through new approaches, the pharmaceutical industry is ideally placed to support healthcare professionals with new initiatives to provide engaging and appropriate educational tools for use with young patients.

72 Smart Pills for Oral Drug DeliveryIt seems that there are smart products of one sort or another everywhere we look, with new devices and models constantly being introduced. A smart pill is an ingestible capsule with miniaturised micro-electronics and may be used in a wide range of applications from use as a smart tool in drug development to a key element in a smart connected care environment. Jeff Shimizu of Medimetrics explains that this emerging technology presents significant opportunity for the pharma industry to exploit modern digital innovations and take a lead position in the future of healthcare.

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Contents

CLINICAL & MEDICAL RESEARCH

76 Key Considerations for Conducting Clinical Trials in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a form of chronic, progressive fibrosing interstitial pneumonia that is of unknown cause, occurring primarily in older adults. The prognosis is extremely poor, with an average survival of two to three years following diagnosis. While the number of clinical trials in this area has increased in recent years, there remains an urgent and unmet need for new therapies. Vikki Brandi and Juan Gispert of Quintiles aim to identify key methodological, practical, and ethical issues involved in IPF clinical trials, focusing on country and site identification, feasibility, and study design.

LABS AND LOGISTICS

88 Clinical Trial Logistics Meeting the Needs of an Evolving Pharmaceutical Industry

The management of clinical trial distribution has changed very much as a result of changes in the wider pharmaceutical industry. Martin Lamb of Biotec Services International discusses how this service has developed, and drivers for some of the change. While the management of the clinical supply chain is a critical part of drug development, it can be viewed as a high-cost, low-value-adding component of drug development for a pharma company to take on single-handed. But external clinical supply specialists, by spreading this cost over multiple sponsors, have been able to invest in improving distribution models to provide a truly global clinical trial supply chain.

94 Thermal Packaging and Good Distribution Practice: A Natural Fit?From the perspective of the thermal packager it has always been best to assume that whatever can go wrong will go wrong, and that however simple and user-proof the packaging, people will still find a way to do something bizarre with it. Katie Friday of Tower Cold Chain Solutions argues that the advent of the new guidelines is therefore to be welcomed, since they place a very considerable onus on all parties to comply with what are largely well-thought-out and sensible provisions. Beyond this, potentially, they spell an end to a period of significant frustration.

MANUFACTURING

98 Tailor-made Product Attributes Mark Riemer of SternMaid GmbH & Co.KG explores fluid-bed technology, a formative drying process enabling a specific influence on the physical properties of solid and liquid products and their

possible applications. Fluid-bed technology opens up an enormous range of possibilities for optimising products from better solubility, dust reduction, easier tabletting and fortification with vitamins to microencapsulation of active ingredients. Very gentle handling of the products and the diversity of the possible applications have made fluid-bed processing one of the most important formulation methods in the food and pharmaceutical industries.

102 Accelerating the Development of Generic Pharmaceuticals: Developing an Analytical Toolkit Suitable for De-Formulating Complex Reference Products

In its report Critical Path Opportunities for Generic Drugs, the FDA emphasises the need for advances in the field of analytical sciences in order to accelerate the development of generic products. Here, Paul Kippax of Malvern Instruments highlights techniques that are especially helpful in the de-formulation of complex reference products, focusing on triple detection Size Exclusion Chromatography (SEC) and Morphologically-Directed Raman Spectroscopy (MDRS).

110 When Two is Better than One: The Benefits of Two-Floor Production Facilities for Future-Proof Manufacturing Capability

The impact of batch transfer methods on the Lean success of a plant is starting to be recognised earlier in the plant design process. Before deciding on building and process room heights, proper attention must be given to materials handling processes. A single-floor facility design is simply not flexible enough, and a multiple-floor plant could well be too expensive. A two-floor facility is a good compromise as it provides good agility for future demands with a modest investment requirement. Wim Spook of Matcon looks into the pros and cons of these different facility designs, exploring the benefits to the future requirements of the business.

114 Small Changes to Tablet Shape Bring Big ResultsTablet shape is generally given the most consideration as new products are branded by marketing departments, whereas whole campaigns have been built around a tablets colour or shape. Dale Natoli of Natoli discusses the importance of considering the potential of small adjustments to tablet shape to influence everything from production efficiency to consumer acceptance. An improper tablet design can cost millions in lost production and possibly lead to a disastrous product launch.

PACKAGING

118 Gentlewing: The Name Says It AllImplementing innovations in the pharmaceutical market is an ambitious task. In an industry that requires precise and reproducible results, changes to current systems always involve certain challenges. According to Dr Marcus Knll of Bosch, an external study can provide certainty, which was the case with the uniquely shaped 'Gentlewing' mixing device from Httlin GmbH, a subsidiary of Bosch Packaging Technology, based in Schopfheim, Germany. A study conducted by the University of Mainz, Germany, confirmed that the special design of the device offers several advantages to users while achieving the same processing results as a conventional mixer.

122 Impact of Sterilisation Method on Packaging Component Machinability Performance: Steam vs. Gamma Evaluation of the 1ml Long Plunger

The machinability of parenteral packaging components is recognised to have a significant influence on productivity of the drug product manufacturing process. As Simon Ct of West Pharmaceutical Services explains, there are various processes that can be used for washing and sterilising elastomers for aseptic fill, and depending on conditions of processing, the physical and functional characteristics of the component will be altered to some degree. In this case study, elastomeric components intended for aseptic processing are considered with respect to machinability on a lab-scale filling line.

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Editor's Letter

IPI`s Autumn issue is all about the pursuit of innovation. The process of innovation stems from an array of interconnected areas. Discover how making smart

use of modern digital innovations might bring a revolution in healthcare.

Increasing competition, reimbursement concerns and expiry of blockbuster patents are putting the pharmaceutical industry under a lot of strain to move away from entrenched business practices, according to Jeff Shimizu of Medimetrics. Since pharma has already shifted its focus from pills to outcomes, and there is recognition of the role of the many factors beyond the direct action of the drug, those companies that can successfully combine drugs, devices, and technology to bring about better outcomes will be rewarded. Let the era of smart healthcare begin!

The pace of innovation seems to be indeed speeding up. The biopharmaceutical industry is driving unprecedented progress in drug discovery and development, and innovation in drug delivery devices is needed for novel pharmaceutical compounds. But novel active ingredients used to manufacture essential pharmaceuticals are associated with new packaging and administration challenges. Their vastly more complex molecules have to be packaged differently and dosed more precisely than their humble predecessors. Thats why new drugs with innovative active ingredients are being launched in conjunction with equally innovative delivery devices.

Device design drives innovation and Peter Wallrabe of Gerresheimer Medical Plastic Systems warns that the development of a new device - from the initial idea to a small production run for clinical tests - is a demanding process as a result of the complex technological, design and regulatory issues involved.

Experts say the old model of the pharmaceutical blockbuster is gone. Scrutinising the FDA`s report, Critical Path Opportunities for Generic Drugs, Gurfateh Singh and Paul Kippax of Malvern Instruments note that while the development pathways for generic and innovator drugs have much in common, there are also some critical distinctions to be taken into account. Commercialisation of a generic begins with de-formulation, the unpicking and rationalisation of those innate qualities of the reference listed drug (RLD) that deliver its performance. But as innovators push the boundaries of pharmaceutical product engineering and pharmaceutical products become ever more sophisticated, de-formulation becomes even more strenuous. With increasingly complex RLDs, formulation scientists working on generics now need even better characterisation technology than was used for the innovator product.

Embracing innovation can also mean the chance to prompt a competitive advantage through the use of innovative business practices. Looking into the overall trends seen in outsourcing, Dr Chitra Lele of Sciformix Corporation addresses the opportunities and challenges raised by todays marketplace, in

which no corner of the biopharmaceutical business (regardless of the postcode) remains unaffected by the pressure to increase the compliance and quality of products, whilst simultaneously improving on productivity and making significant cost cuts.A critical part of drug development is the management of the clinical supply chain. According to industry forecasts, clinical trial logistics spend will reach this year $2.99 billion, rising to $3.16 billion by 2018. Talking about the use of IRT technology to control overages and waste in clinical studies, which is becoming more critical as unit dose costs for new drugs continue to rise, Martin Lamb of Biotec Services International foresees that, in fact, the advent of mobile technology and lower-cost fully-configurable IRT systems is likely to increase the number of trials employing this technology. There is no sign whatsoever that biopharmaceutical development will slow down - quite the contrary - and in order to control increased costs and risks associated with the future developments, pharma needs to choose wisely between investing in expertise and assets internally, or working strategically with external partners to ensure the supply chain is efficiently cared for.

Cecilia StroeEditor

Come and Visit us at CPHI/ICSE Stand 3D357th 9th October 2014Paris Nord Villepinte, France

Bakhyt Sarymsakova, Head of Department of International Cooperation, National ResearchCenter of MCH, Astana, Kazakhstan

Catherine Lund, Vice Chairman, OnQ Consulting

Deborah A. Komlos, Senior Medical & Regulatory Writer, Thomson Reuters

Diana L. Anderson, Ph.D president and CEO of D. Anderson & Company

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

Francis Crawley. Executive Director of the Good Clinical Practice Alliance Europe (GCPA) and a World Health Organization (WHO) Expert in ethics

Georg Mathis Founder and Managing Director, Appletree AG

Heinrich Klech, Professor of Medicine, CEO and Executive Vice President, Vienna School of Clinical Research

Jagdish UnniVice President- Beroe Risk and Industry Delivery Lead- Healthcare, Beroe Inc.

Jeffrey Litwin, M.D., F.A.C.C. Executive Vice President and Chief Medical Officer of ERT

Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Maha Al-Farhan, Vice President, ClinArt International, Chair of the GCC Chapter of the ACRP

Nermeen Varawalla, President & CEO, ECCRO The Pan Emerging Country Contract Research Organisation

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmac

Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group

Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting

Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai)

Stefan Astrom, Founder and CEO of Astrom Research International HB

Steve Heath, Head of EMEA - Medidata Solutions, Inc

T S Jaishankar, Managing Director, QUEST Life Sciences

Editorial Advisory Board


Regulatory & Marketplace

Regulatory Scenario of Herbal Medicines: A Global ReviewAbstractIn the last few decades, there has been exponential growth in the field of herbal medicine. It is becoming popular in developing as well as in developed countries owing to its natural origin and lesser side-effects. The growing use of botanicals is forcing moves to evaluate the health claims of these agents and to develop standards of quality and manufacture. Regulation of herbal medicines is a key means of ensuring safety, efficacy and quality of herbal medicinal products. This paper aims to facilitate the registration and regulation of herbal medicines by establishing the foundation of a harmonised regulatory standard to meet common demands of a region. Herbal drugs regulations in India are discussed in detail, followed by an overview of the regulatory status of herbal medicine in the USA, Australia and Europe. An overview and a comparison have been laid out to highlight the similarities and differences.Key words: Herbal Medicine, Traditional Medicine, Alternative Medicine, Complementary Medicine.

Introduction Although modern medicine is well-developed in most of the world, large sections of the population in developing countries still rely on traditional practitioners, medicinal plants and herbal medicines for their primary care.

Traditional Indian medical systems such as Ayurveda and Unani also rely heavily on plant products, and in the United States it has been estimated that 30% of patients now use herbal remedies1, 2, 3. Herbal medicines, which formed the basis of healthcare throughout the world since the earliest days of mankind, are still widely used, and have considerable importance in international trade. Recognition of their clinical, pharmaceutical and economic value is still growing, although this varies widely between countries4. Medicinal plants are important for pharmacological research and drug development, not only when plant constituents are used directly as therapeutic agents, but also as starting materials for the synthesis of drugs or as models for pharmacologically active compounds. Regulation of exploitation

and exportation is therefore essential, together with international cooperation and coordination for their conservation so as to ensure their availability for the future5.

The legal situation regarding herbal preparations varies from country to country. In some, phytomedicines are well-established, whereas in others they are regarded as food and therapeutic claims are not allowed. Developing countries, however, often have a great number of traditionally used herbal medicines and much folk-knowledge about them, but have hardly any legislative criteria to establish these traditionally used herbal medicines as part of the drug legislation. For the classification of herbal or traditional medicinal products, factors applied in regulatory systems include: description in a pharmacopoeia monograph, prescription status, claim of a therapeutic effect, scheduled or regulated ingredients or substances, or periods of use. Some countries draw a distinction between "officially approved" products and "officially recognised" products, by which the latter products can be marketed without scientific assessment by the authority5.

The various legislative approaches for herbal medicines fall into one or other of the following categories5:

Same regulatory requirements for all products;

Same regulatory requirements for all products, with certain types of evidence not required for herbal / traditional medicines;

Exemption from all regulatory requirements for herbal / traditional medicines;

Exemption from all regulatory requirements for herbal / traditional medicines concerning registration or marketing authorisation;

Herbal / traditional medicines subject to all regulatory requirements; and

Herbal / traditional medicines subject to regulatory requirements concerning registration

or Marketing authorisation.

Where herbal medicines and related products are neither registered nor controlled by regulatory bodies, a special licensing system is needed which would enable health authorities to screen the constituents, demand proof of quality before marketing, ensure correct and safe use, and also to oblige license-holders to report suspected adverse reactions within a post-marketing surveillance system6.

ChallengesCountries face major challenges in the development and implementation of the regulation of traditional, complementary / alternative and herbal medicines. These challenges are related to regulatory status, assessment of safety and efficacy, quality control and safety monitoring. Challenges Related to the Regulatory Status of Herbal MedicinesBefore manufactured drugs came into widespread use, herbal medicines played an important role in human health. There are great differences between countries in the definition and categorisation of herbal medicines. A single medicinal plant may be defined as a food, a functional food, a dietary supplement or a herbal medicine in different countries, depending on the regulations applying to foods and medicines in each country. This makes it difficult to define the concept of herbal medicines for the purposes of national drug regulation, and also confuses patients and consumers.

Lack of Knowledge About Herbal Medicines Within National Drug Authorities:The general lack of knowledge about herbal medicines within national drug authorities and the lack of appropriate evaluation methods are factors that delay the creation or updating of national policies, laws and regulations for traditional medicines, contemporary / alternative medicines and herbal medicines.

In order to meet these challenges, the WHO Traditional Medicine Strategy was developed, with its four primary objectives: framing policy; enhancing safety, efficacy and quality; ensuring access; and promoting rational use.

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Resolution WHA56.31 on traditional medicine was adopted at the Fifty-sixth World Health Assembly in May 2003. The resolution requested WHO to support Member States by providing internationally acceptable guidelines and technical standards, and also evidence-based information, to assist Member States in formulating policy and regulations to control the safety, efficacy and quality of traditional medicines.

Herbal Drug Regulations in IndiaIn the Republic of India, the national policy on traditional medicine (TM/CAM) was introduced in 1940. National laws and regulations were also issued in 1940, and updated in 1964, 1970 and 1982. The national programme was issued in 1964. The national office, the Department of Medicine and Homeopathy, was established in 1995 as part of the Ministry of Health and Family Welfare.

Herbal drug products constitute a major share of all the officially recognised systems of health in India, viz. Ayurveda, Yoga, Unani, Siddha, Homeopathy and Naturopathy, except Allopathy. The IMCC (Central Council of Indian Medicine) Act, Research Councils Indian Council of Medical Research (ICMR), Council for Scientific & Industrial Research (CSIR), Department of AYUSH (Ayurveda, Yoga & Naturopathy, Unani, Siddha and Homoeopathy) and the Drugs and Cosmetics Act 1940 (Amendment) regulate herbal medicines in India. Herbal remedies and medicinal plants to be incorporated in modern systems (allopathic) must follow the Drug Controller General of India (DCGIs) regulations of the Central Drug Standard Control Organization (CDSCO). As per Drugs and Cosmetics Act 1940 amended in 1964, Ayurvedic, Siddha or Unani drug includes all medicines intended for internal or external use or in the diagnosis, treatment, mitigation or prevention of disease or disorder in human beings or animals, and manufactured exclusively in accordance with the Formulae described in the authoritative books of Ayurvedic, Siddha and Unani (Tibb) systems of medicine, specified in the First Schedule7.

Herbal medicines are regulated as prescription and over the counter (OTC) medicines and dietary supplements. Herbal medicines may be sold with medical, health and nutrient content claims. India has two multi-volume

national pharmacopoeias, the Ayurvedic pharmacopoeia of India and the Unani pharmacopoeia of India. Both are considered to be legally binding. Regarding national monographs, several sources are used, including a national database on medical plants used in Ayurvedic medicine and monographs contained in the national pharmacopoeias.

Recent amendments in Drugs and Cosmetics (First Amendment) Rules 2008 have introduced Schedule T for recording utilization of raw materials by Ayurvedic or Siddha or Unani licensed manufacturing units. Drugs and Cosmetics (Second Amendment) Rules 2008 permitted the use of excipients given in the Indian Pharmacopoeia or Bureau of Indian Standards Act 1986 or the Prevention of Food Adulteration Act 1954 and Food Products Order for use in Ayurvedic, Siddha and Unani drugs. Good clinical practice (GCP) guidelines published by ICMR also pertain to traditional drugs. According to these guidelines, traditional herbal medicines have been classified into three groups: 8

1. Traditional herbal drugs as per classical texts, regular use and prescribed pharmacopoeia

Reverse pharmacology approach2. Traditional formulations for a new

indication / new process / new combination / new herbal- or plant-based new chemical entity (NCE) acute, sub-acute and chronic toxicity data to be generated (Schedule Y of Drugs & Cosmetics Act, 1940)

3. Formulations GMP-compliant Standardization Department of AYUSH, ICMR and CSIR

Work together to achieve safe, effective AYUSH products for the identified diseases and to develop new drugs.

No control mechanism is used for these requirements, as the long-standing use of herbal medicines in the Ayurveda, Unani and Siddha systems demonstrates their safety for human use. There are 4246 registered herbal medicines. Essential drug lists exist separately for the three systems of traditional medicine in India; the Ayurveda list has 315 herbal medicines on its essential drug list, the Unani list has 244 herbal medicines and the Siddha list has 98. These lists were issued in 2000 and 2001 respectively.

There are currently plans to establish a post-marketing surveillance system. In India, herbal medicines are sold in pharmacies as prescription and over the counter medicines, in special outlets, by licensed practitioners and without restriction. Annual herb sales figures, based on sales of 162 medicinal plants between 1999 and 2000, were estimated at 6705 million Indian rupees (US$ 149 million)9.

AYUSH objectives are to control drug quality, laying down pharmacopoeial standards, overseeing working of the Pharmacopoeial Laboratory of Indian Medicines (PLIM), partnership with the Quality Council of India (QCI), and to oversee functioning of the Indian Medicine Pharmaceutical Company Limited (IMPCL). AYUSH also controls enforcement of good manufacturing practices (GMP), setting up of common facilities following the cluster approach and implementing the scheme for drug quality control. With the advent of an intellectual property rights (IPR) regime, AYUSH department has also started digitalisation of traditional medicinal formulations, knowledge and manuscripts, and documentation and promotion of local health traditions.

The National Medicinal Plants Board (NMPB), Department of AYUSH has prepared India-specific guidelines on good agriculture practices (GAPs) on the pattern of good agriculture and field collection practices (GAFCPs) developed by the WHO for medicinal plants. In the preparation of this standard, assistance has been taken from GAFCPs developed by the WHO in 2003 and good agricultural practices enunciated by the GlobalGAP Secretariat, which is being implemented in over 80 countries. The standard provides requirements for good field collection practices on different aspects for harvesting and post-harvest management of medicinal plants. Adoption of organic and good agriculture and collection practices is expected to lead to better resource management by sensitising farmers, growers and other stakeholders.

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EDINBURGH BIOQUARTER

INSPIRING LOCATIONEdinburgh BioQuarter is an academic medical centre with a focus on interdisciplinary research and translational medicine, with particular strengths in regenerative medicine and connected health.

Edinburgh BioQuarter is an academic medical centre with a Edinburgh BioQuarter is an academic medical centre with a focus on interdisciplinary research and translational medicine, with focus on interdisciplinary research and translational medicine, with

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Applicable laws:Drugs and Cosmetics Act, 2008 (DCA)Drugs and Cosmetics Rules, 1945 (DCR)Drug (Prices Control) Order, 1995Drugs (Magic Remedies) Objectionable Advertisement Act, 1954Pharmacy Act, 1948.Marketing Authorisation Approval ProcessA flowchart for the process is shown in Figure 1.

Herbal Drug Regulations in Australia:They are termed as complementary medicines (also known as 'traditional' or 'alternative' medicines) and include vitamin, mineral, herbal, aromatherapy

and homoeopathic products. Complementary medicines may be either listed or registered, depending on their ingredients and the claims made.

Australia has a risk-based approach, with a two-tiered system for the regulation of all medicines, including complementary medicines:

Lower-risk medicines can be listed on the Australian Register of Therapeutic Goods (ARTG).

Higher-risk medicines must be registered on the ARTG.

Some complementary medicines are exempt from the requirement to be included on the ARTG, such as certain preparations of homoeopathic medicines10.

Eligibility for Registration as a Complementary Medicine:Before submitting an application for registration of a complementary medicine, it is first necessary to establish that the product contains substances that are, in fact, complementary medicine substances.

Essentially, if the substance is a designated active ingredient, that has an established identity and tradition of use, it is a complementary medicine substance. The Office of Complementary Medicines (OCM) also evaluates excipients that are used in complementary medicines and substances referred to the OCM by other regulatory areas in the TGA.

Route of Evaluation and the Registration Process:

Applications for the registration of complementary medicines are made via the Overthe Counter Medicines Electronic Lodgement System (OPAL) and the dossier is sent to the OCM. After the appropriate fees are paid, applications pass through four or five phases: preassessment, evaluation and peer review, possible consideration by the Advisory Committee on Complementary Medicines (ACCM), decision and, if acceptable, implementation.

Preassessment involves a brief review of the application data to determine whether the application is eligible for evaluation by the OCM. The preassessment process also determines whether the appropriate fees have been paid and whether key data have been provided. Applications passing preassessment move to the evaluation phase. The submitted data are evaluated and a report of the findings is prepared. Evaluation reports are reviewed within the OCM to ensure consistency in evaluation. Comment may be sought from the ACCM which may make a recommendation to the Delegate of the Secretary of the Department of Health and Ageing. The Delegate assesses the evaluation report and any ACCM recommendations before deciding on the application.

Relevant Regulatory Requirements:A number of important regulatory requirements relate to applications for registration of complementary medicines, including the following:

1. The Therapeutic Goods Act 19892. The Therapeutic Goods Regulations

19903. Therapeutic Goods Orders (TGOs)4. The Therapeutic Goods Advertising

Code (TGAC)

Registration:1) Lodgement:Applications for new registered complementary medicines are lodged electronically using the online application system currently used for registered OTC medicines. The submission of the data dossier remains the same the applicant is still required to submit a hard copy of the dossier to the OCM.

2) Pre-assessment of Registration Applications:There are three possible outcomes of the



preassessment process:

The Therapeutics Good Administration (TGA) may reject the application if there are profound deficiencies, if no fees have been paid, if the medicine is not a complementary medicine or if the medicine is required to be in the Register for Listed Goods.

The TGA may grant conditional acceptance where additional fees or additional significant information is sought and the evaluation cannot proceed until the fees are paid or the information is supplied.

The TGA may accept the application where there are no obvious deficiencies, or only minor deficiencies that are not considered significant enough to prevent evaluation, and all fees are paid. The application then proceeds to the evaluation stage.

3) Evaluation:In the evaluation stage, the quality, safety and efficacy of the product are critically evaluated and an evaluation report is produced.4) Advisory Committee for Complementary Medicines (ACCM):

The ACCM is constituted under Regulation 39 of the Regulations. Evaluation reports on most registration applications for complementary medicines are presented to the ACCM for consideration and recommendation to the TGA. Sponsors have the opportunity to provide written comment on the evaluation report prepared by the OCM. Sponsors will be sent a copy of the evaluation report and must respond within the given timeframe (usually five working days).

5) Finalising Registration Following ACCM Consideration:Recommendations from the ACCM and any other recommendations or information from the TGA will be taken into consideration by the appointed delegate of the Secretary of the Department of Health and Ageing. The delegate will make a decision on the application.

A letter will be sent, formally advising the sponsor of the outcome of the application. If there are any conditions placed on the registration of the new complementary medicine, the sponsor will be notified of them and they will be

discussed with the sponsor.

The Australian Register of Therapeutic Goods (ARTG) entry on the provisional record will be amended, if necessary, and the letter and its attachments will be sent to the sponsor. The sponsor will then advise the TGA of any necessary corrections to the provisional record and return the letter and its attachments to the ARTG entry officer, who will then issue a final certificate of Registration11 as in Fig 2.

Herbal Drug Regulations in the EU:According to Council Directive 65/65/EEC, which has been implemented into national law in all Member States, medicinal products require prior marketing approval before gaining access to the market. In almost all Member States, herbal medicinal products are considered as medicinal products. As such they are in principle subject to the general regulations for medicines as laid down in the various national medicines laws. This definition is in line with the EU Guideline "Quality of Herbal Remedies" (now replaced by "Quality of Herbal Medicinal Products"). It includes plants, parts of plants and their preparations, mostly presented with therapeutic or prophylactic claims. Different categories of medicinal products containing plant preparations exist or are in the process of being created. For instance, draft legislation in Spain includes the definitions herbal medicinal products and phytotraditional products. The latter are however not considered as pharmaceutical specialties and

are therefore not classified as herbal medicinal products12.

European Directive 2004/24/EC has taken full effect on 30th April 2011; it is illegal for companies to sell manufactured unlicensed herbal medicines within Europe without the appropriate licence i.e. a marketing authorisation (MA) or a traditional herbal registration (THR).

The UK differs slightly from the rest of Europe in that herbal practitioners were regulated as from April 2012, allowing for unlicensed manufactured herbal medicines to be prescribed following a face-to-face consultation.

There are several different routes to market for herbal products within Europe:

Food (functional food, novel foods, dietary food for special medical purpose, foods for particular nutritional use PARNUTS, food supplement),

Cosmetic, Traditional herbal medicinal product

(THMP), Medicine for human use (well-

established use, full marketing authorisation), or

Veterinary product.

It is important, therefore, to determine the classification of the herbal product (13).Registration:Two Routes to Market:a. Marketing Authorisationb. Traditional Registration

a. Marketing Authorisation:To market a product as a licensed medicine with approved indications.

Requirements are: Product quality Product safety Product efficacy (clinical studies)

of international standards14.

b. Traditional Registration Under THMPD (Traditional Herbal Medicinal Products):To market a product under the EU Directive 2004/24/EC on traditional herbal medicines that came into force on 30th April 2004, the Directive provides a section below the "well-established medicinal use" area comprising those medicinal products with indication claims for relatively slight diseases and defined dosage levels and methods of administration, and which are of sufficient



pharmaceutical quality and proven safety. The efficacy must be plausible on the basis of long-standing use and experience. The time period of tradition must be at least 30 years within the EU, and products from outside the European Union must prove at least 15 years within Europe. The Directive is also eligible for combinations of herbal and certain non-herbal components, e.g. vitamins and minerals, provided that the action of the vitamins or minerals is ancillary to that of the herbal active ingredient. Any labelling and advertisement has to contain a statement that the efficacy and safety of the product are exclusively based on information from long-standing use and experience.

In addition, the Directive provides the establishment of the Committee for Herbal Medicinal Products (HMPC) within the European Agency for the Evaluation of Medicinal Products (EMA) consisting of one representative from each EU Member State. The former Herbal Medicinal Product Working Party (HMPWP) was "upgraded" in this direction. The new committee carries out tasks related to the "well-established medicinal use" in the "normal" marketing authorisation procedure as well as to traditional herbal medicinal products within the simplified registration procedure. Its tasks furthermore relate to establishing Community monographs in these two areas as well as to set up a "European tradition list".

The "traditional" registration procedure therefore offers an additional option for herbal medicinal products as an alternative to "well-established medicinal use"15.

Requirements are: Product quality Product safety Evidence of traditional use

Simplified registration procedure for herbal products which fulfil the following criteria:

Use without supervision of medical practitioners

Specified strength Oral/external or inhalation only Evidence of traditional use Traditional use shows it is not

harmful.

In brief the QUALITY parameters for all

herbal products will be more or less the same in both the marketing authorisation and THMPD registration, with the exception of demonstrating efficacy as this is replaced by the historical / traditional use of the products in THMPD 14.

Herbal Drug Regulations in the US:Herbal medicines are not regulated as drugs in the United States, but they are given special status as dietary supplements, along with vitamins, minerals, other nutritionals, and homeopathic and Ayurvedic remedies 16.

The Dietary Supplement Health and Education Act (DSHEA) of 1994 classifies herbs as dietary supplements. This law defines supplements quite broadly as anything that supplements the diet. 17.

DSHEA states botanicals can be labelled and advertised as having certain healthy or nutritional properties as long as no therapeutic claim is made. Those botanicals making a therapeutic claim can be approved as drugs by the USFDA. The Food and Drug Administration (FDA) has published specific guidelines for industries manufacturing such botanical drug products. These guidelines explain when a botanical drug may be marketed as an OTC drug and when FDA approval of the new drug application is required for marketing. It provides guidelines for submitting an investigational new drug (IND) application for botanical drug products, including those botanicals currently lawfully marketed as foods and dietary supplements in the United States18 as in Fig 3.

Marketing Authorisation:In the USA, the Food Drug and Cosmetics Act characterises a product primarily on the basis of its intended use. For a botanical product, this intended use may be as a food (including a dietary supplement), a drug (including a biological drug), a

medical device (e.g., gutta-percha) or a cosmetic, among other things. It takes into account the products accompanying labelling claims, advertising materials, and oral or written statements (21 Code of Federal Regulations (CFR) 201.128) (Food and Drug Administration (FDA), 2000).

For products classified as drugs, the FDA regulates them under the authority of the Food Drug and Cosmetics Act and its amendments. Under current regulations, if there is no marketing history in the USA for a botanical drug product, if available evidence of safety and effectiveness does not warrant inclusion of the product in an existing, approved category of OTC (over-the-counter) drugs, or if the proposed indication would not be appropriate for non-prescription use, the manufacturer must submit a new drug application to obtain FDA approval to market the product for the proposed use. If existing information on the safety and efficacy of a botanical drug product is insufficient to support a new drug application, new clinical studies will be needed to demonstrate safety and effectiveness.

The DSHEA extended the definition of dietary supplements beyond vitamins and minerals and established a formal definition of a dietary supplement using new criteria. The Congressionally-mandated Commission on Dietary Supplement Labels (CDSL) suggested that some botanicals may qualify as OTC products under existing statutes; these state that a product may avoid new

drug premarket approval requirements and may be eligible for marketing under an OTC drug monograph if the product is generally recognised as safe (GRAS) and effective under the conditions for use for which it is labelled, and if the product has been used to a material extent and for

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a material time under those conditions. The FDAs response to the Commission stated that it does not regard marketing experience outside the USA to meet conditions of historical use.

Most botanical products in the USA are marketed as dietary supplements. Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), an orally ingested product that meets the definition of a dietary supplement under section 201(ff) of the Food Drug and Cosmetics Act may be lawfully marketed using a statement that:

1. Claims a benefit related to a classical nutrient deficiency disease (and discloses the prevalence of the disease in the USA);

2. Describes how the product is intended to affect the structure or function of the human body;

3. Characterises the documented mechanism by which the product acts to maintain such structure or function;

4. Describes general wellbeing derived from consumption of the product (section 403 r (6)(A) of the Food Drug and Cosmetics Act, 21 U.S.C. 343 r6(A))19.

Under DSHEA, if dietary supplements contain new dietary ingredients that were not marketed in the United States before October 15, 1994, the FDA is required to be notified by the manufacturer or distributor at least 75 days before they are marketed (this differs dramatically from what the FDA requires for pharmaceuticals, a product category that has more restrictive regulatory oversight). However, the criteria for approval of herbal mixtures as medicines have started to relax from this requirement. In June 2004, the FDA issued new guidelines allowing the approval of herbal mixtures if they are shown to be safe and efficacious.

According to FDAs Guidance for Industry Botanical Drug Products, botanical drugs are derived from vegetable matter and are usually prepared as complex mixtures. Their chemical constituents are not always well-defined. In many cases, the active constituent in a botanical drug is not identified, nor is its biological activity well-characterised. Therefore, the chemistry, manufacturing and controls (CMC) documentation that should be provided for botanical drugs will often be different from that for synthetic or highly-

purified drugs, whose active constituents can be more readily chemically identified and quantified.

Because of the complex nature of a typical botanical drug and the lack of knowledge of its active constituent(s), the FDA may rely on a combination of tests and controls to ensure the identity, purity, quality, strength, potency, and consistency of botanical drugs. These tests and controls include:

1. Multiple tests for drug substance and drug product (e.g., spectroscopic and/or chromatographic fingerprints, chemical assay of characteristic markers, and biological assay)

2. Raw material and process controls (e.g., strict quality controls for the botanical raw materials and adequate in-process controls)

3. Process validation (especially for the drug substance).

In October 2006, the FDA approved the first such herbal mixture under the new guidelines, which was developed by the German company MediGene for treating genital warts16.



Comparison of regulations, major legislation and categories of India, Australia, the EU and the US is shown in Table 1.

ConclusionHerbal medicine has become a topic of increasing global importance, with both medicinal and economic applications. European regulations are most comprehensive among most of the global regulations for herbal medicinal products. The FDA guidelines on botanical drug products established OTC drug and new drug application (NDA) parallel routes close to the route followed for a synthetic new chemical entity. Indian regulations are also developing vis a vis global regulations for herbal drug products. Indian regulations are still at a nascent stage when compared to the regulations of Europe and the US. Harmonisation of regulations, like that in European countries, could overcome the barrier for efficient trade as well as uniform standards for herbal medicinal products.

References1. Chan K. Some aspects of toxic

contamination in herbal medicines. Chemos 2003; 52:136171.

2. Ernst E. Serious adverse effects of unconventional therapies for children and adolescents: a systematic review of recent evidence. Eur J Pediatr 2003; 162:7280.

3. Chan TYK, Chan JCN. Chinese herbal medicines revisited: a Hong Kong perspective. Lancet 1993; 342:15324.

4. Jayasuriya DC. A review of legislation concerning medicinal plants. 1990

5. Jayasuriya DC. The regulation of medicinal plants - a preliminary review of selected aspects of national legislation.

6. DeSmet PAGM. Should herbal medicine-like products be licensed as medicines? British Medical Journal 1995;310:1023-1024.

7. Drugs and cosmetics (first and second amendment) rules 2008. Ministry of Health and Family Welfare, Govt. of India.

8. ICMR, Ethical guidelines for biomedical research on human participants. Director-General, Indian Council of Medical Research, New Delhi, 2006.

9. National Policy on Traditional Medicine and Regulation of Herbal Medicines - Report of a WHO Global Survey 2005; 168 pages.

10. Australian Government, Department of Health, Complementary medicines. Available at: http://www.tga.gov.au/industry/cm.htm

11. Australian Government, Department of Health and Ageing Australian Regulatory Guidelines for Complementary Medicines (ARGCM) Part I: Registration of Complementary Medicines Version 4.2, August 2011. Available at: http://www.tga.gov.au/pdf/cm-argcm-p1.pdf

12. European Commission, Volume 2A Procedures for marketing authorization, Chapter 1, Marketing Authorization, June 2013. Available at: http://ec.europa.eu/health/files/eudralex/vol-2/a/vol2a_chap1_2013-06_en.pdf

13. Tai-Ping Fan, Greer Deal, Hoi-Lun Koo, et al. Future development of global regulations of Chinese herbal products. Journal of Ethnopharmacology. 2012; 140(3):568-586. Available at: http://www.sciencedirect.com/science/article/pii/S0378874112001134

14. Gunawant D. Regulatory Requirements For

Marketing Of Ayurvedic Products (Herbal) In Europe. Available at: http://www.ayurveda.hu/2007102628conf_arogya/speech%2015%20%20regulatory%20requirements%20for%20marketing%20of%20ayurved.pdf

15. Herbal medicinal products in Europe. Available at:http://.bah-bonn.de/index.php?id=722. Accessed September 22, 2013

16. Liu F, Salmon JW, PhD. Herbal Medicine Regulation in China, Germany, and the United States, Integrative Medicine. 2010; 9(5):54-61

17. Bent S. Herbal Medicine in the United States: Review of Efficacy, Safety, and Regulation, J Gen Intern Med 23(6):8549.

18. Warude D and Patwardhan B. Botanicals: Quality and regulatory issues. Journal of Scientific and Industrial Research. 2005; 64:83-92.

19. ARC monographs. Volume 82. Available at: http://monographs.iarc.fr/ENG/Monographs/vol82/mono82-6A.pdf

T. M. Pramod Kumar - Professor & Head of Department of Pharma-ceutics, JSS College of Pharmacy, JSS Univer-sity, Mysore. Email: [email protected]

Shilpi Khattri - Ph.D. Research Scholar, Reg-ulatory Affairs, JSS College of Pharmacy, JSS University, Mysore. Email: [email protected]

Balamuralidhara V. - Assistant Professor, Department of Pharma-ceutics, JSS College of Pharmacy, JSS Univer-sity, Mysore. Email: [email protected]

Vandana K. is a Regu-latory Affairs Executive in Liquent Parexel, Ban-galore. She has done her M. Pharma (Reg-ulatory Affairs) and B. Pharma from JSS Uni-versity, Mysore. Email: vandu.kshatri@

gmail.com

Table 1: Comparison of regulations, major legislation and categories of India, Australia, the EU and the US

INDIA AUSTRALIA EU US Regulatory agency CDSCO TGA EMA FDA Major legislation or guidance documents

Drugs and Cosmetics Act 1940 & Drug and Cosmetic Rules 1945

AustralianRegulatory Guidelines for Complementary Medicines(ARGCM)

European Union Directive2004/24/EC

Guidance for Industry Botanical Drug Products

Category where herbal products can be registered

Herbal medicines Complementary Medicine

Traditional Herbal MedicinalProducts,Prescription or OTC drugs

Botanical Drug Products(food/drug/medical device/cosmetics)

Mutual recognition No No Yes (for EU Member States only)

No

Uniqueness Herbal medicines are regulated as prescription and over the counter medicines and dietary supplements.

Level of evidence in supporting efficacy and safety; Early market access for low-risk complementary medicines through Listed medicine system (two-tier system)

30/15 years of traditional use; Benefit-riskmethodology

Clinical trials in the USrequired despite traditional use history; Marketing under OTC Drug Monograph versus Approved NDA

Pharmacopoeia Ayurvedic pharmacopoeiaand the Unani pharmacopoeia

BritishPharmacopoeia

EuropeanPharmacopoeia

United States Pharmacopeia (USP)



The Interim Exec Community calls for a Conscious Coupling of RPOs and Interims SpecialistsPharmaceutical companies have widely adopted strategies to outsource elements of their business operations, as part of an ongoing drive to deliver a more flexible model that unlocks cost efficiencies and alleviates some aspects of risk associated with drug development. Recruiting talent is one such element. However, pharma companies should be wary of saving on recruitment at the risk of missing out on the best candidates, particularly when it comes to senior staff. Director of Interims of RSA, Dafydd Wright, explains.

Volume recruitment relies on reducing risk through the use of IT systems and (often) subcontracted manpower to drive candidate attrition. Bespoke hiring at executive level uses a relationship-driven, knowledge- and networking-led approach.

The emergence of the recruitment process outsourcing (RPO) provider field has seen a downward shift in the quality of the talent acquisition process, often criticised by expert recruiters and candidates alike, because RPO services

are first designed to drive down cost per hire, without addressing how quality of hire will be maintained or improved in the new process.

Pharmaceutical companies have an opportunity to address this to their own competitive benefit through demanding the utmost from their RPO provider to adopt a balanced approach to talent acquisition. This will require greater visibility on which subcontracted recruiting firms the RPO will seek to engage with downstream and pharma clients need to drive home a pharmaceutical industry message that there is an expectation of working with expert recruiters as well as volume recruiters within the service model.

This will benefit all levels of the hiring process, including interim management, drive better PR understanding of the hiring organisation's key qualities, leave successful and unsuccessful candidates alike with a sense of satisfaction beyond the process, and create a talent pull that will drive future hiring programmes.

Critically, pressure for this change is coming from the interim executive community of candidates and providers.

Interim executive firms are not designed to and simply do not want to wade through mountains of job vacancies to identify the one relevant and available interim role. Neither do they want to sign up to preferred supplier agreements constructed for high-volume business models. Therefore they avoid positioning their services alongside the 50 or more recruitment firms that bear no resemblance to their core services for fear of a branding disaster. Most importantly, they do not want to lose sight of what matters direct discussions with senior management to understand exactly what the client needs from the interim, what success looks like, and how an interim executive will add value.

Interim candidates mirror these sentiments; they want relationship-driven outcomes and interesting projects to discuss their skillsets against something that is lacking in standard RPO setups.

At present, pharmaceutical industry

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adoption of the standard RPO model has led to a separation of the suppliers, which fails to add value for all; and ultimately wastes valuable time. Let us examine a pivotal case study.

A medium-sized pharmaceutical organisation with a long-term established RPO needed a middle- to senior-management marketing specialist, with projects ranging from pre-launch to lifecycle management. The interim requirement was circulated across 10 to 50 firms registered with the RPO and failed to deliver. The client subsequently engaged with a specialist executive interims firm directly. That firm restarted the discussion, understood the requirements and identified the "right" candidate. A few days later a service agreement was put into effect.

Were the specialists at the executive interims firm just better at finding good candidates? Not in this case.

Ironically, the "right person" had already been contacted for this project and submitted to the client under the RPO. However, under the volume process, the client had declined interest in the candidate. When asked why, they said the sub-supplier feedback had been sparse and incorrect representations had been made for the candidate. In contrast, the executive interims firm was able to rapidly get this individual in front of the client, with the right message of endorsement.

Had the RPO process allowed for

person-to-person communication, as opposed to an IT-led system, they would have been directed to the right person at the right time, with the right outcome for the client and for the RPO.

This example demonstrates fundamental differences in strategy to access top-tier talent. Business-critical solutions that rely on interim executive services only through mainstream RPOs are often doomed to failure; and when RPO providers address key performance indicators (KPIs) with their clients, these failings are easily lost in the volume of everyday recruiting metrics. Pharmaceutical businesses must instruct their RPOs to consider engaging specialists, for their own benefit and for that of their client.

A voice of choice is emerging from the interim executive community and this is as encouraging as it is concerning. Online forums are rife with gripes about volume-led/RPO approaches. Ask any interim candidate how appreciated they feel when the first question tabled is one of price; or when they are rejected at the first hurdle because the dialogue centres on, "But my client's maximum rate is[not enough]".

One recent conversation with an executive-level interim candidate centred on the fact they simply did not wish to be represented by a recruiting firm whose brand was more aligned to volume recruiting and that relied on weekly timesheet reporting requirements that

were built for unskilled or semi-skilled use.

Interim executives take immense pride in the services they deliver, whom they deliver them to and the types of projects they see as attractive. They naturally seek commercial terms that reflect the value they will provide. So the service approach should be to understand the services an interim is prepared to deliver, the skills they bring, and how the value adds up against their proposed rate which is often something that cannot be defined until a first meeting (post-endorsement) with the client, and is not something the standard RPO model can bring to their pharmaceutical clients.

Interim executives appreciate honest and knowledgeable discussions on behalf of pharmaceutical clients, and when using qualified interim executive partners, pharmaceutical clients will see an uplift in quality and hence value, represented overall as better hits on target and a reduction in time to engage.

Informed decision-making is about choice through excellent market intelligence. The pharmaceutical industry is in an ideal position to engage in proactive communication with their current and future RPO providers to require inclusion of specialist firms alongside generalists, as there is strength in variety. There will be differences in how to engage the two, but the model will evolve through client demand, pushing for value-led conversations between specialist recruiters and RPO firms to create valuable outcomes for all involved.

Dafydd Wright is an award winning lead-er in Interim Manage-ment specialising only in the pharmaceuti-cals and life science sectors. He favours a people-orientated, consultative approach which focuses on in-

terim management as a solution rather than a fill-in. Dafydd has a degree in Applied Microbiology and has worked and lived in the UK and Finland. Email: [email protected]

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The 3E Principle: Key Considerations for Selecting and Outsourcing to a Vendor

AbstractInfluenced by forces such as macroeconomics, politics, regulations, population growth and aging, there has been a major shift in the way biopharmaceutical companies conduct business. There is ever increasing pressure to comply with evolving regulations along with cost reductions in order to grow business. As companies expand their product portfolios into new geographies, regulatory scrutiny along the entire product lifecycle has seen a substantial increase, with all areas of the business being affected. The result of this is that the volume of outsourcing done by the biopharmaceutical companies has significantly increased.

This paper will outline the The 3E Principle of Effectiveness, Efficiency and Economics, which are key parameters organisations should consider when selecting an outsourcing partner to assist with knowledge-based activities in drug development and post-marketing stages of the product lifecycle. The 3E Principle will be considered for each of the following service areas: safety and risk management (SRM), scientific writing, regulatory affairs and statistics and programming.

The article will focus on the overall trends currently seen in outsourcing, and will demonstrate that the 3E Principle applies differently to each service area, and the drivers differ based on the size of the company, i.e., whether it is a mid to large or small business. It will conclude that those biopharmaceutical companies who outsource have a number of varying priorities, and the challenge that is of vital importance is for the outsourcing vendor to have the ability to deliver results effectively against the companys strategic objectives.

Selecting the right vendorWhen selecting and subsequently outsourcing to a partner organisation, there are a number of different questions and considerations that are required to be made. These are dependent on the requirements and strategy of the

sponsor organisation, as well as what is being outsourced. Businesses must ensure that they are considering all the relevant factors and prioritising them appropriately when looking to contract work to external partners.

Market Shifts Produce Changes in Outsourcing StrategyThe reasons for outsourcing now go far beyond labour arbitrage, which used to be seen as the core reason for using an outsourcing partner. Todays biopharmaceutical companies conduct their business very differently from their predecessors they are much more influenced by macroeconomics, politics, regulations, population growth and aging, as well as the flattening of the globe. This range of factors each provides its own set of opportunities and challenges which need to be assessed.

The challenges presented to companies in the current market cannot be ignored. Companies are expanding their product portfolios and moving into new geographies, each with their unique nuances. Drug discovery and development are becoming more complex and resource-intensive, despite increased automation and advanced technologies, and there is enhanced focus on biologics. Regulatory scrutiny throughout the product lifecycle has substantially increased fuelled by recent scares around product safety and a consequent increase in public and government awareness. We regularly hear about mergers and acquisitions, layoffs and facility closures, and with an increasing generics market, there is now more competition within the sector than ever before. Due to patent cliffs, pharmaceutical innovators took an anticipated loss of approximately $78 billion between 2009 and 20141.

Thanks to the new challenges presented in todays marketplace, no corner of the biopharmaceutical business, regardless of the geography, is immune from the pressure to both increase the compliance and quality of products, while simultaneously improving on

productivity and making significant cost cuts. Achieving this is a difficult balance, and established companies, along with smaller new entrants, are looking for new and innovative ways to manage their businesses in this new environment.

Expanding product portfolios and moving into new geographies allows biopharmaceutical companies to continue to compete within the growing global marketplace. However, having a portfolio of products on the market across multiple regions means organisations must comply with the differing requirements of multiple regulatory agencies. This requires significant time and people hours, and may also contribute to compliance issues due to lack of understanding or adherence to all applicable regulations.

The strategies companies adopt to manage this expansion are diverse and can include captive centres, joint ventures with global outsourcing companies, expanded use of full-service clinical research organisations (CROs) and functional service providers (FSPs), use of diverse geographies, and any other creative approaches companies can envision one example being a build-operate-transfer, or BOT model.

Through the increased use of external vendors for execution of such strategies, companies can focus and dedicate their internal staff and resources to their core business of developing biopharmaceutical products.

The 3E PrincipleThe 3E Principle considers the all important whys of doing business with partners - Effectiveness, Efficiency, and Economics. While every company has its own specific set of priorities, these principles can be broadly applied for effective decision-making when utilising and selecting an outsourcing vendor. In each case, the relative importance of these three principles also differs by the function that is being outsourced, i.e., safety vs writing vs statistics, etc.

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Effectiveness. Effectiveness comprises the delivery of quality and regulatory compliance in a manner that is consistent and reliable. This can often be a challenge for a sponsor company, due to the large volume, magnitude and variety of tasks and functions involved, together with the need to adapt processes constantly in a dynamic, global regulatory landscape. Selecting specialist partners, who focus on specific areas and continually learn and adopt, facilitates the desired level of effectiveness.

Efficiency. Efficiency is defined as the ability to manage peaks and troughs in workload with minimal impact on productivity and cost. This includes streamlining processes and implementing LEAN methodology to drive process efficiencies, leading to gains that are then transferred to the sponsors. Specialised outsourcing partners provide just-in-time resources in fully outsourced or hybrid models.

Economics. Managing labour costs is an important reason for outsourcing and off-shoring, but it must be ensured that it is delivered without compromising quality and compliance. The goal is to select outsourcing partners who can absorb employee overhead and chase cost-effective geographies on an ongoing basis for access to an expanded talent pool. This provides scale and skill in a seamless manner, while maintaining the economic advantage.

Safety and Risk ManagementWithin drug development and marketing, patient safety is the most important factor to consider. Regulatory reporting compliance is critical for each reportable adverse event and each aggregate safety report, as well as compliance with company standard operating procedures (SOPs) and all applicable regulations. The pharmacovigilance function tends to be most scrutinised by regulators, and any non-compliance can lead to serious consequences. Changes in the drug development process, globalisation and the dynamics of collaboration in the biopharmaceutical industry lead to evolving regulations for safety reporting in many regions of the world. Having the correct knowledge and expertise and keeping on top of a dynamic regulatory landscape is thus crucially required and

hence effectiveness - the first E - is the primary requirement of any outsourcing partner.

When it comes to mid to large pharmaceutical companies with sizeable portfolios, the impact of volume fluctuations on resource needs is not high. Process and productivity improvements are expected on an ongoing basis given the nature of the business, and these are important. Overall, however, efficiency ranks lower than effectiveness as part of the decision to outsource and vendor selection.

In many cases, cost reduction is a major consideration when mid to large pharma companies decide to outsource safety operations, especially post-marketing spontaneous reporting, given the high volumes to be processed. Increasingly, this has been achieved by outsourcing safety operations and retaining the strategy in-house. Though the entire area of safety and risk management (SRM) has been traditionally seen as a core function and hence retained in-house, with the sheer volume of reports to be processed, this method is seen as the most effective strategy. Risk is sometimes minimised by outsourcing only single-case processing while retaining aggregate safety reporting and safety surveillance in-house. Some companies may also choose to outsource to multiple providers and may outsource a subset of cases, for example literature cases, separately, where the risk and impact of failure are low.

However, small companies tend to be highly risk-averse since they have much more riding on a handful of molecules or products under development. On the other hand, many also dont have the ability or the resources to set up safety operations in-house. This leaves no option but to outsource, but they often do so to established near-shore providers rather than looking offshore. Another option is to use the same full-service CRO for safety that they use for clinical development. Cost reduction is not typically as important a consideration for such companies, but in recent years more have started to choose offshore partners. This is due to the increased prevalence of delivering safety services in a globally distributed model throughout the sector.

For the risk management part of SRM and for other safety activities that, though resource-intensive, also require significant

domain expertise (e.g., writing periodic safety update reports and performing signal identification and analysis, running patient registries as part of risk management plans), effectiveness and efficiency feature higher than economics when outsourcing decisions are made. Though there was previously a tendency to consider these as core activities and keep them in-house, the growing volume of work in this area, due to the evolving regulatory requirements and availability of the right skills and expertise (e.g., with scientific process organisations (SPOs), who make it their business to deliver domain-intensive services in safety surveillance and risk management) has led to the outsourcing and offshoring of some of these activities as well.

Scientific WritingScientific writing can compromise many different areas, from safety writing (aggregate reports, etc), clinical writing (clinical study reports, protocols, investigator brochures etc.) and regulatory writing (sections of the common technical document (CTD) involving clinical and non-clinical overviews and integrated summaries of safety and efficacy) to the preparation of medico-marketing literature, such as product toolkits and manuscripts for publications.

There are clear differences between these writing categories, but for scientific writing the main factor is having adequate time and resources available when they are required. Delivering on regulatory reporting compliance or meeting publishing schedules often requires working to very tight deadlines. Thus, efficiency is the main driver for outsourcing of scientific writing work and is a major criterion for partner selection. In todays environment, economics comes in second, and effectiveness is the third principle that plays a role.

Regulatory AffairsDue to an increasing industry focus on the gradually evolving and perhaps not well-defined local regulations in developing/emerging markets, companies must have crucial access to intellectual property in regulatory affairs related to these markets and the specific countries in question. In this case, effectiveness, efficiency and economics are all crucial considerations, but perhaps are prioritised slightly differently depending on the activity.

Pharmaceutical operators aiming to achieve operational excellence in the face of increasing cost pressures and drives to cut downtime, increase operational reliability and efficiency, often require expert assistance. ABB Consulting offer expertise in: inspection, integrity management, operations improvement, process safety, projectservices, site and asset closure, technical engineering, technical software, technicaltraining and competency. We benefit customers by reducing risk, optimising cost and improving manufacturing efficiency. www.abb.com/consulting

ABB ConsultingTel: +44 (0)1925 741111E-mail: [email protected]

ABB Consulting. Safe, reliable, efficient operations.

IPT - Innovations in Pharmaceutical Technology (A4) Mar 2014.indd 1 10/03/2014 15:29:21



For example, in process-oriented activities such as dossier compilation and submissions, together with product labelling, efficiency is most important, followed by effectiveness and then economics. Alternatively, for small companies, access to the required expertise (for regulatory strategy) and the required processes and technology (for dossier submission and product labelling) is the main requirement. Thus effectiveness is most important, followed by efficiency and then economics.

Statistics and ProgrammingAlthough statistics and programming are of

IPI - Volume 6 Issue 3 - Sept 2014

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