Biomarkers of Drug-Induced Liver Injury

Issue 17 2012

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Biomarkers of Drug-Induced Liver Injury An update on progress

In Association with

SAP ER P Implementation & Validation Strategy in Pharma / Biopharma Business

Quality Challenges in Drug Delivery The role for quality by design and excipients

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First published September 2012.

Foreword Reducing Post-Marketing Drug Withdrawals Promise of new biomarkers Adverse effects of drugs can sometimes

the market. This has become the challenge for

outweigh their benefits. Exposure to a drug

agencies and authorities to assess the benefit-

may injure sensitive organs, particularly liver,

risk of stopping the drug.

the most important organ in drug toxicity. To date,

However, new biomarkers hold a lot of prom-

more than 900 drugs have been identified for

ise of reducing drug attrition rates and saving

causing liver injury. Withdrawal of safety-related

lives from drug toxicity.

drug marketing leading to drug failures is the

In the cover story of this issue of Pharma

main reason behind Drug-Induced Liver Injury

Focus Asia, Peter Gaskin, Principal, Aptuit

(DILI).

Consulting, talks about the current scenario

According to a Prospective Pilot Cohort

of post-marketing withdrawal of drugs due to

study that was conducted for a 24-week period

drug-induced liver injury. The article also sheds

in 2012, 12 (0.04%) patients out of a total of

light on how improved biomarkers are helping

28,145 were identified as having possible DILI,

to reducing the number of drugs removed from

and 11 of these accepted to be included in the

the market due to safety concerns and of reduc-

protocol. During the one-week proactive period,

ing drug attrition rates, particularly when used

seven patients out of a total of 1407 inpatients

together in a multiplexed assay.

(0.498%) were identified with possible DILI, and

This issue also features articles on SAP

five were included in the protocol. Research says

ERP implementation strategy and how anima-

that identification of DILI is difficult, even among

tion software could help find cures for cancer

hospitalised patients.

and HIV.

Limitation of traditional biomarkers limits the pre-clinical testing and clinical development from eliminating all human hepatotoxins. DILI is considered the most common single adverse drug reaction leading to refusal of market approval

Prasanthi Potluri

subsequently leading to drug withdrawal from

Editor

CoverStory

Contents

14

Biomarkers of Drug-Induced Liver Injury

An update on progress Peter Gaskin, Principal, Aptuit Consulting, UK

Strategy

MANUFACTURING

04 SAP ERP Implementation Strategy & Validation Activity Before Implementation in Pharma / Biopharma Business

36 Continuous Process Performance Monitoring Using Nelson Rules

Shaligram Rane, Head Quality; SAP–Project Leader Prashant Modi, Head IT; SAP–Deputy Project Manager Kruti Shah, Sr. Executive–QA; DMS

Hitesh Patel, Assistant General Manager, Quality Assurance Shaligram Rane, Sr. General Manager, Quality Rustom Mody, Executive Vice President, Science & Technology

Intas Biopharmaceuticals Ltd., India

Intas Biopharmaceuticals Ltd., India

Research & Development

INFORMATION TECHNOLOGY

20 Quality Challenges in Drug Delivery The role for quality by design and excipients

44 Can Animation Software Help Find Cures for Cancer and HIV?

Alen Guy, Technical Director Annie Zhang, Wooensdag Sales Manager

V R Srivatsan, Managing Director, ASEAN region, Autodesk Asia

Pharmaceuticals, IMCD China

43 EVENTS 50 Books 54 RESEARCH INSIGHTS

26 Similar Biologics A golden bird to tame Rajneesh Kumar Krishan K Tripathi Department of Biotechnology, Ministry of Science and Technology, India

04

44

Advisory Board

Editor Prasanthi Potluri Alan S Louie Research Director, Health Industry Insights an IDC Company, USA

Christopher-Paul Milne Associate Director, Tufts Center for the Study of Drug Development, Tufts University, USA

Copy Editors V Rashmi Divakar Rao Silpa Tummala Jenny Jones Debi Jones Art Director M A Hannan Project Managers Prabha Nandikanti Breiti Roger Khaja Ameeruddin Jeff Kenney

Douglas Meyer Senior Director, Aptuit Informatics Inc., USA

Project Associate Vineetha G Veronica Wilson

Frank A Jaeger Director, New Business Development Solvay Pharmaceuticals, Inc., USA

Compliance Team P Bhavani Prasad P Shashikanth Sam Smith Steven Banks

Georg C Terstappen Chief Scientific Officer, Siena Biotech S.p.A., Italy

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

Laurence Flint Associate Director, Clinical Research Schering-Plough Research Institute, USA

Neil J Campbell CEO, Mosaigen Inc. and Partner Endeavour Capital Asia Ltd., USA

CRM Yahiya Sultan Naveen M Subscriptions incharge Vijay Kumar Gaddam IT Team Ifthakhar Mohammed Azeemuddin Mohammed T Krishna Deepak Yadav D Upender Sankar Kodali Head-Operations S V Nageswara Rao

Pharma Focus Asia is published by

In Association with

A member of

Phil Kaminsky Founder, Center for Biopharmaceutical Operations University of California, Berkeley, USA

Rustom Mody Director, Quality and Strategic Research Intas Biopharmaceuticals Limited, India

Confederation of Indian Industry

Ochre Media Private Limited, Media Resource Centre #204, 2nd Floor, Navketan Complex, Sarojini Devi Road, Opp. Clock Tower, Secunderabad 500 003, Andhra Pradesh, INDIA Tel: +91 40 4961 4444 Fax:+91 40 4961 4488 Email: info@ochre-media.com www.pharmafocusasia.com|www.verticaltalk.com|www.ochre-media.com

Sanjoy Ray Director, Technology Innovation Merck Research Laboratories, USA Sasikant Mishra Management Consultant and Ex-Deputy Director CII, Drugs and Pharma Sector

Š Ochre Media Private Limited. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, photocopying or otherwise, without prior permission of the publisher and copyright owner. Whilst every effort has been made to ensure the accuracy of the information in this publication, the publisher accepts no responsibility for errors or omissions.

The products and services advertised are not endorsed by or connected with the publisher or its associates. The editorial opinions expressed in this publication are those of individual authors and not necessarily those of the publisher or of its associates.

Copies of Pharma Focus Asia can be purchased at the indicated cover prices. For bulk order reprints minimum order required is 500 copies, POA.

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3

Strategy

SAP ERP Implementation Strategy & Validation Activity Before Implementation in Pharma / Biopharma Business In the 21st century, electronic records are most preferable option in every field. Pharma / Biopharma business is continuously growing, simultaneously new regulations has been strengthened on routine basis. To full fill the requirement, SAP-ERP system is the best option for tracking and traceability of each GMP activity including financial growth.

Shaligram Rane, Head Quality; SAP–Project Leader Prashant Modi, Head IT; SAP–Deputy Project Manager Kruti Shah, Sr. Executive–QA; DMS Intas Biopharmaceuticals Ltd., India

4

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ISSUE - 17 2012

T

he Pharma industry operates under drug regulations imposed by various drug administrations.

This necessitates continuous monitoring and tracking. A high profile ERP package is essential to meet this requirement.

For monitoring online activity and to ensure Good Manufacturing Practices, it is necessity to implement electronic documentation generation and controls.

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5

Strategy

Limitation of in-house developed multiple systems

Generally, there is a tendency to develop isolated systems inhouse to cater to various functions such as sales & distribution, purchase, finance & accounts and HR & Payroll. There are many functionality limitations within each of these software and, above all, no linkage. Other important issues are: lack of data security, poor GMP compliance, difficulty in tracing problems, and efficiency planning across multi-centric organisations. Hence there is strong need to have a single ERP system to tie-up all the processes.

ERP package and implementation partner selection

You must have two things in place beforehand as you start discussion: a dedicated team comprising techno-functional champions and user requirement specification (URS) / As-is.

Above two will give immense benefit while selecting the suitable ERP package as well as implementation partner who has domain expertise. You will also have fair idea about what the ERP is going to do for you and what not. A score card based on various discussions may additionally help you finalise the ERP package and implementation partner.

Project initiation

Challenging tasks

The ERP implementation deserves full attention from top to bottom and needs to be considered as a separate project which will motivate the entire team.

Many modules are available in SAP ERP but generally Finance (FI), Controlling (CO), Material Management (MM), Production Planning (PP), Sales and distribution (SD), Plant Maintenance (PM), Quality Management (QM), Document Management System (DMS) & HR with Payroll are most preferable. A Document Management System is a very good eco-option and need lot of efforts during and after implementation for on-line activity.

Based on organisation needs, project systems module can also be considered.

Figure 1 provides the SAP R / 3 modular structure overview.

Based on organisation size, it is vital to have a team for SAP implementation may comprise of 10 to 20 dedicated employees who are champions / experts in their respective functions and 10-15 external consultants who are experts on individual module with domain expertise and continuous support related to Infrastructure, Basis and ABAP programming from in house IT department.

After finalisation of SAP modules and implementation partner, the implementation exercise should begin. General timeline is about six months to one year (depending on size of the organisation as well as age of company because it has direct impact on management of old data). The greatest challenge is to collect data, arranging it in specified format of SAP and then transferring relevant data from existing systems to SAP after verification. The shift from separate state databases (in-house software) to a centralised distribution model (SAP) is expected to eliminate duplication of data, reduce operational costs, reduced cycle times, improve customer satisfaction and provides management with visibility across a unified supply chain for improved forecasting and optimised inventory management.

It is important to define unique sequential numbering system in SAP for various GMP functions for better traceability such as: batch numbering, QC reference, analytical report, change control, deviation, laboratory investigation, out-of-specification, out-of-trend, non-conformance report, document request, log book issuance request, equipment malfunction, etc. All batch

R / 3 Modular structure overview of SAP

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Dealing with gaps

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The gaps identified after the blue printing phase can be categorised as below 1) SAP Functionality gap: Where standard SAP functionality cannot be configured to fully satisfy a business requirement, this is known as a functionality gap. It may be tackled by changing the requirement, implementing a manual procedure, or developing a technical enhancement 2) Knowledge Transfer gap: Core team members have lack of sufficient knowledge 3) Configuration gap: Gap due to improper configuration The identified gaps can be resolved with the help of SAP consultant, ABAPer and lots of hard work of all SAP core team members / end users by accepting the required changes.

Figure 1

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ISSUE - 17 2012

Strategy

records, data recording sheets, certificate of analysis and certificate of conformance can be uploaded in the system for convenience and immediate access and it can be linked with material code and production planning for printing and recording real-time data.

The 'Document Management System' module in SAP provides online access to standard operation procedures, specification, master process and control records, batch process and control records, data recording sheet, protocol, validation report standard testing procedure, artworks etc. All the documents can be linked with material code so that when inspection lot of material is created, SAP can provide a link to the current approved documents (e.g.

Inspection plan, Specification, Test methods, BPCR) found in Document Management System.

Adoption of any major system changes is normally difficult. Major emphasis is to be given to adoption of best practices in place of habitual process and this requires serious training.

Core team members should ensure the of training various end users so as to reduce chaos during implementation by planning and continuous interaction with end users. There is a major challenge during implementation of ERP at the C&F agent level which is spread across the country / international location and the cost of the project, including hardware, software, networking and training.

Running the show post go live

After implementation, every module is expected to run well in real-time and it is easier to dig-out the information whenever required by the user. Core team members shall continuously monitor the system and provide support to end user as well. The organisation should be able to track the production at every stage with quality parameters including cost and efficient production planning. The system gives entire traceability from manufacturing to distribution including all information about purchasing, vendor,

material used lot, quality attributes and critical process parameter, intermediate, drug substance, drug product, dispatch, delivery and stocks. Successful implementation of the complete business processes onto the ERP system on time and within the stipulated budget depends on full support from top management as well as depth knowledge, experience and dedicated efforts of the implementation team.

Key benefits

The key benefits for a centralised system can be planted during planning stages by careful business blueprinting and adoption of standard processes wherever possible. The organisation can also take this opportunity to be environment friendly by considering the elimination of forms, logbooks and other paper work.

The most important benefit is the online data available to top management which helps them in analysis of what happened and designing new strategies for the future.

Additionally, it will reduce manual time and effort for documenting the sampling with electronic sample data that would able the SAP R / 3 users to track the location status of samples with real time access.

Another key benefit is the ability to automatically evaluate results based on current specifications. Another key benefit could be the automated supplier scorecards used to track supplier performance.

Infrastructure architecture

To host the SAP landscape, robust infrastructure is suggested and it can be finalised with the help of implementation partner as under: • Multiple high-performance servers to host SAP Development / Quality / Production landscape • High availability and fail over of production servers must be considered • Storage devices keeping future data growth in mind

• Tape library for backup purpose • Careful selection of database and operating system • Other servers for IDES and Solution Manager • The SAP infrastructure should be powered by multiple APC UPS for redundancy • The server room temperature shall be maintained by dual cooling system for better results and fall back.

The controls in place for moving configuration / development from development server to quality server and then to production server are by transports. All the transport activity should be controlled by change control system to manage requests for changes.

Once proposed changes are approved, changes should be transported to the quality server for testing and then to production.

The primary objective of implementing security in the SAP system is to ensure that only authorised users are able to access the systems, these users are only able to perform the tasks required for their specific job functions.

Roles shall be used to define rights to execute SAP transactions with specific conditions which is called as SAP 'Authorisation'. These roles can be grouped into business process-related SAP roles, and further grouped in to SAP composite roles or positions.

Backup / Disaster recovery

As the organisation will be performing various business processes / transactions through SAP, it is very important to have proper procedure for the data backup and recovery of SAP server. The IT team should perform online backup of SAP using standard DB13 command. it is recommended to use tape library as a data backup device. Full backup should be taken every day to minimise the loss to business data. Retention period for SAP online backup tape media should be minimum one week. Provision for offsite storage of backup media in fireproof storage cabinet.

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7

Strategy

Summary table of GAMP 5 categorisation Category

GAMP 5

1

Infrastructure Software (OS middleware, DB Managers etc.)

2

No longer used–Firmware is no longer functionally,distinguishable

3 4 5

Non–Configured Software– Includes Default Configurable Software Configured Software– Configured to satisfy business process Custom (Bespoke) Software Table 1

Validation approach

The transaction list is required to identify the processes with consideration of GMP standpoint in order to establish which processes need to be validated and which do not, so that the associated effort can be significantly focused on GMP critical processes. The GMP categorisation is decided on the basis of the pertinent GMP guideline.

The SAP ECC 6.0 ERP application software falls under the category 4 & 5–Configurable software packages as well as customised software as defined in GAMP 5 guidelines. The GAMP 5 categorisation and SAP ECC 6.0 system detail categorisations is summarised in Table 1.

Validation scope

Existing Documents •URS •Blue Print Document •‘As Is’ •‘To Be’ •Existing Qualification Documents •Users Manual

A validation master plan (VMP) document needs to be developed to list specific validation deliverables and activities required during each phase. This ensures that the validation role and approach is well understood and agreed upon sponsors, project team members, and process owners.

The content of the VMP forms the baseline for managing and delivering the validation process for project according to deliverables and approaches identified within VMP.

SAP System (Current)

SAP ECC 6.0 Validation Master Plan GMP Critical Transaction List GAP Analysis (With Current Requirements and GMP acceptance Criteria)

Validation steps Risk Analysis System Design & Infrastructure Risk

Functional Risk Analysis

Process Flow & System Usage Risk

operation Qualification

Performance Qualification

Installation Qualification

Traceability Matrix & Validation Summary Report

Figure 2

Validation approach

The approach considered for existing system at IBPL is retrospective approach as SAP System is already in use (Refer Figure 2). During the validation

8

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ISSUE - 17 2012

process, efforts must be made to find out available information on specifications, documentation and current practices of the organisation.

Following are the general basic steps involved in all the Validation processes: 1. Gap Analysis: GAP here means incompleteness or missing links. GAP analysis means analysing the SAP system through available documentation, and current status of SAP with reference to the guidelines of regulatory agencies and attempt to find out from available implemented systems.

The checklist prepared in GAP analysis has current requirement defined as acceptance criteria. Total number of GAP check list has been prepared for each module as below (Refer Table 2). Find some examples of GAP analysis of each module (Refer Table 3). The applicability covers SAP ECC 6.0 system Hardware and software infrastructure and Application server.

Strategy

2. Plan of action: Based on the gap analysis organisations can create action plan along with client, and decide which gaps can be closed technically and which are to be attended by other procedures.

Approach for the action plan • When the negative results of the spot checks are realised, determine if Gaps are due to improper configuration / implementation (in case of system is capable). Note down the actual observation and intimate to core team to correct the same • When the negative results of the spot checks are realised, determine if Gaps are due to the system’s incapability to satisfy the requirements, than note down the observations and suggest implementing immediate manual procedure to control the system’s requirement and informing to core / technical team (Implementation partner) to implement the same through system control • When the negative results of the spot checks are realised, determine if Gaps are related to non-availability of documents / records, then note down the observations and intimate to project coordinator to define further action plan.

3. Risk Assessment: After the plan of action, carry out detailed risk assessment of relevant modules. In this step, the organisation must determine the important transaction codes and classify them into typical three categories as per GAMP guidelines. The further validation procedure is based on this classification.

Assess the Severity of Impact Risk assessment requires not only the identification of the immediate effects of the risk but also the long-term impact on the business of those effects. These effects must take into account a wide variety of issue including impact on regulatory compliance, financial impact and company reputation with customers and suppliers Assess likelihood Determine the likelihood (frequency or probability) of an adverse event occurring.

Total number of GAP check list has been prepared for each module Sr. No.

Name of Module

GAP Check List

1

Document Management System

12

2

Material Management

15

3

Quality Management System

16

4

Production Planning

6

5

Plant Maintenance

9

6

IT Infrastructures

1 Table 2

Example of GAP analysis of each module Name of Module

GAP Description

Action Taken

Document Management system

User can create document without specifying of Category of document’

System control has been implemented in the transaction

2

Material Management

Audit trail is not available for any change in source list.

3

Quality Management

Verification procedure for MIC attachment to Inspection Plan not available.

Existing SOP has been amended and relevant person to be trained

4

Production Planning

Release review procedure for BOM

Procedure control has been implemented

5

Plant Mainte- User can change the work nance centre.

Authorisation has been given to Engineering Dept. to change the work centre

6

IT Infrastructures

IT policy has been updated for Update and Maintain User administration record

Sr. No. 1

SAP User Administration Policy is not available.

ME04 serves the purpose for audit trail.

Audit review procedure has been prepared

Table 3

Assess probability of detection Identify if the adverse event can be recognised or detected by other means in the system. Adverse event having high probability of detection, may not pose serious threat because it can be recognised quickly and suitable corrective action taken to mitigate its impact.

If adverse event has a low probability of detection, then the risk condition

need to seriously consider a review of the design or the implementation of alternative procedures to avoid the event.

Overall priority

Overall priority is calculated using multiplication of the all three assessment ranking and decided based on following table (Refer Table 4).

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9

Strategy

After Risk analysis has been completed, overall report has been prepared with mitigation plan and how much risk will be reduced after mitigating the risk.

Installation qualification

This consists of server, client, Hardware, network components and Network infrastructure, operating programs with utilities. The installation qualification activity also includes identification of live database and test database.

Calculation for RPN number Category

Low (Min) X Low (Min) X Low(Min) 1X1X1

≥1

Low (Max)

Low(Max) X Low (Max) X Low (Max) 4X4X4

≤64 (<80)

Medium (Min)

Low X Low X Medium 4X4X5

≥80

Medium (Max)

Medium (Max) X Medium (Max) X Medium (Low) 6X6X5

≤180

High (Min)

Medium (Max) X Medium (Max) X Medium (Max) 6X6X6

> 180

High (Max)

High (Max) X High (Max) X High (Max) 10 X 10 X 10

≤1000 Table 4

Annual review plan

Once system is validated and all process has been running smoothly, it is highly recommended to monitor the SAP system periodically for the improvement.

Annual review report (applicable EU guideline for product review) which summarizes the identified gaps, any deviation or error, changes made during year. It may also include the summary of corrective action and preventive action.

In a nutshell, following success factors could be considered during SAP ERP implementation:

10

P h a rm a F o c u s A s i A

ISSUE - 17 2012

A u t h o r BIO

Performance qualification

The performance qualification consists of the Integration and Process flow verifications which describes the inter relationship between all modules, systems and procedural controls.

In the Validation Summary Report the results will be summarised with the test objectives.

In the traceability matrix all the requirement specifications will be mapped with individual qualification activity.

RPN

Low (Min)

Operation qualification

This consists testing of information flows in terms of functions and transactions at the level of individual processes. The test strategy is completed with functional and negative tests which are identified as measures in individual transaction wise risk analysis activity.

We had a good opportunity to validate the system not only from a business process point-of-view but also from IT security. Infrastructure was also part of validation activity where in we checked / challenged various parameters on servers as well as at clients end. This helped to boost up our confidence on our systems.

At the time of implementation, based on our assumptions, we created roles in SAP for assigning to users for their routine activities. At the time of validation activity, we had a better understanding of roles and responsibilities and we could realign roles / authorisations based on actual business needs.

RPN Category

• Involvement / commitment of top management and all key users • Strong implementation partner having domain expert consultants • Project management to keep control on deliverables, time and cost • Adoption of standard processes rather than customisation • Less no of developed / customised processes • Minimum interfacing with non-SAP systems • Post go-live support to end users • Knowledge transfer from implementation partner to in-house team.

Shaligram Rane is currently Sr. General Manager–Quality (QC & QA) of Intas Biopharmaceuticals Ltd. He is associated with the Intas for the past seven years where he has been directly involved in technical, techno-commercial and business progression of five rDNA products and is currently involved with 10 other biosimilars. He holds extensive experience in the quality control and quality assurance (QC and QA) of pharmaceuticals, biosimilar products and services for the Indian, ROW and regulated markets. His academic qualifications (M.Sc. M.Ed. and Ph.D.) are in the area of Organic Chemistry and Analytical Chemistry.

Prashant Modi has 11 years of experience in designing, implementing and maintaining enterprise level IT Infrastructure & Services like systems and networking as well as SAP ERP application as Basis Admin and MM consultant. He worked with ITES organisations like Allied Digital Systems, Wipro and HCL at esteemed client sites like Torrent Pharma and ONGC. Kruti Shah is Sr. Executive in Quality Assurance dept. of Intas Biopharmaceutical Ltd. She is B. Pharm with seven years experience.

She is core team member of Document Management System (DMS), project coordinator during SAP-ERP validation and having expertise in handling of Material Management, Quality Management and Production planning modules of SAP-ERP.

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Suppliers who made the right choice A Choksey Chemical Industries 0091 22 22673868 / 22674006 achokseychemical@rediffmail.com ACE Chemicals 0091 080 51240325 / 26, 22273541 / 42 bhavyadoshi@acechemicalsindia.com www.acechemicalsindia.com Ace Process Equipment 0091 22 4021850 sales@aceeqpt.com www.aceeqpt.tradeindia.com Anil Printers Limited 0091 0253 2382388 / 2382488 anilprintersltd@rediffmail.com www.anilprintersltd.com Anish Pharma Equip. Pvt. Ltd. 0091 253 2381831 ravi_samant@rediffmail.com www.anish.org Aseptic Projectss 0091 22 2374 1072 / 2372 2064 info@asepticprojectss.com www.asepticprojectss.com Bang & Olufsen Medicom a / s 0045 96 84 58 00 medicom@bang-olufsen.dk www.medicom.bang-olufsen.com BIT Life Sciences, Inc 0086 411 84799609–827 charles@bitlifesciences.com www.bitlifesciences.com Bharat Box Group 0091 11 22528066 rachit_agg@rediffmail.com www.bbfgroup.com Biocultr BV 0031 71 521 5443 biocult@sandtcourses.nl www.biocult.com BIT Life Sciences, Inc 0086 411 84799609 leo@bitlifesciences.com www.bitlifesciences.com Bonfiglioli Engineering 00356 2148 2206 h.carbone@bonfiglioliengineering.com www.bonfiglioliengineering.com Brevetti Angela Srl 0039 0444 474200 info@brevettiangela.com www.brevettiangela.com Chemische Werke Hommel GmbH & Co KG 0049 2591 2305-0 info@hommel-pharma.com hommel-pharma@directbox.com Choksi Laboratories Limited 0091 731 2493592 / 3 info@choksilab.com www.choksilab.com Crystal Pharmatech Co Ltd 0086 512 69369978 alex_chen@crystalpharmatech.com www.crystalpharmatech.com DeltaT GmBH 0049 641 48092 40 info@deltaT.de www.deltaT.de Dr. Lauterbach & Partner 0049 0 6332 / 485 0 sales@dr-lauterbach.de www.dr-lauterbach.de EFD Inc., 00401-434-1680 ETS Nederland BV 0031 0 575 545500 info@toxicology.nl www.toxicology.nl Fem Care Pharma Ltd 0091 0253 2390278 / 2375886 fempmt@yahoo.co.in www.femcareworld.com

GleneaglesCRC Pte Ltd 0065 6317 2363 dy_sadasivan@gleneaglescrc.com www.gleneaglescrc.com GMP Technical Solutions 0091 22 6608 3700 enquiry@gmptech.net www.gmptech.net Guava Technologies 001 510 576 1400 info@guavatechnologies.com www.guavatechnologies.com Haldies Chemicals Pvt. Ltd. 0091 2117-235356 / 235661 info@halides-pltd.com Health Protection Agency 0044 1980 612100 business@hpa.org.uk www.hpa.org.uk / business / High Class Art Intl Co Ltd 00886 4 2371 5313 info@highclassintl.com www.highclassintl.com HMG India 0091 22 28549059 / 28408699 response@hmgind.com www.hmgind.com Hrushikesh Water Sciences Pvt. Ltd 0091 20 27451031 / 46703689 info@watersciences.biz www.watersciences.biz Isuta (Malaysia) Sdn.Bhd 00604 3982 770 enquiry@isuta.com www.isuta.com J K Industries 0091 2764 227975 info@jkindus.com www.jkindus.com Kores (India) Limited 0091 22 27613444 korescd@vsnl.com www.korescd.com Lao Soung Machinery Co, Ltd 00886 229900668 laosoung@ms10.hinet.net www.laosoung.com.tw Lomapharm® Rudolf Lohmann GmbH KG 0049 51 55 63 208 sales@lomapharm.de www.lomapharm.de Lotus Labs Pvt Ltd 0091 80 22370912 / 13 / 14 ychugh@lotuslabs.com www.lotuslabs.com M.H. Material Handling S.r.l.

0039 02 96720176 info@mhmaterialhandling.com www.mhmaterialhandling.com MachinePlatform 0031 0 79 3317121 info@machineplatform.com www.machineplatform.com Madison Communications Pvt Ltd 0091 11 40551500 / 1600 rawat@del.madisonindia.com www.madisonindia.com Matrix Laboratories Limited 0091 40 27700363 / 30496427 mbsugar_nsk@sancharnet.in www.matrixlabsindia.com MB Sugars & Pharmaceuticals Ltd. 0091 2554 251 883 mbho@mbsugars.com www.mbsugars.com Mercury Manufacturing Company Ltd 0091 44 2262 8002 / 2262 8593 info@mercuryfurniture.com www.mercuryfurniture.com Meridian Enterprises Private Ltd. 0091 22 66084200 / 66084210 office@meridianentp.com www.meridianentp.com

Merck and Co Inc 001 215 652-2937 janet_schneider@merck.com www.merck.com Messe Dusseldorf 0049 211 / 4560-01 contact@ppccro.com www.messe-duesseldorf.de Micro Therapeutic Research Labs Pvt. Ltd 0091 44 2223 8846 / 56 / 65 info@microtheraps.com www.microtheraps.com Morepen Laboratories Ltd 0091 11 233 24443 / 237 12025 sales@morepen.com www.morepen.com Nitika Chemicals 0091 712 2641001 rskhurana@nitikachemicals.com www.nitikachemicals.com Notox B.V. 0031 (0) 73 640 67 00 notox@notox.nl www.notox.nl Pack Cheon Machinery Co. Ltd 0082 32 517 8014 packon@packon.com www.packon.com Padm Industries 0091 22 28593909 / 28520271 vaibhav_cjp@yahoo.co.in www.indiamart.com / padmindustries Palam Pharma Pvt. Ltd 0091 79 25831892 / 25890579 palam@icenet.net www.palampharma.com Pall India Pvt Ltd 0091 80 40164100 anand_subramanian@ap.pall.com www.pall.com Panoli Intermediates India Pvt. Ltd 0091 11 26174227, 26196368 varmasamir@yahoo.comwww. panoliindia.com Parag Exports 0091 265 2641098 parag_exports@yahoo.co.in www.paragexports.com Parth Engineers & Consultant 0091 79 25841154 info@parthec.com www.parthec.com Parexel International 001 781 434 5305 Sean.McIntosh@parexel.com www.parexel.com PG Foils Limited 0091 2937 2871151–55 pgfoils@pgfoils.in www.pgfoils.in Plus Creations (P) Ltd 0091 130 2366516 sales@pluscreations.org www.pluscreations.org Prachi Pharmaceuticals Private Ltd 0091 22 24132411 prachint@bom7.vsnl.net.in prachint@vsnl.com Pratham Technologies Pvt. Ltd. 0091 20 24355765 prathamtech@vsnl.com www.prathamtech.com Precikot Pharma Pvt. Ltd. 0091 250 2457011 info@precikot.com www.precikot.com Prime Pharmaceutical Sdn Bhd 00604 5074787 / 5074788 primep@streamyx.com www.primepharma.com.my

Protech Pharmaservices Corporation 00886 2 2657 7777 contact@ppccro.com www.ppccro.com PRTM 0081 3.5326.9090 infojp@prtm.com www.prtm.com Radpharm Scientific 0061 2 6251 6533 www.radpharm.com.au Recon Machine Tools Pvt. Ltd. 0091 22 26875931 sales@reconmachine.com www.reconmachine.com Romaco AG info@romaco.com www.romaco.com Royal Artist 0091 22 28320800 response@royalartist.com www.royalartist.com S.Zhaveri Pharmakem Pvt Ltd 0091 22 66 60 7756 / 57 vikas@szhaveri.net www.szhaveri.com Saeplast 00354 460 5000 saeplast@saeplast.is www.saeplast.com Samex 0091 261 2590950 / 25934203 info@samexoverseas.com mehul_jhaveri@hotmail.com www.samexoverseas.com Santapet Polymers Limited 0091 22 2342 0381 info@santapetpolymers.com www.santapetpolymers.com Saz Boilers 0091 20 26970840 saz@vsnl.com www.sazboilers.com Servotex Engineers 0091 22 28454982 servotex_engineers@yahoo.com www.indiamart.com / servotexengineers Shakti Pharmatech Pvt. Ltd. 0091 2717 250405 sales@shaktipharmatech.com. www.shaktipharmatech.com Shiv Shakti Process Equipment Pvt. Ltd. 0091 22 26768480 office@shivshaktiequipments.com www.shivshaktiequipments.com Sigpack Systems AG 0041 52 674 65 00 www.sigpack.com Skan AG 0041 61 485 44 44 info@skan.ch www.skan.ch Speciality Meditech Pvt. Ltd 0091 141 5105136 speciality_meditech@yahoo.com www.indiamart.com Spectrum Pharmatech Consultants Pvt. Ltd. 0091 22 25977000 hemant.lokare@spectrumpharmatech.com www.spectrumpharmatech.com Srinidhi Engineers 0091 22 28497424 / 32964483 srinidhirk@gmail.com www.srinidhiengineers.com Stamfag Punching Tools 0041 44 914 35 35 info@stamfag.ch www.stamfag.ch Starcom Mediavest Group 00971 4 4276435 Samar.jalil@dubai.starcomworldwide.com www.smvgroup.com

Sujyot Engineering 0091 79 25856044 / 26639686 info@boxstrappingmachine.com www.boxstrappingmachine.com Superlite Lighting Co. Pvt. Ltd 0091 22 26852822 info@superliteindia.com www.superliteindia.com Swami Vessels Pvt. Ltd 0091 257 2211294 / 2211447 response@swamivessels.com www.swamivessels.com Syngene International Pvt. Ltd. 0091 80 2808 2808 / 2783 2169 arun.nataraj@biocon.com www.biocon.com Trebing & Himstedt Prozessautomation GMBH & Co 0049 385 39572-0 sinkmann@t-h.de www.t-h.de Turchette Advertising Agency 001 73 227 8080 rsiciliano@turchette.com www.turchette.com Tyagi Air-Wave Equipments Pvt. Ltd 0091 120 2820548 / 2829333 tyagiairwave@yahoo.co.in www.airwaveindia.com UBM India Pvt Ltd 0091 22 66122600 bhaskar-chivukula@ubm.com www.ubm.com Uma Brothers 0091 22 25004510 / 25004579 umabros@vsnl.com www.umabrothers.com UPM-Kymmene India Pvt. Ltd. 0091 22 2767 0031 Santosh.Kumar@upmraflatac.com www.upmraflatac.com Vertis Biotechnologie AG 0049 8161 141 12 11 www.vertis-biotech.com Wintech Pharmachem Equipments Pvt. Ltd. 0091 250 2456495 winpharma@vsnl.net www.wintechpharmachem.com WLE Technology Sdn Bhd 0060 3-7845 0598 / 0798 enquiry@wengloong.com www.wengloong.com Yogesh Pharma Machinery Pvt. Ltd. 0091 79 40233800 to 804 bizypmpl@gmail.com www.pharmaequip.in Zenithmedia GmbH (Siemens) 0049 89 71 05 18 0 Henning.Kittner@zenithmediamuenchen.de www.zenithmediamuenchen.de

If your interested to advertised please contact: advertise@pharmaceutical-tech.com +91 40 4961 4444

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Research & Development

Biomarkers of Drug-Induced Liver Injury An update on progress Drug-Induced Liver Injury (DILI) is responsible for the post-marketing withdrawal of many drugs. The limitations of routine safety biomarkers (e.g. standard clinical pathology parameters) in predicting DILI have long been recognised both by the industry and regulators. There are a number of common mechanisms of liver toxicity, and this article reviews the biomarkers in development and their applicability to different mechanisms of toxicity.

Peter Gaskin, Principal, Aptuit Consulting, UK

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ILI has been the most frequent single cause of safety-related drug marketing withdrawals for the past 50 years and continues to be a significant cause of drug failure.

Significant effort has been expended to try to reduce the failure rate of drugs due to hepatotoxicity and overtly hepatotoxic agents are typically removed during screening or in pre-clinical development.

However, it has proved to be more difficult to eliminate DILI for all drugs as only the most potent hepatotoxins show severe DILI in the 1,000-3,000 subjects typically studied in clinical trials included in a New Drug Application (NDA) or Marketing Authorisation Application (MAA).

The liver is a multifunctional organ and drugs cause liver injury by many different mechanisms so a single biomarker is unlikely to be sufficient to detect all possible routes of liver damage.

Traditional clinical chemistry biomarkers used to assess drug induced hepatotoxicity have often been insensitive and not always specific to liver injury. For example,

Research & Development

ALT increases with Cytochrome P450 induction and is also present in muscle, meaning that it is difficult to use as a definitive marker of liver damage. ALP is inducible (in dogs) and is also found in a range of tissues, making it a non-specific marker of liver damage and potentially inaccurate for predicting DILI, especially in dog studies.

Due to limitations of traditional biomarkers, pre-clinical testing has not been able to eliminate all human hepatotoxins from progressing into clinical development (Greaves et al., 2004).

Without good clinical biomarkers of DILI, clinical development has also had limited success in preventing drugs which cause liver damage from reaching market.

Consequently, there is a significant need for improved pre-clinical and clinical biomarkers for DILI and it is likely, due to the multiple possible mechanisms of liver toxicity, that a panel of such biomarkers will be required to ensure that the potential for DILI is identified early in drug development.

In response to the Critical Path Initiative the Predictive Safety Testing Consortium (PSTC) has developed a legal framework to share the cost of qualification and to protect intellectual property associated with biomarker qualification.

The PSTC is collaborating closely with the US, European and Japanese regulators and the European IMI SAFE-T Consortium is to identify and qualify safety biomarkers for a range of druginduced toxicities including: cardiac hypertrophy, kidney, liver, skeletal muscle, testicular toxicity, and vascular injury.

A number of techniques are being used by members of the PSTC and IMI SAFE-T Consortium to measure biomarkers, including RNA expression profiling (e.g. albumin mRNA and miRNA 122), LC-MS (e.g. conjugated and unconjugated bile acids), Immunoassay (e.g.

Keratin 18, PON-1) and activity assays (e.g. GLDH). Whilst many biomarkers are still undergoing qualification, progress is being made and some are starting to be used clinically to measure DILI (Harrill

et al., 2012). Below I discuss some of the more promising biomarkers of DILI and some of the evidence supporting their use in the assessment of DILI. mRNA biomarkers

Paracetamol (acetaminophen) is a widely used drug, but is also the leading cause of liver failure both in Europe and in the USA. In 2004 Heinloth et al. (2004) used paracetamol as a model hepatotoxicant to show the potential of liver gene expression profiling to provide sensitive markers of hepatotoxicity. Bushel et al.

(2007) demonstrated that peripheral blood gene expression signatures correlated well with exposure level and could act as early biomarkers of paracetamol toxicity. Miyamoto et al. (2008) selected a1-microglobulin / bikunin precursor (Ambp) and albumin mRNAs as tentative liver-specific biomarkers and demonstrated their presence in the plasma of rats following initiation of liver damage by administration of hepatotoxicants paracetamol or D-galactosamine HCl

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Research & Development

Mechanisms of Drug Induced Liver Injury

Figure 1

microRNA biomarkers

(D-gal), but not following bupivacaine HClâ&#x20AC;&#x201C;induced skeletal muscle damage.

In a study performed in our labs we took at similar approach to that taken

by Bushel et al. (2007) to identify suitable biomarkers of hepatotoxicity. Rats were administered paracetamol orally at dose levels of 100, 600 and 1200 mg / kg / d for 1, 3 or 14 days. In addition to typical toxicology endpoints blood samples were collected for gene expression profiling.

Treatment with intermediate and high doses of paracetamol showed typical signs of hepatotoxicity, both in clinical chemistry and in histopathology from Day 1. Histopathology showed a clear time and dose-related response, with 100 mg / kg / d representing the No Adverse Effect Level (NOAEL). Centrilobular necrosis and inflammation were seen in animals at the 24 h, 3 day and 14 day time points, with the changes progressing and increasing in severity over time at the high dose. After three days of dosing at the highest dose of 1200 mg / kg / d, livers showed centrilobular necrosis with inflammation and centrilobular alteration (cytoplasmic condensing, slight rounding and enlargement of cells around the central vein). By Day 14, livers of all rats showed acute centrilobular necrosis and

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in gene expression were first observed at 24 h, which were more pronounced at 3 days and seemed to diminish in magnitude by 14 days, mirroring the adaptive response seen histopathologically.

A similar pattern was observed at 1200 mg / kg / d although the magnitude of change was greater both in the number of genes reaching significance at all time points and the degree (fold-change) of differential expression. A particularly marked innate immune signalling and T-cell marker response was observed at days three and 14 was indicative of an early inflammatory event, which predicted the immunocyte infiltrate confirmed histopathologically.

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inflammation with centrilobular alteration and notable cytoplasmic rarefaction.

An adaptive response was seen in the liver of animals administered 600 mg / kg / d, indicating some recovery over the 14 day dosing period, which was not seen at the high dose.

Figure 2-A) Control rat liver (x40 magnification) showing normal cellular pathology. B) Liver of rat administered paracetamol at 1200 mg / kg / d for 3 days (x40 magnification) showing centrilobular necrosis with inflammation and centrilobular alteration seen in some animals. C) Liver of rat administered paracetamol at 1200 mg / kg / d for 14 days (x40 magnification) showing centrilobular necrosis and inflammation with centrilobular alteration and notable cytoplasmic rarefaction.

Clinical chemistry changes seen on day one and day three were not seen on day 14, although there was a clear development in histopathological changes in the liver over this time. In addition to the histopathological and clinical chemistry changes the study also showed statistically significant, dose and time dependent changes in gene expression profiles of whole blood from rats dosed at 600 mg / kg / d and 1200 mg / kg / d. At a dose of 600 mg / kg / d subtle changes

The recent discovery that small non-coding, regulatory microRNAs (miRNAs) are stable and can be detected in circulating blood has led to their assessment as possible safety biomarkers.

Wang et al. (2009) assessed expression levels of miRNAs in liver and plasma of BALB / C mice following a single intraperitoneal injection of 75,150 or 300 mg / kg paracetamol. Following treatment with paracetamol, levels of liver specific miRNAs, including miR-122 and miR-192, were increased (proportionately to dose and exposure duration) in both liver and in plasma.

Furthermore, the expression levels of miR-122 and miR-192 also mirrored ALT levels and histopathological changes, although changes in miRNA levels were seen as early as one hour after exposure indicating that they act as very sensitive and tissue specific biomarkers of DILI. The work of Bushel, Miyamoto, Wang, Laterza, ourselves and others suggests that both messenger RNA and miRNA expression profiling in the peripheral circulation can provide surrogate biomarkers of liver damage. The added value of using RNA expression is that it has the potential to provide a suite of biomarkers suitable for different mechanisms of DILI.

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Research & Development

A

B

C

Figure 2

Other biomarkers Bile acids

Levels of lithocholic acid (LCA) and it’s metabolites are sensed by PXR which subsequently regulates the expression of a suite of enzymes and transporter molecules to increase drug metabolism and reduce bile acid synthesis to protect the liver against choleostasis (Staudinger et al., 2001). Unconjugated and conjugated bile acids, including LCA, have been identified by the PSTC and others as potential biomarkers of cholestatic hepatoxicity.

GLDH

A u t h o r BIO

Like ALT, glutamate dehydrogenase (GLDH) can be easily measured in plasma and is more liver specific than ALT or AST. A GSK investigation of plasma GLDH as a potential biomarker of DILI in rats was conducted following treatment with methapyrilene, dexamethasone, cyproterone, isoniazid, lead nitrate, and Wyeth-14643 (O’Brien et al., 2002). GLDH activity was increased up to 10-fold more, and up to 3 fold more persistently than ALT, and occurred when hepatocellular injury was present, but when plasma ALT was not increased. GLDH activity was not inhibited by either isoniazid or lead nitrate, and GLDH activity was unaffected by

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induction. GLDH was found to be a sensitive and effective biomarker of acute DILI which performed better in the rat than ALT, AST, SDH or ALP. Keratin-18

Antoine et al. (2010) have used biomarkers Keratin-18 and high mobility group box-1 protein (HMGB1) to further elucidate the mechanisms associated with paracetamol DILI. In mice given a single intraperitoneal injection of 530 mg / kg paracetamol, necrosis was the main mechanism of hepatocyte cell death.

However, Keratin-18 cleavage, DNA laddering and pro-caspase 3 processing indicated that whilst necrosis was the dominant mechanism, that apoptosis was responsible for some paracetamol induced hepatocyte cell death as part of an endogenous protective response to paracetamol toxicity. Use of an HMGB1neutralizing antibody confirmed a significant role of HMGB1 in the induction of inflammation following paracetamol intoxication, which was postulated to be associated with the regenerative response following initial damage. In fasted animals the inhibition of HMGB1 oxidation due to ATP depletion was demonstrated to reduce apoptosis and further promote the inflammatory response.

Peter Gaskin has over 20 years experience of successful drug development in the bio-pharmaceutical and contract research industry. With a background in mechanistic toxicology and through application of translational approaches he aims to reduce attrition rates and speed translation of pre-clinical research into successful clinical candidates.

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PON-1

An initial assessment of Paraoxonase-1 (PON-1) by the IMI SAFE-T Consortium has indicated that due to marked variability and decreased activity with liver dysfunction that it is not a suitable candidate biomarker for DILI (Adler et al. 2010 and SAFE-T presentation March 2012). Following an initial assessment ALT isoenzymes have also been removed from the priority list of candidates for development due to poor performance.

Other biomarkers

I have, out of necessity, focussed primarily on blood biomarkers in this editorial, but it should be noted that there is also work ongoing to identify suitable biomarkers for DILI in urine using proteomics (Smyth et al. 2009) and metabonomics (Nicholson et al. 2002); the attraction being the non-invasive manner of sampling.

Summary

Whilst post-marketing withdrawal of drugs due to drug-induced liver injury continues, much progress has been made since the FDA’s Critical Path Initiative.

A number of promising biomarkers have shown significant improvement over traditional clinical chemistry endpoints and are progressing into qualification. These hold out the hope of reducing the number of drugs removed from the market due to safety concerns and of reducing drug attrition rates, particularly when used together in a multiplexed assay.

Research & Development

End-to-end Solutions for Life Sciences and Healthcare Companies Bio-Analytical Technologies® (India) Pvt. Ltd., established in 2003, and headquartered in Pune, India, is a rapidly growing Bio-IT company, with an ISO 90012008 accreditation. From just handful of employees and basic infrastructural facilities in the initial year to almost 200 employees and state-of-the-art infrastructure is a great achievement among itself for a company, which is providing software solutions in the niche domains of Life Sciences, Biotechnology and Healthcare. The company serves to a global clientele including Fortune 500 companies.

The company has three groups Software Technology Group, Biotechnology Group and Embedded technology Group; these groups together empower company to act as a ‘One Stop Solution Provider’ for its clients. The clients can utilize company’s offshore

development center, having excellent competency in the Software, Domain and Embedded / Hardware for their complete outsource software product development needs.

The company has a unique blend of domain and technology professionals, which are its greatest asset. A rare combination of BioIT experts i.e. software professionals, domain specialists, doctorates, researchers, scientists and technologists, subject matter experts, embedded technology professionals, etc. allows company to take the end-user perspective into account making sure that the solutions are tailored to client’s business goals.

The company’s well-equipped Analytical Research and Instrumentation labs are managed by highly qualified and experienced professionals from Analytical Chemistry and Life Sciences Domain. The Research Scientists have hands-on experience on Analytical Instruments (LC-MS / MS, HPLC and GC) and most of them are Masters / Doctorate with expertise in all stages of Method Development, Validation Protocols and testing methodologies. Strong domain knowledge coupled with computing acumen makes the company chosen end-to-end software solution provider in the Pharma, Bio-Pharma, CRO and Healthcare domains.

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Quality Challenges in Drug Delivery The role for quality by design and excipients

This article deals with how some companies have adapted to the Quality by Design (QbD) environment, and also looks at some of the core elements of solid dose drug delivery and the raw materials used. The context for this latter part will look at how drug delivery companies can work with excipient suppliers to strengthen the robustness of their technology through better understanding of the supply chain.

Alen Guy, Technical Director Annie Zhang, Wooensdag Sales Manager Pharmaceuticals, IMCD China

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rug delivery companies and the products borne from them are often characterised by complex partnerships between companies, with licensing agreements and strategic relationships. The challenges they seek to face and overcome rely upon strong technology delivering drugs to targeted sites in the patient.

Outsourcing of opportunities has dramatically increased over the last decade. As a result, drug delivery companies (large and small) have found themselves closer to the early stages of a drugs development. This has landed there technology firmly in the quality by design QbD sphere.

This article deals with how some companies have adapted to the QbD environment, but also looks at some of the core elements of solid dose drug delivery and the raw materials used. The context for this latter part will look at how drug delivery companies can work with excipient suppliers to strengthen the robustness of their technology through better

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understanding of the supply chain.

Drug delivery companies are an increasingly important part of drug product development as pharmaceutical companies have required more outsourced expertise.

A â&#x20AC;&#x2DC;classicâ&#x20AC;&#x2122; drug delivery company builds its value around intellectual property in a number of ways. There is typically a platform of technology related to improving API properties, drug product compliance or combinations of added value properties.

Whether the platform(s) utilised are targeted at solubility or bioavailability improvement, alcohol-resistant controlled release, drug-abuse or compliance benefit through novel dosage form, the need and use of excipients is inevitable and widespread.

The examples given in table 1 show a small selection of the companies involved in oral drug delivery worldwide. All of these companies apply proprietary technology or significant know-how to the successful formulation

of drug products. However, the proprietary nature of formulation platforms essentially requires them to use a limited number of excipients to achieve their aims. In the current regulatory climate and the drive towards QbD in the largest markets the drug delivery companies face some interesting challenges.

Many drug delivery companies seek to develop products that are differentiated from innovator products or designed to increase product lifecycle for the innovator, thereby keeping generic competition at bay! Whichever route they take the regulatory pathway will take them through, most often, an ANDA route. In a few cases a completely new submission with fresh clinical data will be undertaken. In either case a QbD route can lay before them.

Is QbD attractive for drug delivery companies?

The real point of QbD lies in creating a quality and risk management system that minimises the need for costly

Research & Development

inspection-based quality, as well as providing significant knowledge to support the submission in such a way that the manufacturer can safely adjust the process during the manufacturing stages without the need for costly regulatory work.

A drug delivery company, often, not only creates the opportunity and formulation, but also controls the manufacturing, raw materials and the outputs to the drug company. This in itself means advanced companies have a lot of data regarding what does and does not work for their technology. In other words, they should have de facto carried out many risk analyses regarding critical quality attributes of formulations with respect to excipient properties and process parameters.

Does this mean drug delivery companies undertake regular assessments of excipient suppliers? In my experience this is often not the case. Normally it might be imagined the drug delivery company has a robust system that can tolerate a range of suppliers for excipients such as mannitol, microcrystalline cellulose, lactose, HPMC etc.

What about other pressures? The current economic climate is such that even areas that have very little impact on the final cost (especially Excipients) come under cost strain. Sourcing groups seek to optimise and create lean supply chains, minimise outgoings and stock handling.

This might mean certain suppliers appear more attractive to them than they might to the R&D group and formulators.

So, QbD should be attractive to drug delivery companies, as their entire technology platform should have been designed to predict and understand the elements of risk associated with formulations and the processes they own. From the standpoint of attracting new customers, this element of their knowledge should be utilised and exploited. Can and should a drug delivery company incorporate a full raw materials assessment into their development program?

Catalent gives consideration to QbD principles quite openly through its activities with dry powder inhalers, but also 22

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Examples of drug delivery companies and technologies employed for drug product formulation Company Name

Drug Delivery Systems / Tradenames

Aptalis

Advatab, Biorise, Microcaps

Catalent

Zydis, Optimelt

Skyepharma

Medicated Chewing gum, Geomatrix, Geoclock.

Flamel

Micropump, Liquitime

Orexo

sublingual mucoadhesive tablet, oral fast-dissolving tablet

SPI Pharma

Pharmaburst, Actimask

Bend Research

Spray-Dried Dispersions, Osmotic Tablet Technology Table 1

most recently with multiparticulate oral controlled release development. This was announced (June 21, 2012) as part of its alliance with Bend Research in Oregon.

Indeed, catalent also published in the Journal for Patient Compliance, coining or using a phrase â&#x20AC;&#x2DC;Adherence by designâ&#x20AC;&#x2122; an approach derived from QbD principles. However, this is a drug delivery construct that is best intentioned towards more targeted delivery, where the design element is more about drug product design rather than quality that has been designed into a process to meet a desired outcome.

However, the acceptance of the principles as being important is key here when considering your drug delivery partner.

Skyepharma makes no implicit statement regarding QbD but their commitment to inhalation projects ensures they will have quality managers concerned with ICH and QbD guidelines.

Aptalis, Flamel nor Orexo make any QbD assertion in an open manner. SPI Pharma doesnâ&#x20AC;&#x2122;t either, but this is not surprising given they are more specialised in providing materials for the customer to formulate rather than manufacturing finished products in their own facilities.

Bend Research does, however, makes a lot of assertions with recent press releases with Catalent and Dow Chemical, as well

as highlighting their commitment to process engineering and Quality-by-design on their website.

When looking at these companies I see some distinctions appear quickly. I can summarise them in the following, Table 2.

Some drug delivery companies are more likely to have their own QbD programs for a variety of reasons. Primary among them is that they are either 1) largescale manufacturer of finished goods or 2) Process-driven and scientific innovators or 3) both. How this is distinct from the classic model is that they are not bound by their platforms, they are freed by the fact they utilise whatever means they can to yield a desired outcome as per the original reasons stated regarding the purpose and goals of drug delivery companies.

Classic single platform drug delivery companies are trying to fit the optimal drugs into the constraints of the technology they are utilising and are covered by the IP they possess.

What can a drug company or potential partner / licensee do to ensure that QbD principles are being partially or wholly executed when working with a drug delivery company?

1. Decide, during the strategic development phase, whether a QbD approach is both viable and desirable. This will be dictated by lifecycle expectations,

Research & Development

value and ultimately the regulatory drivers prior to submission, such as OGD desire for QbD with Generic submissions from January 2013.

2. Really question the company about the

robustness of the technology! When the composition of a typical drug product is given, ask about the sourcing management and validation of the raw materials. It must be clear that the excipients

DD companies basic description of offering and recognised commitment to QbD–OSDF (Oral Solid Dosage Form)

utilised have a verifiable provenance.

It is more preferred if the excipient supplier has its own QbD program, rather than a supply chain dedicated to a simple adherence to specification or monograph.

This is easier said than done.

However, the potential benefits to the partners in such an agreement are numerous.

Company Names

Description of Service Offered

Broad Business Model

Commitment to QbD

Aptalis, Skyepharma, Orexo, Flamel

Classic Drug Delivery OSDF

Fee-For Service, Specialty

None open

Catalent

Classic with device Fee-For Service

Specialty

Yes, via Inhalation

SPI Pharma

Excipient Technology. Supplier of Technology. Manufacturer of ingredients.

Supplier with some fee-forsuccess

None

Bend Research

Hybrid

Process and formulation

YES Table 2

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size of the excipient, water-binding capacity and shape can be a big factor in areas such as roller-compaction and direct compression.

If this is the case, any sensitivity to large changes (within monograph specification and in specifications not listed) could have a dramatic effect on the drug product outcome. These may not show themselves until the process scales-up and go unobserved at the bench or pilot scale. These are the unknown unknowns paraphrased from Donald Rumsfeld(x).

In such a case if the QbD guidance was to be followed expplicitly, the drug delivery company submission would be subjected to a QbD type assessment of its technology. It is at this point that some may baulk at the idea.

However, a DD company that proceeds with a QbD approach ahead of time and identifies general QTPP for products it wishes to develop, can then proceed with identifying typical CQA and as such have a solid template. A knowledge space and a likely design space may well be sketched out before an active has been selected. This could significantly shorten the QbD DOE time and not unduly delay drug product development.

A u t h o r BIO

1. The DD company understands more about its technology platform. It might be surprised at how versatile it could be. More IP could be discovered this way.

2. The cost structure during manufacturing will have been optimised.

3. The post-approval regulatory framework will be easier to navigate 4. The licensee / partner will have much more confidence in the stability and safety of the product for long-term supply. This infers a presumed lower risk of product recall due to failures in dose uniformity and contamination.

A number of excipient companies are looking closely at their input to QbD. This could have far-reaching impact on drug and drug delivery companies.

Such organisations look to excipient companies to provide a stable product, with a solid history of production.

Now, however, QbD and a greater emphasis on regulation of excipients has led to a higher degree of scrutiny by personnel dealing with approving products.

Take, for instance, the guidance of an IR generic drug product. The example set forth in this guidance highlights the need to be fully aware of the potential impacts on the critical quality attributes of the formulation and product and how these relate to and meet the requirements of the Quality target product profile!

The drug delivery company’s knowledge of API aspects tends to be very high and in some cases deliberately managed, through milling or nano-sizing or polymorphism and salt selection. However, knowledge of excipient variance is still basic in many cases. Excipients most often come from natural sources–Cellulose, starch, lactose, minerals, other vegetable and animal products. As such, they have some inherent natural variability.

It has been shown in many studies that in certain processes the particle

Summary

Drug delivery companies are seeing a rich opportunity from outsourced R&D activity and the patent cliff a lot of innovatie companies face. Generic medicines that can be differentiated from the pack are being seen as potentially highly valuable to the marketplace. However, regulatory bodies in the major markets are paying ever closer attention to the raw materials used in drug products, not just the active ingredient. This will mean, for some, that QbD considerations will have to be put into development programs.

Clearly some DD companies already have QbD principles embedded in their mission or philosophy, but others seem slow to adopt even the language of QbD. It is likely that this space will have some time before it will fully need to comply, but by starting now the drug delivery companies could yield significant benefit in the medium-long term Excipient suppliers should explore this space carefully and with an eye to increasing awareness and the knowledge of the DD companies.

Drug product licensees and DD partners must include the potential requirements for QbD before selecting their development partners.

Alen Guy joined IMCD in 2010 as the Technical Director in the IMCD Business Group Pharmaceuticals. Dr Guy started his academic career in the field of high performance liquid chromatography where he learned much about how good health and general well-being work together. He has presented at numerous drug delivery and pharmaceutical conferences on topics such as co-processing of active ingredients and excipients, excipient innovation, orally disintegrating tablet technology, tastemasking and solid dose development.

Annie Zhang is a Technical Sales Manager at Pharmaceutical Business Unit of IMCD Group, based in Shanghai, China. She joined IMCD in 2011 to spearhead the Group’s pharmaceutical business in China. Ms Zhang began her pharmaceutical career as a formulation development and research fellow at China’s renowned–Shanghai Institute of Materia Medica-Chinese Academy of Sciences in 1997. During her tenure at the Institute, Ms. Zhang was responsible for formulation screening and optimisation for finished products, quality analysis and preparation of submission documents to SFDA etc.

Strategy

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Similar Biologics

A golden bird to tame Biologics are inherently different from chemicals drugs in terms of their source, structural complexity, fragility of the active substance, manufacturing, quality control and stability. Since chemical drugs have well-defined structure, their quality can be easily optimised and maintained, while the large and complex bio-molecules are difficult to manufacture everytime in a similar fashion and therefore, highly susceptible to heterogeneity.

Rajneesh Kumar Krishan K Tripathi Department of Biotechnology, Ministry of Science and Technology, India

I

n the past three decades, biotechnology-led medicines have revolutionised the treatment of several life threatening and rare diseases. The substances produced by living cells and used in the treatment, diagnosis or prevention of diseases are referred to as biologic drugs or biologics or biopharmaceuticals or recombinant therapeutics. Since the approval of first biopharmaceutical, recombinant insulin in 1982, the range and market of biopharmaceuticals has grown significantly. More than 250 biological products approved in various countries and 500 new products are in pipeline.

Biopharmaceuticals are now important therapeutic option for a variety of chronic and non-chronic diseases including the rare diseases.

Biologics are inherently different from chemicals drugs in terms of their source, structural complexity, fragility of the active substance, manufacturing, quality control and stability. Since chemical drugs have well-defined structure, their quality can be easily optimised and maintained, while the large and complex bio-molecules are difficult to manufacture everytime in a similar fashion and therefore, highly susceptible to heterogeneity. As a result,

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avoiding the batch to batch variation during their manufacturing is a highly challenging task. Besides, these manufacturing variations more often lead to immunogenic reactions and compromise the patient’s safety.

The patents of the first generation of biotechnology products have either expired or will expire shortly, thereby opening the market for introducing the follow on substitutes of the original biologics, these follow-on substitutes are popularly known as ‘biosimilars’. There are a number of terms used to describe these substitutes such as biosimilars, biologics, biogenerics, biopharmaceuticals, follow-on-proteins etc. These terms are confusing and do not include vaccines and blood products produced through recombinant route.

Recently, Review Committee on Genetic Manipulation (RCGM), Department of Biotechnology has adopted a substitute term ‘Similar Biologics’, which is defined as recombinant biologics similar to the original innovator product based on the comparability studies.

In 2009, recombinant proteins accounted for more than 65 per cent of the total global biopharmaceutical sales.

Growth in this class is expected to be low

in most of the developed markets as a result of biosimilar entry and increasing cost containment measures. The market share of emerging markets (Brazil, Russia, India, China, Mexico, Turkey and South Korea) is likely to increase from less than 5 per cent in 2009 to more than 8 per cent by 2015. The similar biologics have the potential to provide affordable biotech medicines, however, the issues and challenges associated with them needs establishing the appropriate regulatory pathways to ensure quality, safety and efficacy. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) was the first to recommend the guidelines for biosimilars but it is the European Union (EU), who implemented them first in 2006. EU was followed by several other countries like Australia, Canada, Malaysia, Japan and organisation like World Health Organization (WHO).

International status

European Medicines Agency i.e. EMA was first to develop a regulatory pathway for biosimilars, which they designated as ‘Similar Medicinal Biological Products

Strategy

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Research & Development

(SMBP)’. Article 10(4) of the EU’s Code for Human Medicines Directive (2001 / 83 / EC) was amended in 2004 (by Directive 2004 / 27 / EC) to authorise the abbreviated approval of biologic products that claim to be similar to an original innovator product. However, the legislation leaves a wide margin of discretion to the Committee for Medicinal Products for Human Use (CHMP; EMA) to develop product class-specific guidelines that determine the extent of nonclinical and clinical testing required to establish the safety and efficacy of a SMBP. EMA first released overarching guidelines on quality issues of SMBPs containing biotechnology derived proteins as active substance followed by separate guidelines focused on non-clinical and clinical issues.

In addition to these general guidelines they also drafted customised guidelines for different biotechnology based products such as Insulin, Erythropoietin (EPO), Granulocyte Colony Stimulating Factor (GCSF), Interferons and Growth Hormone.

In the USA, biologics are authorised for marketing through two regulatory pathways i.e. Biological License Application (BLA) procedure under Public Health Service Act (PHS, 1944) for regulation of biological produced by biotechnological methods (e.g., MAbs and therapeutic proteins) and abbreviated New Drug Application (NDA) procedure under Food Drug & Cosmetic Act (FD&C, 1938), which covers conventional pharmaceutical and certain natural proteins (e.g. insulins and growth hormone). The ANDA procedure allows approving only a limited range of biosimilars. In March 2010, US Federal Government amended Section 351 of the Public Health Services Act to create abbreviated biologic approval pathway for a 'highly similar’ biologic product.

A biosimilar must possess no clinically meaningful differences in the safety, purity and potency from the original innovator product and the product may be interchangeable if the product is biosimilar and show no clinically significant difference to the reference product.

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Very soon, more biotech based drugs are going to be out-of-patent and the related guidelines will decide the strategy of investment, molecule selection and marketing plans.

The new act also includes a 12 year data exclusivity period for all original products (with a six-month extension for products supported by paediatric studies). The act also provides one year data exclusivity to a first biosimilar approved for marketing to boost the availability of biosimilars. Though there is a mechanism now, the FDA is still not ready to give final shape to its biosimilar guidelines as a result of highly debatable data exclusivity and patent issues. Currently, both EMA and FDA guidelines are under revision.

WHO has developed a framework of general principles as monograph and part of its 'Biological Standardisation Process'. and prepared a 'Guidelines on evaluation of similar biotherapeutic products (SBPs)'. Biosimilar is designated here as 'Similar Biotherapeutic Product (SBPs)' and defined as a 'biotherapeutic product claimed to be similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product (RBP), which must have been licensed by national regulatory authorities on the basis of a full registration dossier'. However, WHO emphasises that its framework is generalised and will only apply to well-established biologics. Its guidelines emphasise the high standard of safety and require at least one clinical study for approval. In addition to pre-marketing safety study, the applicant has to submit a well devised plan for post-marketing clinical safety and surveillance.

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a joint initiative

involving both regulators and researchbased industry representatives of the European Union, Japan and the USA in scientific and technical discussions of the testing procedures required to assess and ensure the quality, safety and efficacy of medicines. The goal of ICH is to promote international harmonisation by bringing together representatives from the three ICH regions (EU, Japan and USA) to discuss and establish common guidelines. In July, 1997, ICH recommended the harmonized tripartite guidelines, for the preclinical safety evaluation of biotechnology-derived pharmaceuticals. The active substance include proteins and peptides, their derivatives and products of which they are components; they could be derived from cell cultures or produced using recombinant DNA technology including production by transgenic plants and animals. The guidelines may also be applicable including recombinant DNA protein vaccines, chemically synthesized peptides, plasma derived products, endogenous proteins extracted from human tissue and oligonucleotide drugs. The primary goals of preclinical safety evaluation are: 1) to identify an initial safe dose and subsequent dose escalation schemes in humans; 2) to identify potential target organs for toxicity and for the study of whether such toxicity is reversible; and 3) to identify safety parameters for clinical monitoring. In these guidelines, the biosimilars have not assigned any separate name and the list of products covered is too wide though they are considering them on case-by-case basis and don’t consider them as ‘same’.

Indian scenario

In India, Review Committee on Genetic Manipulation (RCGM), Department of Biotechnology is responsible for preclinical, export and import approval of biotechnology based recombinant drugs, while Central Drugs Standard Control Organization (CDSCO) and the Drugs Controller General of India (DCGI) is responsible for approvals of clinical trials, new drug applications,

Research & Development

Recombinant biological products (total 38) marketed in India Molecules

Therapeutic Applications

Human insulin

Diabetes

Erythropoietin

Treatment of anemia

Hepatitis B vaccine (recombinant surface antigen based)

Immunisation against Hepatitis B

Human growth hormone

Deficiency of growth hormone in children

Interleukin 2

Renal cell carcinoma

Granulocyte Colony Stimulating Factor

Chemotherapy induced neutropenia

Granulocyte Macrophage Colony Stimulating Factor

Chemotherapy induced neutropenia

Interferon 2Alpha

Chronic myeloid leukemia

Interferon 2Beta

Chronic myeloid leukemia, Hepatitis B and Hepatitis C

Interferons Gamma

Chronic granulomatous disease and Severe malignant osteopetrosis

Streptokinase

Acute myocardial infarction

Tissue Plasminogen Activator

Acute myocardial infarction

Blood factor VIII

Haemophilia type A

Follicle stimulating hormone

Reproductive disorders

Teriparatide (Forteo)

Osteoporosis

Drerecogin (Xigris) alpha

Severe sepsis

Platelet Derived Growth Factor (PDGF)

Bone marrow induction and osteoblasts proliferation

Epidermal Growth factor (EGF)

Mitogenesis and organ morphogenesis

Eptacogalpha (r-F VIIa) r-coagulation factor

Haemorrhages, congenital or acquired hemophilia

Bevacizumab

Treatment of various cancers, including colorectal, lung and kidney cancer,

Trastuzumab

Treatment of breast cancer

Rituximab

Treatment of many lymphomas, leukemias, transplant rejection and some autoimmune disorders.

Darbopoetin alpha

Treatment of anaemia

Human Serum Albumin

Treatment of liver disease with ascites.

Insulin Glargin

Treatment of Type I Diabetes Mellitus

Insulin Lispro

Treatment of Diabetes Mellitus

Insulin Aspart

Treatment of Diabetes Mellitus

Met-h-GCSF

Chemotherapy induced neutropenia

Peg-r-metHu-GCSF

Chemotherapy induced neutropenia

h-Interferon alpha 2b

Treatment of Chronic Hepatitis B

Peg-Interferon alpha-2b

Treatment of Chronic Hepatitis B

h-INF beta-1a

Treatment of multiple sclerosis (MS)

Peg-h-GCSF

Chemotherapy induced neutropenia

h-PDGF-BB-beta-TCP

Bone marrow induction and osteoblasts proliferation

r-h-Chorionic Gonadotropin Hormone

Role in Pregnancy

Hemophilic factor IX

Treatment of hemophilia

Cetuximab

Treatment of metastatic colorectal cancer and head and neck cancer.

Luteinising Hormone

Treatment of Reproductive disorders Table 1 www.pharmafocusasia.com

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Research & Development

marketing and the import of drugs in association with Directorate General of Foreign Trade (DGFT). The state drug control authorities are responsible for licensing a drug maker’s research and manufacturing facilities, while Institutional Biosafety Committees (IBSC) oversees the containment facilities.

As of now, no separate pathway for approval of recombinant drugs under the category of 'similar biologics' exists in India. Over 40 biologics are marketed in India, out of which around 25 are similar biologics. Another 25 similar biologics are in the final stages of development.

In India, whichever similar biologics is available, they are approved as ‘new drug’ under Drugs and Cosmetic Act, 1940.

Table-I represent the r-DNA technology based biopharmaceuticals already having marketing authorisation. Table II & III includes the r-DNA technology based biopharmaceuticals for pre-clinical studies or recommended for clinical studies to DCGI by Department of Biotechnology in a financial year 2010-2011. Under the current relaxed regulatory environment, Phase I & II clinical trials are typically not required for similar biologics approval in India unless it is found necessary in special cases. Phase III trials with a minimum of 100 patients are mandatory for establishing bioequivalence.

Currently, there are two serious concerns about the Indian regulatory system related to similar biologics. First, number of drug regulatory authorities involved in approval procedure, which makes the overall process time consuming and unnecessary lengthy. Second is the lack of clearly defined guidelines for similar biologics approval. The Indian government acknowledged the need for tighter regulatory standards. The major regulatory initiatives have been taken to make the approval process streamline through establishing a single window mechanism. Department of Biotechnology (DBT) has drafted a bill for the development of Biotechnology Regulatory Authority of India (BRAI), which will be tabled in the monsoon season (2011) of Parliament for discussion and 30

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hopefully will be cleared for developing the BRAI as an independent authority. BRAI will be an “autonomous and professionally led body to provide a single window mechanism for the biosafety clearance of genetically modified products and processes.” In other words, BRAI will replace many of the other bureaucracies. BRAI will also include a training center for its biotech regulators, to build and maintain their professional competence.

DBT is also in the process of preparation of separate guidelines for preclinical evaluation of similar biologics. DBT holds series of public meetings especially with Indian biotech industries to find out the issues related to the manufacturing and marketing of similar biologics. RCGM is a group of experts having both academic and on-field experience is entrusted for the formulation of similar biologics draft guidelines. RCGM is performing the judicious analysis of all the factors that affects the quality, safety and efficacy of a similar biologics product. It is pertinent to discuss some of these issues briefly.

A similar biologic is generally compared with an original innovator product to establish the safety and efficacy of the product. There are two major concerns related to the selection of a reference product. First, in the absence of availability of original innovator product in India, whether a similar biologics, already authorised for marketing in India, can be used as a reference product?

Second, whether some of supporting data of a reference product may be used as a part of subsequent similar biologics clearance and approval? In general, the

European Medicines Agency i.e. EMA was first to develop a regulatory pathway for biosimilars, which they designated as ‘Similar Medicinal Biological Products (SMBP)’.

EMA Guidelines (2004) indicate that the chosen reference product must be authorised in the country on the basis of a complete dossier. Utilising the reference product data for similar biologic approval makes the process less time consuming and expensive but it is not acceptable on grounds of manufacturing heterogeneity often observed in biopharmaceuticals.

Also any differences observed between a similar biologics and a reference product will have to be justified by appropriate studies on a case-by-case basis.

In general, the biophramceuticals are large, complex and heterogeneous molecules with more variable molecular weights in comparison to chemically originated small-molecules. The inherent complexity of these molecules makes their manufacturing susceptible to variation. Therefore, it is essential to maintain rigorous quality control at each step of manufacturing i.e. from fermentation to packaging. Changes may occur in the expression systems used for production, culture conditions (e.g. temperature and nutrients), purification and processing, formulation, storage and packaging. Small changes in, or differences occurred during manufacturing processes may have a significant impact on the quality, purity, biological characteristics and clinical efficacy of the final product e.g. ‘Valtropin’, a similar biologic growth hormone is different from its reference product ‘Humatrope’, probably because different cell lines are used in the production of these two drugs: yeast for Valtropin and Escherichia coli for Humatrope. Another example is the occurrence of pure red blood cell aplasia as a result of production of neutralising antibodies against a particular form of Epoetin-alpha.

Structural differences between proteins may arise for a number of reasons, including oligomerisation, modification of the protein primary sequence, glycosylation patterns or the conformational state. The analytical homogeneity is extremely crucial between a similar biologic and reference product to maintain the quality of a product. There are numerous examples where presence of process and product related

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List of r-DNA biotech medicines approved for pre-clinical studies during 2010-11.

Products

Institute / Industry

Pegylated Erythropoietin (PEG-EPO)

Intas Biopharmaceuticals Ltd., Ahmedabad

Recombinant anti-CD 20 mAb Recombinant human Follicle Stimulating Hormone (rhFSH) Pegylated recombinant human Interferon Alfa 2b (PEG-IFN) Reliance Life Sciences Pvt. Ltd., Mumbai

Darbepoetin alfa Recombinant humanized mAb against VEGF-A Recombinant mAb against HER2 receptor Recombinant human Pegylated Granulocyte Colony Stimulating Factor (rhPEG-G-CSF) Recombinant human Parathyroid Hormone [rhPTH(1-34)]

Lupin Limited, Pune

Recombinant human Granulocyte Colony Stimulating Factor (rhG-CSF) Recombinant human Interleukin-11 (rhIL-11) Recombinant anti-CD 20 chimeric mAb Recombinant mAb against HER2 receptor

Biomab Pharmaceuticals (India) Pvt. Ltd., Mumbai

Recombinant human Pegylated Granulocyte Colony Stimulating Factor (rhPEG-G-CSF)

Bioviz Technologies Pvt. Ltd., Hyderabad

Darbopoetin alfa

Hetero Drugs Ltd., Hyderabad

Recombinant Interferon -1b (rhINF- -1b)

Zenotech Laboratories Ltd., Hyderabad

Rituximab-Recombinant anti-CD 20 monoclonal antibodies

Cadila Healthcare Ltd., Ahmedabad

Recombinant human Granulocyte Colony Stimulating Factor (rhG-CSF)

Biogenomics Ltd., Thane

Recombinant human Insulin Analog (B28Lys, B29Pro) Recombinant human Exendin-4 (VB 63)

Virchow Biotech Pvt. Ltd., Hyderabad

Recombinant Enfuvirtide internally coated Live attenuated Rabies Vaccine

Intervet India Pvt. Ltd., Pune

Recombinant human Insulin

Bigtec Pvt. Ltd., Bangalore

Recombinant Anti-Staphylococcal Protein P128

Gangagen Biotechnologies Pvt. Ltd., Bangalore

List of r-DNA biotech medicines recommended

by RCGM to DCGI for appropriate phase of clinical trials during 2010-11.

Products

Table 2

Institute / Industry

Polysialylated Erythropoietin

Serum Institute of India Ltd., Pune

Recombinant monoclonal antibody targeting Vascular Endothelial Growth Factor “VEGF”

Biocon Ltd., Bangalore

Recombinant human Granulocyte Colony Stimulating Factor (rhGCSF)

Lupin Ltd., Pune

Recombinant human Follicle Stimulating Hormone (rhFSH)

Intas Biopharmaceuticals Ltd., Ahmedabad

Pegylated recombinant human Interferon Alfa 2b (rhPEG-IFN-α-2b) Recombinant Anthrax Vaccine

Panacea Biotec Limited, New Delhi

Recombinant anti-CD 20 Chimeric mAb

Reliance Life Sciences, Mumbai

Recombinant human Growth Hormone (rhGH) Palivizumab-Recombinant monoclonal antibody Abciximab-Recombinant chimeric monoclonal antibody (IgG1k) Modified Streptokinase

Symmetrix Biotech Pvt. Ltd., Mumbai

Recombinant Epsilon Toxoid

Indian Immunologicals Ltd., Hyderabad

Recombinant human Granulocyte Colony Stimulating Factor (rhG-CSF)

Scigen Biopharma Pvt. Ltd. (SBPL), Pune

Recombinant human Granulocyte Colony Stimulating Factor (rhG-CSF)

Cadila Pharmaceuticals Ltd., Ahmedabad

Recombinant Anti-Rho(D) Immunoglobulin

Bharat Serums and Vaccine Ltd., Mumbai Table 3

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impurities resulted in substantial variation in a similar biologic. For example, almost 60 per cent of patients treated with recombinant human Growth Hormone (rhGH) powder manufactured by API Covance (Somatropin Sandoz powder) developed anti-GH antibodies and all patients developed antibodies against E.coli proteins, while only about 2% and 0% of patients develop anti-GH and anti-HCP antibodies respectively when treated with a innovator / reference product ‘Genotropin’ (Pfizer), [4]. The additional purification steps are included in order to ensure the tolerability and efficacy of the product.

Another hurdle in quality assurance is the inherent limitations of the biological assays. Therefore, the biological assays should be performed simultaneously and parallelly on a similar biologic and reference product under the same laboratory conditions to mitigate or reduce the assay errors. The most important among all the biological assays is the toxicity studies including toxicokinetic measurements such as determination of antibody titres, cross-reactivity and their neutralising capacity. A biological product may be toxic due to its degradation during storage in the distribution chain before reaching to the end consumer. Therefore, the comparability studies may also include the comparative data for accelerated and long term stability to make sure the quality and safety of a product during storage.

The analytical comparison of a similar biologic with a reference product does not guarantee about the behaviour of a product in human biological system.

Therefore, it is undoubtedly essential that the applicant must submit elaborate in-vitro and in-vivo pharmacological and toxicological studies data as a part of application dossier. Safety pharmacology, reproduction toxicity, mutagenicity and carcinogenicity studies may not be required unless specifically desired in a particular case.

Generally, the biological products obtained from one system are immunogenic when introduced in another biological system. Mostly similar biologics 34

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are recombinant proteins and antibodies, their introduction might trigger a severe immunogenic reaction especially when the patient is already exposed to a molecule. Immunogenicity should be evaluated using appropriate studies and methods to characterize type, concentration and titre of antibodies. When neutralizing antibodies are detected, the impact on Pharmacokinetic (PK) and Pharmacodynamic (PD) parameters and overall efficacy and safety should be analysed well. This is particularly true for proteins with post-translational modifications such as glycosylation where small differences in glycosylation pattern can result in significant differences in immunogenicity profile.

Conventional generics of chemical origin are considered to be therapeutically equivalent to a reference product if it has pharmaceutical equivalence (i.e. identical active substance) and bioequivalence (i.e. comparable pharmacokinetics). The inherent complexity of biopharmaceuticals makes it difficult to avoid heterogeneity among different batches and from different manufacturers. The challenging task is to decide whether abbreviated clinical trial should be made mandatory or data requirement should be restricted and desired only on case by case basis. Clinical trial for a similar biologic is estimated to cost US$ 26.5 - 53mn. After including the cost of approval through the regulatory process and the cost of marketing and detailing, the estimated cost would be US$ 50mn and US$ 300mn with a manufacturing plant. This is certainly a huge investment for any single copy-cat drug.

The estimated cost will definitely reduce the profit margin. Therefore, the major question is can clinical trials be skipped by taking the comparability studies as standard in cases which are known to be safer. The argument in favor of restricting the clinical trials is that if a similar biologic is substantially similar to a reference product during comparability studies and then most probably it will behave in the same fashion in human system as the reference product. Argument in favor of making the clinical trials mandatory is that

even animal (pre-clinical) studies do not guarantee the absolute safety and efficacy of any biological product in a human system. So, RCGM need to weigh the pros and cons of all possibilities related to clinical trials and then appropriately implement the best possibility in case of similar biologics.

Once a product is authoried for marketing, it is desirable to access and monitor its effect in terms of safety and toxicity in human population. In case, the Indian regulatory authorities restricting the clinical trials during approval of similar biologics, the post-marketing surveillance will be extremely important e.g. In Korea, three biosimilars of Epoetin-alfa i.e. ‘Eporon’ (Dong-A Pharmaceutical Company Ltd), ‘Espogen’ (LG Life Sciences), ‘Epokine’ (CJ Corporation) have been shown to differ in the activity, concentration, isoforms, structural stability from the reference product ‘Epogen’ (Amgen, USA)[5]. Like EMA, the Indian regulatory authority may ask companies to submit self-executable pharmacovigilance plan as a part of approval process or collect the similar biologics field samples randomly and then testing them in governmental laboratories. The second option is more practical especially in the absence of a very well established pharamcovigilance system in India. Recently, Central Drugs Standard Control Organisation (CDSCO) has taken an initiative to establish a Pharamcovigilance Progarmme of India (PvPI), which is expected to be fully operational by 2015. PvPI will definitely open the door for the regulatory authorities to keep stringent on-field vigil for ensuring the safety and efficacy of drugs in general.

Conclusion

The huge Indian market and the margin associated with similar biologics is highly lucrative for many big players in the biotech sector. Many of them are very curious about the regulatory pathway not only in India but also in other markets like USA. Very soon, more biotech based drugs are going to be out-of-patent and the related guidelines will decide the

Research & Development

References 1. Global Biopharmaceutical Market Report (2010-2015) by IMARC available at http:// www.imarcgroup.com/global-biopharmaceutical-market-report-2010-2015/(Last accessed on 16-08-2011) 2. Peterkova, V. et al. (2007). A Randomized,

Double-Blind Study to Assess the Efficacy and Safety of Valtropin, a Biosimilar Growth Hormone, in Children with Growth Hormone Deficiency. Horm. Res. 68(6), 288-293 3.Casadevall N, Rossert J. (2005). Importance of biologic follow-ons: experience with EPO. Best Pract. Res. Clin. Haematol. 18, 381-387 4. Declerck et al. (2010). BiosimilarsControversies as illustrated by rhGH. Curr.

A u t h o r BIO

strategy of investment, molecule selection and marketing plans. While framing the guidelines for similar biologics, Indian regulatory authorities will try to keep a balance between making available the high quality similar biologics at a cheaper price to Indian consumers and cost advantage to biotech industries so that they remain interested in manufacturing them. DBT has advocated to keep biotech medicines out of price control (DPCO) to facilitate growth of this industry for the benefit of society and has the aim that let market forces decide the price through competitive process.

Med. Res. & Opin. 26, 1219-1229 5. Deechongkit et al. (2006). Biophysical comparability of the same protein from different manufacturers: a case study using Epoetin alfa from Epogen and Eprex. J. Pharm. Sci. 95, 1931-1943 Note: The views expressed are personal to the authors and have no relation with their official position in Department of Biotechnology.

Krishan Kumar Tripathi is Doctorate in Microbiology from Panjab University, Chandigarh. He worked in the pharmaceuticals and biological industries and has got extensive exposure to production and quality control techniques of life saving bacterial and viral vaccines. His noteworthy work includes the reduction in immunisation-schedule of neural rabies vaccine, saving livestock and mam-hours to visit clinics, having indirect benefits to economy. Since last 21 years, he has been working in the Department of Biotechnology, Govt. of India Rajneesh Kumar Gaur completed his doctorate in Structural biology from RWTH, Germany and having almost 8 years of experience in active science research. He is currently engaged in planning, co-ordination and International cooperation in Department of Biotechnology, Ministry of Science and Technology, New Delhi, India. He is interested in S&T policy matters.

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Manufacturing

Continuous Process Performance Monitoring Using Nelson Rules Process monitoring is the method of collecting process data and statistical evaluation of critical process parameters to identify unplanned and unforeseen process changes and shifts / drifts, in order to verify and demonstrate that the process is operating in a state of control. Process data is statistically evaluated using control charts by applying Nelson rules. These rules are used as a tool to determine if some measured variable is out of control i.e. unpredictable versus consistent. These rules are for detecting 'out-of-control' or 'non-random conditions'.

Hitesh Patel, Assistant General Manager, Quality Assurance Shaligram Rane, Sr. General Manager, Quality Rustom Mody, Executive Vice President, Science & Technology Intas Biopharmaceuticals Ltd., India

R

egulatory agencies expect, that there should be a system, for process monitoring for detecting unplanned departures from the process during manufacture and to identify future process improvement opportunities, in order to provide continual assurance that the process is in a state of control (validated state) during manufacture to ensure desired product quality.

Process monitoring is the method for collecting process data and statistical evaluation of critical process parameters to identify unplanned and unforseen process changes and shifts / drifts, in order to verify and demonstrate that the process is operating in a state of control.

Process monitoring also helps to identify areas for continual improvement.

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Manufacturing

Following guidance has been issued by various agencies related to process monitoring.

• FDA process validation guide (stage 3)[ 1 ] states that: An ongoing program to collect and analyse product and process data that relate to product quality must be established (§ 211.180(e)). The data collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products. The data should be statistically trended and reviewed by trained personnel. The information collected should verify that the quality attributes are being appropriately controlled throughout the process.

• 21 CFR 211.110 (a) [ 2 ] states that: To assure batch uniformity and integrity of drug products, written procedure shall be established and followed that describe the in-process controls and tests, or examinations to

be conducted on appropriate samples of in-process materials of each batch. Such control procedure shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and drug product.

The GMP regulations at 21 CFR 211.110(b) also require the use of ‘suitable’ statistical procedures to evaluate drug variability.

The ICH Q8 guidance (2.3) [ 3 ] states that: In order to provide flexibility for future process improvement, when describing the development of the manufacturing process, it is useful to describe measurement systems that allow monitoring of critical attributes or process end-points.

Collection of process monitoring data during the development of the

manufacturing process can provide useful information to enhance process understanding.

The ICH Q10 guidance (3.2.1) [ 4 ] identifies monitoring as a key element of the pharmaceutical quality system and states that: Pharmaceutical companies should plan and execute a system for the monitoring of process performance and product quality to ensure a state of control is maintained. An effective monitoring system provides assurance of the continued capability of processes and controls to meet product quality and to identify areas for continual improvement.

Continuous process monitoring

Good process design and development anticipates significant sources of variability in critical process parameters and establishes appropriate detection, control, and / or mitigation strategies,

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Manufacturing

as well as appropriate alert and action limits. However, a process is likely to encounter sources of variation that were not previously detected or to which the process was not previously exposed.

There are two different approaches that are used in monitoring of biopharmaceutical manufacturing processes.

The first approach focuses on data from a single lot. Such data associated with a particular lot are reviewed before releasing that lot. A data point beyond a control limit referred to as out of specification (OOS) for a given process, would cause a non-conformance that would have to be accounted for as part of the lot disposition process. The second monitoring approach analyses process performance data across lots

looking for trends i.e. to identity any out of trend (OOT) from the normal process.

Intas Biopharmaceuticals Limited (IBPL) has an ongoing programme to collect and analyse product and process data that relate to product and process quality as required by various regulatory bodies. The data collected by IBPL includes relevant process trends, quality of incoming materials or components, in-process materials, and finished products and is statistically trended on an ongoing basis (live) and also annually in the form of Annually Product Quality Review (APQR). The trends are reviewed by trained personnel to ensure that quality attributes are being appropriately controlled throughout

the process and to identify variability in the process to signal potential problems and identify areas of process improvements as expected by various regulatory agencies.

IBPL uses many tools and techniques to detect variation, characterise it, and determine the root cause.

Review includes scrutiny of critical process parameters (as defined in the batch manufacturing record) as well as analysis of inter-batch variation as a part of a comprehensive continuous process verification program.

Data is statistically analysed using control charts. A control chart is a plot of a process parameter or product characteristic over time, which includes upper and lower control limits (UCL

Following are the rules[5,6]: Rule 1

Rule 2

One point is more than 3 standard deviations from the mean.

8&/

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Nine (or more) points in a row are on the same side of the mean.

8&/

V V

V V

B ;

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Highlighted samples are grossly out of control.

Rule 3

V

B ;

Inference: Some prolonged bias exists.

Rule 4

Six (or more) points in a row are continually increasing (or decreasing).

8&/

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Fourteen (or more) points in a row alternate in direction, increasing then decreasing

8&/

V

V V

B ;

38

V

B ;

V

/&/

/&/

Inference: A trend exists.

Inference: This much oscillation is beyond noise.

This is directional and the position of the mean and size of the standard deviation do not affect this rule.

This is directional and the position of the mean and size of the standard deviation do not affect this rule.

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and LCL, respectively) and a centerline calculated from the process data.

These upper and lower control limits are derived statistically, and provide bounds for the natural variability of the process. Upper and lower control limits are typically established at Âą3 Standard Deviations above and below an established process mean; individual points are evaluated against these limits using Nelson rules.

The Nelson rules were first published in the October 1984 issue of the Journal of Quality Technology in an article by Lloyd S Nelson [5,6].

These rules are used as a tool to

determine if some measured variable is out of control i.e. unpredictable versus consistent. These rules are for detecting 'out-of-control' or 'non-random conditions' The Nelson rules are applied to a control chart on which the magnitude of some variable is plotted against time.

The rules are based around the mean value and the standard deviation of the samples.

The Nelson rules were based on dividing the control chart into eight segments using one, two, and three standard deviations above and below the centerline. These rules are very useful

Rule 5

in process monitoring; particularly Nelson rules 1 through 4.

Control chart and Nelson rules assist in determining whether observed variability is likely to be because of â&#x20AC;&#x153;chanceâ&#x20AC;? (isolated incident) or the result of some (perhaps as yet unidentified) process shift or change.

Variation in the process could be due to common or special causes of variation. Common causes refer to the many unknown sources of variation that go into producing a natural variation that is predictable within limits.

Special causes (also known as assignable cause) refer to the sources of variation

Rule 6 Two (or three) out of three points in a row are more than 2 standard deviations from the mean in the same direction.

8&/

V

Four (or five) out of five points in a row are more than 1 standard deviation from the mean in the same direction.

8&/

V V

B ;

V V

B ;

V

/&/

/&/

Inference: There is a medium tendency for samples to be mediumly out of control.

Inference: There is a strong tendency for samples to be slightly out of control. The side of the mea n for the fifth point is unspecified.

The side of the mean for the third point is unspecified.

Rule 7

Rule 8 Fifteen points in a row are all within 1 standard deviation of the mean on either side of the mean.

8&/

Eight points in a row exist with none within 1 standard deviation of the mean and the points are in both directions from the mean.

V

8&/

V B ;

V

V V

B ;

V

/&/

/&/

Inference: With 1 standard deviation, greater variation would be expected.

Inference: Jumping from above to below whilst missing the first standard deviation band is rarely random.

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Manufacturing

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Use of nelson rules in monitoring process performance

Following are the examples in which Nelson rules helped in monitoring and identifying common cause or special cause of various in the manufacturing process.

40

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that are not part of the natural variation and usually can be traced to an assignable cause.

als were released by Quality Control since the test values were within the defined release specification. Yield again increased as soon as fresh materials from different manufacturing lots were used. (one material lot was changed from

batch no. 40 and second material lot was changed from Batch No 43). The cumulative impact on Pegylation yield (%) was found after batch no. 43.

As a CAPA, for better control of the pegylation process two additional tests

Nelson Rule

Statistical Number of Samples Required for Violation

1

2

2

9 or more

Example 1

3

6 or more

While monitoring the step yield of a pegylation process for one of the products, a shift in the trend from batch No 017 was observed as shown in Figure 1.

The reason for the shift was identified to be due to change of manufacturing lot of two critical raw materials used in the pegylation process. Both materi-

4

14 or more

5

2 or 3

6

4 or 5

7

15

8

8

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Nelson rules and statistically valid number of samples required.

Table 1

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Manufacturing

Example 3

When interpreting with limited number of batches it shows breach of Nelson rule 1, but at the time of APQR (with more number of data points) it shows no violation of nelson rules.

In another case the converse was observed. There was no violation

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during online monitoring (with limited number of batches). However, rule 1 was violated when trend from more batches was plotted.

Summary

Nelson rules are useful in detecting process related problems. Except in case of rule 1 the samples required before a rule is found to be breached is anywhere from 2 to 15.

Table-1: Nelson rules and statistically valid number of samples required.

Thus, when the problem is detected (after the statistical number of observations are made as shown in above Table) the product produced from these batches would already be released to the market. This is because the rule is not breached until the required statistical numbers of manufacturing lots are produced as shown in Table-1. Nevertheless, it helps in identifying a problem and with appropriate CAPA more process consistency can be addressed.

Nelson rules are very useful in monitoring and controlling process and providing opportunity for process improvement.

Quality department at IBPL continuously trends and provides

feedback on process performance to production department based on the on-going (live) trending. Both departments together evaluate data, discuss possible trends or undesirable process variation, and decide on the CAPA which would help in controlling process thereby ensuring desired product quality.

References: 1) FDA -Guidance for Industry: Process Validation: General Principles and Practices â&#x20AC;&#x201C; Revision 1 January 2011.

2) US 21 CFR PART 211â&#x20AC;&#x201D;Current Good Manufacturing Practice For Finished Pharmaceuticals 3) ICH Q8(R2) Pharmaceutical Development 4) ICH Q10 Pharmaceutical Quality System 5) Nelson rules - http://pediaview.com/ openpedia/Nelson_rules 6) Nelson rules - http://aleduc.iweb.bsu. edu/itmfg265/Misc/nelson_rules.htm 7) Paul Konold, Rob Woolfenden II, Cenk Undey, Anurag S. Rathore, PhD BioPharm International Volume 22, Issue 5 Monitoring of Biopharmaceutical Processes: Present and Future Approaches Enhance your control strategy with robust monitoring methods

Hitesh Patel is Asst. General Manager Quality Assurance of Intas Biopharmaceuticals Ltd, a leading company in the field of Biosimilars. He has over twenty one years of experience. He is associated with the Intas for the past 7 years. His academic qualification (B.Sc.) is in the area of Chemistry.

A u t h o r BIO

were introduced in the testing of one of the critical materials, thereby better process control was achieved.

Pegylation yield (%) in all batches were within the set acceptance criteria of NLT 65% and found more than this defined specification.

Another example was of step yield in anion exchange chromatography step for one of the product.

In the above graph, batch no. 86 had clearly broke Nelson rule 1 which clearly indicates process was grossly out of control. On investigation it was found that column was packed with new resin after batch no 85.

The control chart clearly showed the impact of a change made in the process. Initial batches (72 to 85) had less % step yield (average 36.21%) which then significant increased (average 51.31 %) from batch no. 86 onwards due to change of resin. This indicates that the column resin plays an important role in consistent performance of the chromatography step. To better control the process. It was decided to define the, frequency of replacement of resin after observing trend from more number of batches.

While interpreting Nelson rules online with limited number of batches initially and latter with more number of batches, (generally at the time of annual product review) it is possible to observe different rules being breached for the same batch at different time point. This happens because of shifting of the centre line and its corresponding 3 standard deviation. With more batches, the mean (centre line) changes and with it the applicable Nelson rule changes. This is depicted in the example below.

Shaligram Rane is Sr. General Manager (Quality) of Intas Biopharmaceuticals Ltd, a leading company in the field of Biosimilars. He has over twenty years of experience. He has been directly involved in technical, techno-commercial and business progression rDNA products. His academic qualifications are M.Sc. M.Ed. and Ph.D. Rustom Mody has been directly involved in technical, technocommercial and business progression rDNA products from clone to commercialisation. He holds extensive experience in research of biosimilar products. His academic qualifications are M.Sc. & Ph.D. I did my Post-Doctorate at University of Nebraska Medical Centre at Omaha (USA).

Events Nov 07–09, 2012

API China / Interphex China

Nanjing International Exhibition Center, Nanjing, China http://www.apichina.com.cn Nov 21–23, 2012

CPhI / ICSE / P-MEC / BioPh India Mumbai, India www.cphi-india.com Nov 27–30, 2012

Pharma Quality & Compliance Summit Asia 2012 Hilton Hotel, Singapore www.pharmaquality-compliance.com Dec 04–06, 2012

PHARMCHINA

China Import and Export Fair Pazhou Complex, Guangzhou, China http://www.pharmchina.com.cn Jan 12-16, 2013

SLAS 2013

February 26-27, 2013

Taiwan Trials 2013

Taipei, Taiwan http://www.imapac.com/index.php?page=BiologicsW orldkorea2013 March 05–07, 2013

Vaccine World Summit 2013 Pune, India www.imapac.com March 05–07, 2013

INFARMA 2013

Barcelona, Spain–Europe http://www.eventseye.com/fairs/f-infarma-1355-1.html March 18-21, 2013

BioPharma Asia Convention

Resorts World Sentosa, Singapore http://www.terrapinn.com/exhibition/biopharma-asia/ index.stm April 16-18, 2013

Biologics World Korea

Seoul, Korea http://www.imapac.com/index.php?page=BiologicsW orldkorea2013 April 23–25, 2013

Gaylord Palms Hotel and Convention Center in Orlando, Florida www.slas2013.org

Interphex 2013

Jan 15-18, 2013

May 08–10, 2013

Pharma Bio World Expo 2013

Javits Center, New York City www.interphex.com

BIO tech

Bombay Exhibition Center, Western Express Highway, Goregaon (E), Mumbai http://www.pharmabioworld.com

Tokyo Big Sight, Tokyo, Japan http://www.bio-t.jp/en

February 18-19, 2013

ISPE Singapore Conference

Advances and Progress in Drug Design Copthorne Tara Hotel, London, UK www.smi-online.co.uk

June 02–04, 2013

Education Platform for the Regional Pharma Manufacturing Industry, Suntec, Singapore http://www.ispesingaporeconference.com

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43

INFORMATION TECHNOLOGY

Can Animation Software Help Find Cures for Cancer and HIV? Visual effects software is more commonly associated with the movie and gaming industries, but is today being used in pharmaceutical and life science research laboratories to digitally visualise, simulate and replicate micro biological processes that may bring us closer to solving some of humanityâ&#x20AC;&#x2122;s most pressing medical problems.

V R Srivatsan, Managing Director, ASEAN region, Autodesk Asia

W

hile 3D animation and visual effects have traditionally been associated with the movie and gaming industries, the same software used to create blockbuster games and movies is now moving beyond the silver screen: into the research laboratories of the leading players in the healthcare, pharmaceuticals and life sciences industries.

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Enter the era of bio-visualisationâ&#x20AC;&#x201C; where the tools used by the likes of Disney and Pixar studios are used to bring complex biological data to life, making it possible to digitally visualise, simulate and replicate micro biological processes on a molecular level, in far greater detail than possible with traditional equipment.

While not yet prevalent in the life sciences industry, these new techniques

and technologies are gradually being employed to communicate complex concepts, research, and models in the biological sphere in a manner that is visual, immersive and engaging. Within the scientific community, animation is gaining prominence and value due to its ability to aid communication, both among industry experts as well as nonspecialist audiences.

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INFORMATION TECHNOLOGY

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With Maya recently available for free to educators, the next generation of scientists and researchers stand to benefit immensely from the power of software.

Beyond the research laboratory, the use of visualisation software and tools is almost essential to communicate effectively with broader audiences, many of which are critical to the growth of the scientific community. Visual communication becomes yet more crucial when new findings in the field develop into products or techniques that are ready to hit the market, in helping to inform and eventually secure buy-in from investors, marketers, regulators and even end-consumers about the product in a way that is easy and engaging for non-technical audiences to consume.

Visualisation software is also gaining ground in the field amongst educators, who are using these tools to make learning more accurate, wholesome and exciting with many of the intricate biological structures, techniques and processes being illustrated and animated in realistic 3D. Already, special plugins exist for Maya users to download special “Molecular Maya” toolkits, designed specifically for professionals in the biological field, to download data from scientific databases that can be automatically translated into 3D models. Pioneered by Dr Gael McGill, Director of Molecular Visualisation at A uthor B I O

Among industry experts, Hollywood’s tools of the trade are particularly useful in the research process, helping researchers to accomplish their work in a matter of months rather than years. For example, being able to visualize and analyse new drug formulations on a molecular level, and thereby simulate adjustments and how these affect medical effectiveness can have profound effects on the time taken for the drug to make it to the market. The added benefit of having digital visualisations of a complex research project also mean that findings can be easily communicated amongst expert team, even across borders, enabling greater collaboration and coordination to ensure commercial success.

Already, moviemaking technology has had a hand in enabling significant scientific breakthroughs in experimental medical studies, including that of cancer research. Using a plug-in called CADnano, built on the Autodesk Maya platform, researchers from the Wyss Institute for Biologically Inspired Engineering at Harvard University have achieved encouraging results with a technique called DNA Origami. The plug-in uses the powerful capabilities of Maya software, a staple in visual effects in the entertainment industry, to model individual strands of DNA into a complex web of patterns that perform “smart” functions in what the team calls a “nanorobot”. In trials conducted at the Wyss Institute, the nanorobots created were able to target specific pathogenic cells, releasing a payload of antibodies on contact with leukemia cells with little collateral damage to surrounding healthy tissue.

These findings, while still in an early stage, provide an encouraging development in the field of the life sciences.

With the open-source plug-in available for researchers the world over, scientists can now leverage the power of 3D visualisation tools to explore yet more exciting possibilities with DNA Origami.

Harvard Medical School and founder of Digizyme, a multimedia biotech company specialising and educational and promotional animations for life sciences applications, the toolkits integrate the Rutgers Protein Database into Maya’s code base so that users no longer need to build molecular animations from scratch. With Maya recently available for free to educators, the next generation of scientists and researchers stand to benefit immensely from the power of software used by Hollywood’s largest production houses to take medical pedagogy to the next level.

This technology has allowed McGill’s team to develop accurate animations of scientific processes that remain hidden to the human eye, because the structures involved are too minute, or the timescales of the processes–rapid like the conformational changes of a protein, or prolonged as with ecological and evolutionary shifts–are beyond the perception of the human senses. His work includes visualisations on the process of viral infection, where viral surface protein spear target cell membranes–which may hold potential keys to unlocking better understanding on how to treat fatal infections like HIV. In equipping not just industry experts, but also young medical students with new ways to explore and discover the natural world, scientists and educators of today can help create an environment that not only promotes better understanding of the life sciences field, but also opens up avenues to pursue and investigate new scientific breakthroughs that may hold the secrets to unlocking cures for some of the world’s most deadly illnesses.

V R Srivatsan has over 22 years of experience in the IT industry, helming various leadership roles with multinational organisations with SAP and Oracle. He is responsible for the overall strategy and growth of Autodesk’s business in the ASEAN region across the various geographies, industries and product segments.

Building strategic partnerships across the region will also be his key focus area.

BioAsia 2013

Exploring the NEXT trends in Biotechnology: Biologics and Biosimilars

T

he emerging global shift from pharmaceutical drugs to biopharmaceuticals and its impact on human life and bio-business clearly underlines the dynamic and self -evolving nature of Lifesciences. But the real challenge for us would be to comprehend the possibilities of this change and ride them into the future. It is this very challenge that is the focus of BioAsia 2013, the 10th edition of one of the most awaited, successful and broad-spectrum global platform on Biotechnology and Lifesciences.

However, merely understanding the challenge from a global perspective and through global participation is not the goal of this dynamic platform.

Over the last nine editions, BioAsia has

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built up a formidable reputation for bringing together the entire universe of Lifesciences face-to-face to discuss, analyze, showcase, explore and connect strengths, trends and perspectives in order to extend the visible horizons in thought, possibility and innovation. To that end, it is both incisive and all invasive, inviting the participation of who's who of this industry, be it countries, pharmaceutical giants, regulatory authorities, thought-leaders, research scholars, trade experts and every other stakeholder of this industry.

Therefore in keeping with the previous successful editions, BioAsia 2013 through the succinct, cutting-edge theme of TECHNOLOGIES. BUSINESS. NEXT will not just showcase but explore

a bio-future waiting to be shaped by the new industry leaders: Biologics and Biosimilars.

Why Biologics and Biosimilars?

The advancements in Biologics are not just rapidly realigning perceptions regarding medical concepts but also opening up an entire world of new opportunities and possibilities in the area of biopharmaceutical drugs. The annual global sales of Biologics leapfrogged from $ 30 billion (1999) to $ 139 billion (2010) clearly underlining it as the next hub of investment opportunities in Lifesciences. Studies also clearly indicate that in the coming decade, Biologics will dominate the global bio-pharmaceutical drugs market,

since 8 of the top 10 blockbusters of 2014-15 are going to be Biologics or biotechnological products. In close conjunction to this spurt of growth in Biologics, Biosimilars has begun to draw increasing interest clearly fueled by the expiry of patents due on at least 48 Biologics with a combined global market size of nearly $ 73 billion across the globe over the next decade. Added to this is the increasing demand for low cost medicines from healthcare players around the world as they struggle to contain soaring healthcare bills especially from aging populations segments.

Given the current environment, the good news is India stands to own quite a few cutting-edge advantages: lower R&D costs, strategic plans for clinical trials, future commercialisation with companies in the US and Europe, a solid foundation in scientific intellectual capital and technical framework ensuring world class quality standards have already given the Indian pharmaceutical companies a head start over their global counterparts. Statistically, the Indian Biologics market already accounts for 62% of $ 3 billion revenue by the biotechnology industry as a whole.

Harnessing the NEXT big idea.

Clearly Biologics and Biosimilars is the NEXT big opportunity in the biotech universe and in order to harness it BioAsia 2013 has identified the 6 key focus areas, viz Biologics Novel Drug Discovery, Monoclonal Antibodies, Regenerative Medicine, Biosimilars, Intellectual Property Rights, Mergers & Acquisitions and Financial Eco-System. The global forum is poised to bring together 50 + countries, 500+ corporate and over 150+ Indian companies, 40+ regulators from top organisations including USFDA, EMA, MHRA, NIH, SFDA and the Central Drugs Standard Control Organisation (CDSCO), India, 60+ high profile speakers, VCs, research organisations and academia in order to debate, discuss, analyse current trends and future opportunities.

Enabling opportunities NEXT.

Pioneering perspectives will be shared through expert sessions and panel discussions, while specially conducted workshops and Bio-park visits to the Genome Valley Industries will unveil labs of the future the nucleus of emerging change and innovation. Exclusive and by-invite-only CEO conclave, Networking Receptions, Power Breakfasts and a specially designed Technology Transfer Summit during the three days will enable leading industry peers to exchange thoughts and views and feel the pulse of the things to come.

Trade being a big part of the industry will be given due and even, special importance through the Bio-bazaar - the one-stop shop for Indian sellers and international buyers to connect - BioAsia Connect or business partnering and the International Trade Show. BioAsia 2013 will go the extra mile to provide the infrastructure to enable brands to showcase their

strengths to the widest possible audience and empower mergers and collaborations through exhaustive business networking.

In all, BioAsia 2013, hosted by FABA in association with Genome valley, State Govt. of AP and Pharmexcil is going to be the window to the future of Lifesciences. Every aspect of it will be on display, but what you see, how much you see and what you make of it will depend entirely on you. However, one thing is for sure. Like all the earlier editions of BioAsia, BioAsia 2013 too will deliver the ultimate platform to anticipate the next required shift in perspective, vision and innovation in Lifesciences.

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Books

Stem Cell Bioprocessing: For Cellular Therapy, Diagnostics and Drug Development Authors: Joaquim M. S. Cabral, Maria Margarida Diogo, Tiago G Fernandes No of Pages: 250 Year of Publishing: January 31, 2013 Description: This book describes the main large-scale bioprocessing strategies for both stem cell culture and purification, envisaging the application of these cells for regenerative medicine and drug screening. Bioreactor configurations are described, including their applications for stem cell expansion and / or differentiation. Stem cell separation techniques are also discussed, aiming towards both isolation and purification of rare stem cell populations. The book also focuses on methodologies currently used for in vitro stem cell culture under static conditions, including the challenge of xeno-free culture conditions, as well as culture parameters that influence stem cell culture. Novel approaches for both stem cell culture and separation in micro-scale conditions are presented, including the use of cellular microarrays for high-throughput screening of the effect of both soluble and extracellular matrix molecules and the use of microfluidic devices for both stem cell culture and separation. A further section is dedicated to application of stem cells for regenerative medicine including on-going clinical trials.

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Clinical Trial Management: An Overview

Nanomedicine and Drug Delivery

Authors: Umakanta Sahoo, Dipti Sawant No of Pages: 250 Year of Publishing: December 18, 2012 Description: Clinical trial management is designed to show the various activities that are involved in clinical trials and understand their processes, which are essential for planning and implementing a successful clinical trial. This book also facilitates the understanding of the importance of ethics in clinical studies and the evolution of various guidelines, rules and regulations for the management of a clinical trial. Recruitment and retention of valuable patients are critical to the success of a clinical trial and hence pose a large number of challenges for the management team to complete the trial in multiple countries with the desired number of patients enrolled in time. This book also helps readers to understand the strategies to tackle issues like enrolment of a special population, cultural and socio-economic and language issues that act as a potential barrier in clinical trial management.

Authors: Mathew Sebastian; Neethu Ninan; A. K. Haghi No of Pages: 270 Year of Publishing: July 01, 2012 Description: Written by some of the most innnovative minds in medicine and engineering, this unique volume will help professionals understand cutting-edge and futuristic areas of research that can have tremendous payoff in terms of improving human health. Readers will find insightful discussions of nanostructured intelligent materials and devices that are considered technically feasible and which have a high potential to produce advances in medicine in the near future.

Drug Interaction Analysis and Management 2013

Analogue-based Drug Discovery III

Authors: : Philip D. Hansten, John R. Horn No of Pages: 2032 Year of Publishing: March 19, 2013 Description: Researched and written by interaction experts Philip D. Hansten, PharmD, and John R. Horn, PharmD, Drug Interactions Analysis and Management assists in the prevention and management of drug interactions. Designed for health care providers who prescribe, dispense, or administer medications, Drug Interactions Analysis and Management emphasizes management options for improved patient outcomes and includes recommendations for alternative medications, as appropriate. Based on clinical as well as case-study findings, each monograph includes a clinical evaluation section with references.

Authors: : Janos Fischer, C. Robin Ganellin, David P. Rotella No of Pages: 404 Year of Publishing: February 26, 2013 Description: Most drugs are analogue drugs. There are no general rules how a new drug can be discovered, nevertheless, there are some observations which help to find a new drug, and also an individual story of a drug discovery can initiate and help new discoveries. Volume III is a continuation of the successful book series with new examples of established and recently introduced drugs.

The major part of the book is written by key inventors either as a case study or a study of an analogue class. With its wide range across a variety of therapeutic fields and chemical classes, this is of interest to virtually every researcher in drug discovery and pharmaceutical chemistry, and--together with the previous volumes--constitutes the first systematic approach to drug analogue development.

Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays Authors: Vogel, H.G.; Maas, J.; Hock, F.J.; Mayer, D No of Pages: 1440 Year of Publishing: January 15, 2013 Description: Safety aspects relied mostly on toxicity studies, which however gave information on changes of organ structure rather than on organ function.

Toxicological and pharmacokinetic studies were adapted to the progress of studies in clinical pharmacology and clinical trails.Today, this former sequential way of working is replaced by simultaneous generation of data including safety, pharmacodynamic and pharmacokinetic aspects. Sometimes, even a bench-to-bedside and bedside-to-bench approach connecting preclinical and clinical data as early as possible is mandatory. This book tries to overcome the separation into toxicology, pharmacokinetics and clinical applications by showing the connectivity between all these disciplines: There is no real safety evaluation possible without combining toxicological, pharmacodynamic and pharmacokinetic data both from a preclinical and from a clinical environment.

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Books

Drug Discovery: Practices, Processes, and Perspective Authors: Jie Jack Li, E. J. Corey No of Pages: 544 Year of Publishing: February 12, 2013 Description: Edited by two distinguished chemists from academia and industry, this book presents an up-to-date overview of major aspects of drug discovery. It covers all ends of the discovery process from target selection to major therapeutic areas. Encompassing historical information, current methods, and future prospects, the coverage addresses novice medicinal chemists, providing them with a jump-start to their understanding of drug discovery. The perspectives on drug discovery, authored by experts in different fields and using case studies, also offer benefits to veteran medicinal and process chemists.

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Comprehensive Biomarker Discovery and Validation for Clinical Application Authors: Peter Horvatovich, Rainer Bischoff, David E Thurston, David Fox, David Rotella No of Pages: 320 Year of Publishing: July 31, 2013 Description: Comprehensive Biomarker Discovery and Validation for Clinical Application provides the reader with an extensive introduction into all aspects of proteomics biomarker discovery, validation and development. It discusses the current status of science and technology, its limitations, bottlenecks as well as future development trends to improve the success rate of translating biomarker discovery into useful clinical tests. The most important feature of the book is to provide an overview of current technologies and the challenges encountered during biomarker discovery and validation, such as patient selection, sample handling, data processing, statistical analysis and registration and approval of validated biomarkers through European and US regulatory authorities. The authors introduce the reader to each of these topics in significant detail and provide examples or guidelines for best practice.

Risk Management Applications in Pharmaceutical and Biopharmaceutical Products Manufacturing Authors: Hamid Mollah, Harold Baseman, Mike Long No of Pages: 422 Year of Publishing: March 26, 2013 Description: This book contains both the theory and practice of risk management (RM) and provides the background, tools, and application of risk in pharmaceutical and biologics manufacturing and operations. It includes case studies and specific examples of use of RM for biological and pharmaceutical product manufacture. The book also includes useful references and a bibliography for the reader who wishes to gain additional knowledge in the subject. It aids in assisting both industry and regulatory agencies to implement compliant and effective risk management approaches, and includes case studies to help with understanding.

Therapeutic antibody engineering: Current and future advances driving the strongest growth area in the pharmaceutical industry Authors: William Strohl, Lila Strohl No of Pages: 696 Year of Publishing: December 28, 2012 Description: The field of antibody engineering has become a vital and integral part of making new, improved next generation therapeutic monoclonal antibodies, of which there are currently more than 300 in clinical trials across several therapeutic areas.

This book examines all aspects of engineering monoclonal antibodies to make them more competitive and looks at ways that the various genetic engineering approaches will affect candidates of the future. The authors go beyond the standard engineering issues (ADCC, CDC, half life engineering, etc.) that are covered by most books and delve into structure function relationships that will help to evolve new antibody structures beyond those already in clinical trials. Chapters discuss how current and future genetic engineering of cell lines will pave the way for much higher productivity, allowing for an overall decrease in cost of goods.

Improving Drug Safety-A Joint Responsibility

Genomic Clinical Trials and Predictive Medicine

Authors: : Rolf Dinkel, Bruno Horisberger, Kenneth W. Tolo No of Pages: 359 Year of Publishing: July 31, 2012 Description: The subject of drug risks and benefits has moved from doctors' offices and pharmaceutical company research laboratories to the front pages of daily newspapers and international conferences. There is a growing body of knowledge about drug risk / benefit appraisal, pharmacoepidemiology, patient behavior and corporate and regulatory trends. This book documents the papers presented and discussions held at an international dialogue conference in April, 1990, at Wolfsberg, Switzerland, which took the topic of risk and benefits of drug therapy one step further to responsibility. It includes a rich menu of issues for those who care about the evaluation of drug therapy, the ethics behind it, the expectations of the patient, and the role of traditional and nontraditional drug safety communications.

The ideas expressed here come from different parts of the world but relate to common drug safety problems, observations, and scientific assessments; they provide insights into innovative approaches, cautious changes, and desired actions.

Authors: Richard M. Simon No of Pages: 164 Year of Publishing: February 31t, 2013 Description: This book focuses on novel approaches that provide a reliable basis for identifying which patients are likely to benefit from each treatment. Aimed at both clinical investigators and statisticians, it covers the development and validation of prognostic and predictive biomarkers and their integration into clinical trials.

The book covers Clinical trial basics, Actionable prognostic biomarkers, Phase II designs, Enrichment designs, Including both test positive and test negative patients, Adaptive threshold design, Multiple predictive biomarkers predictive analysis of clinical trials and Prospective - retrospective design.

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Research Insights ellUnited States Private-Sector Physicians and Pharmaceutical Contract Research: A Qualitative Study Jill A. Fisher1*, Corey A. Kalbaugh2 1

1 Center for Biomedical Ethics & Society, Vanderbilt University, Nashville, Tennessee, United States of America, 2 Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America Background There have been dramatic increases over the past 20 years in the number of nonacademic, private-sector physicians who serve as principal investigators on US clinical trials sponsored by the pharmaceutical industry. However, there has been little research on the implications of these investigators’ role in clinical investigation. Our objective was to study private-sector clinics involved in US pharmaceutical clinical trials to understand the contract research arrangements supporting drug development, and specifically how private-sector physicians engaged in contract research describe their professional identities.

Methods and Findings We conducted a qualitative study in 2003–2004 combining observation at 25 private-sector research organisations in the southwestern United States and 63 semi-structured interviews with physicians, research staff, and research participants at those clinics. We used grounded theory to analyze and interpret our data. The 11 private-sector physicians who participated in our study reported becoming principal investigators on industry clinical trials primarily because contract research provides an additional revenue stream.

The physicians reported that they saw themselves as trial practitioners and as

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businesspeople rather than as scientists or researchers.

Conclusions Our findings suggest that in addition to having financial motivation to participate in contract research, these US private-sector physicians have a professional identity aligned with an industry-based approach to research ethics. The generalizability of these findings and whether they have changed in the intervening years should be addressed in future studies.

Please see later in the article for the Editors’ Summary.

Citation: Fisher JA, Kalbaugh CA (2012) United States Private-Sector Physicians and Pharmaceutical Contract Research: A Qualitative Study. PLoS Med 9(7): e1001271. doi:10.1371 / journal. pmed.1001271 Academic Editor: Joseph S. Ross, Yale University School of Medicine, United States of America Received: November 17, 2011; Accepted: June 12, 2012; Published: July 24, 2012 Copyright: © Fisher, Kalbaugh. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The research was supported by the U.S. National Institutes of Health under Ruth L. Kirschstein National Research Service Award 5F31MH070222 from the National Institute of Mental Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: PPI, principal investigator* E-mail: jill.fisher@vanderbilt.edu

2 Genetic Predictors of Response to Serotonergic and Noradrenergic Antidepressants in Major Depressive Disorder: A GenomeWide Analysis of Individual-Level Data and a Meta-Analysis

Background It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way.

Methods and Findings The NEWMEDS consortium, an academia– industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with highquality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p<5×10−8). No biological pathways were significantly overrepresented in the results.

No significant associations (genome-wide significance p<5×10−8) were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D.

Conclusions­­­ No single common genetic variant was associated with antidepressant response at a clinically relevant level in a Europeanancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study.

Citation: Tansey KE, Guipponi M, Perroud N, Bondolfi G, Domenici E, et al.

(2012) Genetic Predictors of Response to Serotonergic and Noradrenergic Antidepressants in Major Depressive Disorder: A Genome-Wide Analysis of Individual-Level Data and a Meta-Analysis.

PLoS Med 9(10): e1001326. doi:10.1371 / journal.pmed.1001326 Academic Editor: Phillipa J. Hay, University of Western Sydney, Australia Received: March 19, 2012; Accepted: September 4, 2012; Published: October 16, 2012 Copyright: © Tansey et al. This is an openaccess article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Cryptococcal Meningitis Treatment Strategies in ResourceLimited Settings: A CostEffectiveness Analysis 3

Radha Rajasingham1,2, Melissa A. Rolfes2, Kate E. Birkenkamp2, David B. Meya1,2, David R. Boulware2* 1 Infectious Disease Institute, Makerere University, Kampala, Uganda, 2 Division of Infectious Diseases & International Medicine, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America

Background Cryptococcal meningitis (CM) is the most common form of meningitis in Africa. World Health Organisation guidelines recommend 14-d amphotericin-based induction therapy; however, this is impractical for many resource-limited settings due to cost and intensive monitoring needs. A cost-

effectiveness analysis was performed to guide stakeholders with respect to optimal CM treatment within resource limitations.

therapy coupled with high-dose (1,200 mg

Methods and Findings:

be a worthy investment for policy-makers

/ d) fluconazole is “very cost effective” per World Health Organisation criteria and may

We conducted a decision analysis to estimate the incremental cost-effectiveness ratio (ICER) of six CM induction regimens: fluconazole (800–1,200 mg / d) monotherapy, fluconazole + flucytosine (5FC), short-course amphotericin (7-d) + fluconazole, 14-d of amphotericin alone, amphotericin + fluconazole, and amphotericin + 5FC. We computed actual 2012 healthcare costs in Uganda for medications, supplies, and personnel, and average laboratory costs for three African countries. A systematic review of cryptococcal treatment trials in resourcelimited areas summarized 10-wk survival outcomes. We modeled one-year survival based on South African, Ugandan, and Thai CM outcome data, and survival beyond one-year on Ugandan and Thai data. Quality-adjusted life years (QALYs) were determined and used to calculate the cost-effectiveness ratio and ICER. The cost of hospital care ranged from $154 for fluconazole monotherapy to $467 for 14 d of amphotericin + 5FC. Based on 18 studies investigating outcomes for HIV-infected individuals with CM in resource-limited settings, the estimated mean one-year survival was lowest for fluconazole monotherapy, at 40%. The cost-effectiveness ratio ranged from $20 to $44 per QALY. Overall, amphotericinbased regimens had higher costs but better survival. Short-course amphotericin (1 mg / kg / d for 7 d) with fluconazole (1,200 mg / d for14 d) had the best one-year survival (66%) and the most favorable cost-effectiveness ratio, at $20.24 / QALY, with an ICER of $15.11 per additional QALY over fluconazole monotherapy. The main limitation of this study is the pooled nature of a systematic review, with a paucity of outcome data with direct comparisons between regimens.

seeking cost-effective clinical outcomes.

Conclusions

lumbar puncture; QALY, quality-adjusted life

Short-course (7-d) amphotericin induction

More head-to-head clinical trials are needed on treatments for this neglected tropical disease.

Citation: Rajasingham R, Rolfes MA, Birkenkamp KE, Meya DB, Boulware DR (2012) Cryptococcal Meningitis Treatment Strategies in Resource-Limited Settings: A Cost-Effectiveness Analysis. PLoS Med 9(9): e1001316. doi:10.1371 / journal. pmed.1001316 Academic Editor: Jeremy Farrar, Hospital for Tropical Diseases, Viet Nam Received: February 20, 2012; Accepted: August 16, 2012; Published: September 25, 2012 Copyright: © Rajasingham et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This research was made possible through support from the National Institutes of Health (U01AI089244, R21NS065713, K23AI073192). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: 5FC, flucytosine; ART, antiretroviral therapy; CM, cryptococcal meningitis; CRAG, cryptococcal antigen; CSF, cerebrospinal fluid; FTE, full-time equivalents; ICER, incremental costeffectiveness ratio; IV, intravenous; LP, year; WHO, World Health Organisation.

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

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