Abstract
The inaugural Applied Pharmaceutical Analysis–India (APA–India) conference was held between 21 and 24 February 2010 in Hyderabad, India. The theme of the 2010 APA–India meeting was “The best of bioanalytical science in India: the role of bioanalysis and absorption, distribution, metabolism and excretion in translational medicine”. The conference brought together scientists from across India and the rest of the world to stimulate discussion in the areas of discovery bioanalysis, new technologies, regulated bioanalysis and biotransformation, as applied to pharmaceutical analysis in India, the USA and other parts of the world. A total of 37 podium presentations and three webinars were presented at the 2010 APA–India meeting. The analytical tool of focus was MS with an emphasis on application to the Department of Drug Metabolism and Pharmacokinetics studies in a globalized pharmaceutical industry.
The inaugural Applied Pharmaceutical Analysis-India (APA–India) conference was opened with welcoming introductory comments from Adam Brockman (The Boston Society Inc, Lexington, MA, USA). More than 225 participant, from across India and the rest of the world were in the audience when the APA–India conference Chairman, Timothy Olah (Bristol-Myers Squibb, NJ, USA) delivered his opening remarks and thanked all the organizing committee members, invited speakers, vendor sponsors (ThermoFisher Scientific, Waters, Agilent Technologies, Gubbs, PPD, LabIndia Life Sciences, Applied Biosystems and Orochem India) and attendees for making the APA–India meeting a reality. The main theme of the conference was introduced by Dr Olah as “the best of bioanalytical science in India: the role of bioanalysis and absorption, distribution, metabolism and excretion (ADME) in translational medicine.” Dr Olah continued with his opening remarks stating that the goals of the conference were:
To bring together scientists from India and across the world to discuss and assess the current state of bioanalysis being used in drug discovery and development globally;
To identify opportunities and challenges facing the pharmaceutical industry today;
To further enhance the development of a global bioanalytical community of practice.
The conference chair also charged the APA–India attendees:
To be positive participants;
To be respectful of the contributions of all;
To be mindful of time with respect to presentations, questions and breaks;
To be proactive in discussion;
To learn something new each day;
To establish productive lengthy relationships.
The APA–India presiding chair, Ravishankara MN (Sun Pharma, India) delivered the final opening remarks before launching into scientific presentations. The conference was planned such that presentations and discussions day 1, 2 and 3 focused on discovery bioanalysis and new technologies, regulated bioanalysis and biotransformation, respectively.
Discovery bioanalysis & new technologies
The workshop on Monday (Day 1) was organized into four sessions:
Discovery bioanalysis and new technologies.Part I: facilitating drug discovery;
Discovery bioanalysis and new technologies.Part II: lead optimization/modelling;
Discovery bioanalysis and new technologies.Part III: applications in lead selection;
Regulated bioanalysis session I.
The first session was moderated by Deepak Barot (Biocon-BMS Research Center, India). The first talk by Dr Olah, entitled ‘The changing bioanalytical environment to support drug discovery and development‘, was appropriate given the current pharmaceutical industry focus on globalization. Dr Olah underscored the need to create an “integrated bioanalytical process” that begins at compound characterization and continues throughout the development process. He also pointed out that the pharmaceutical industry is striving to be innovative at a time of resource constraint. He also mentioned this has led to global strategic sourcing, which offers the options to:
Selectively increase internal capabilities;
Buy down risks;
Ensure flexibility;
Free up the internal staff for proprietary innovation.
A webcast presentation by Dr Rohan Thakur (taylor technology, NJ, USA) on ‘Accelerating lead optimization: in vivo fast PK studies using the Exactive Orbitrap™’ was an appropriate talk to follow Dr Olah’s presentation. Dr Thakur’s presentation demonstrated how the newly evolving concept of performing an “integrated qualitative and quantitative” assay, using high-resolution MS (HRMS) in the full scan mode, can contribute to being innovative in a time of resource constraint. Dr Vijay Raina (Nektar Therapeutics, India) brought the first session to completion with his presentation on ‘Bioanalytical method development for complex molecules’.
Dr Hosahalli Subramanya and Dr Murali Ramachandra (Aurigene Discovery Technology, India) covered drug discovery in silico and in vitro technologies required for lead optimization respectively. A presentation on high-throughput screening to assess ADME properties by Dr Adam Brockman (Sentrion, MA, USA) demonstrated the utility of a LC–MS/MS system with 45-s total cycle time between injections. Dr Jonathan McNally (Thermo Scientific, CA, USA) informed the attendees about how integration of LC–MS/MS controls into laboratory information management systems provide critical time and cost savings to the bioanalytical workflow. This integration has enabled data acquisition, integration, storage, archival and reporting of raw data from one central database. This, in turn, helps with the current pharmaceutical industry’s focus of globalization by allowing scientists from one part of the world to acquire, integrate, store, archive and report data into one central database and scientists from another part of the world to use the database to make decisions and plan additional studies. The final discovery bioanalysis and new technologies session was started off by Dr Dieter Drexler (Bristol-Myers Squibb, Wallingford, CT, USA) with a presentation on ‘Applications of MALDI–MS for ADMET studies’. Dr Drexler provided examples to show how the speed and sensitivity of MALDI–MS makes it an attractive alternative to LC–MS to study ADME Toxicology properties. Dr Raj Nagaraja (Boehringer-Ingelheim, CT, USA) discussed the ‘Importance of in vitro–in vivo correlations for ADME properties in drug discovery’ A presentation by Dr Punit Marathe (Bristol-Myers Squibb, Hopewell, NJ, USA) on ‘Role of PK–PD modeling in discovery and preclinical development’ completed the discovery bioanalysis and new technologies workshop.
Regulated bioanalysis
A presentation covering the expectations of various regulatory guidances starting from system suitability to reporting of results by Dr Anirudh Gautam (Ranbaxy, India) started the regulated bioanalysis workshop on Monday afternoon. Regulatory compliance during small-molecule bioavailability and bioequivalence studies was discussed by Dr S Ravi Sankar (GVK Bio, India). Similar to other US APA meetings, presentations from the US FDA were well received. Now a regular figure in the US APA meetings, Dr CT Viswanathan delivered a talk entitled ‘FDA experience and expectations on bioanalytical regulatory compliance’ via webcast. Dr Viswanathan, in addition to providing an update on bioanalytical regulatory landscape, also commented on the progress that Indian contact research organisations have made since the last series of FDA audits. His remarks were quite encouraging and congratulatory and at the same time, he also urged bioanalytical scientists in India to continuously strive to improve the quality of data. Dr Hanan Ghantous, from the FDA, gave a presentation detailing the FDA’s perspective on safety testing of drug metabolites and included a discussion on the identification, characterization, and safety evaluation of unique human metabolites and what level of such unique human metabolites would trigger standalone safety testing. Both of the presentations from FDA were broadcast via webcasts and were very well attended despite the late hour in India.
The second day of the conference continued with 12 podium presentations organized into three sessions:
Regulated bioanalysis session II: incurred sample reanalysis (ISR) and repeat analysis in reanalysis investigations;
Regulated bioanalysis session III;
Regulated bioanalysis session IV.
One of the hot topics discussed in every bioanalytical conference is ISR and this was the theme for the morning sessions. Ways to demonstrate assay reproducibility in bioanalytical ISR were discussed by Dr Rajesh Karwa (Glenmark, India). In the following two presentations, Dr Ashutosh Pudage (Accutest, India) and Arshad Khuroo (Ranbaxy, India) discussed ISR for multianalyte methods and learning from real case studies, respectively. The first talk in the regulated bioanalysis session III, ‘Role of quality assurance in bioanalytical method finalization including documentation and updates’ was presented by Dr Vinay Shedbalkar (Pharma Edge, India). Presentations by Ramakrishna Bangaru (Matrix Laboratories, India) and Dr Manish Singh Yadav (Veeda Clinical Research, India) provided the attendees with information about good documentation practices and finalization of robust bioanalytical method, respectively. The last presentation before the lunch break, entitled ‘Comprehensive, faster, simpler, more sensitive bioanalysis and metabolite identification from discovery to development‘, was delivered by Dr Robert S Plumb (Waters Corporation, MA, USA).
Bruce Stouffer’s (Bristol-Myers Squibb, NJ, USA) presentation outlined how outsourcing has to be an integral part of biopharmaceutical strategy to be more productive, innovative and flexible. Appropriately, as a follow-up presentation, Dr Sankar (GVK Bio, India) talked about ways to conduct investigations in bioanalysis. Qualification and control procedures in managing computer systems and data applications used in a regulated laboratory, best practice guidelines for the development and validation of immunoassays for pharmacokinetic studies of macromolecules and method development, metabolite back-conversion and implementation of ISR and associated investigations in regulated bioanalysis were topics covered by Drs Rajeev Batra (Ranbaxy, India), Russel Weiner (Bristol-Myers Squibb, NJ, USA) and Robert Massé (Anapharma), respectively.
Biotransformation
On the third day of the conference, bio-transformation sessions started with a keynote lecture by Professor Krishna Iyer (Bombay College of Pharmacy, India). Professor Iyer, who was introduced by Dr Ajai Chaudhary (Eli Lilly & Co., IN, USA), took the attendees through a historical review of cytochrome P450s and drug metabolism. Professor Iyer’s lecture was a real treat for the attendees to understand the past, present and future of drug metabolism research. Professor Iyer’s lecture also highlighted how CYP450s contribute to species differences in drug metabolism, intra- and inter-individual differences in drug metabolism, interracial differences in drug metabolism, drug–drug and drug–food interactions due to their inhibition/induction, and drug toxicity due to the generation of toxic intermediates/products. The remaining rest of the morning presentations, moderated by Dr Ragu Ramanathan (Bristol-Myers Squibb, NJ, USA) and Ajai Chaudhary focused on biotransformation from discovery to market. A presentation by Ajai Chaudhary on ‘Biotransformation yesterday and today: challenges in drug discovery and development’ introduced the attendees to how biotransformation of drugs can lead to one of four potential consequences:
An active drug to an inactive metabolite;
An active drug to an active metabolite;
An inactive drug to an active metabolite;
An active drug to a toxic metabolite.
Dr Chaudhary further discussed the approaches used for minimizing and fixing the aforementioned consequences in early discovery for minimizing clinical stage attrition.
Next, Dr W Griff Humphreys (Bristol-Myers Squibb, NJ, USA) discussed how the safety testing of drug metabolite guidance has given the pharmaceutical industry a framework with which to gather information and make decisions on the metabolite profiles of new drug candidates during the drug discovery and development process. A cost-disciplined strategy currently being employed at Bristol-Myers Squibb to ensure metabolites are adequately monitored and tested in early clinical studies was also discussed. In the next presentation, Dr Ramaswamy Iyer (Bristol-Myers Squibb, NJ, USA) helped the attendees understand why human and animal ADME studies are needed for drug discovery and development. Using examples from the Bristol-Myers Squibb portfolio, Dr Iyer explained that radiolabeled ADME studies are conducted to answer several questions, namely:
Are animals exposed to human metabolites?
What are the circulating metabolites in humans?
How is the drug-derived material excreted in humans?
What are the enzymes responsible for the metabolism of a drug?
Dr Sanjeev Kumar (Merck & Co, Rahway, NJ, USA) gave the final presentation in the morning session on LC–MS tools and techniques available for structural elucidation of metabolites. At the conclusion of morning presentations, more than 30 min of panel discussion ensued. In addition to general biotransformation-related topics, attendees and panelists honed in on the FDA’s MIST guidance and the strategies employed by the pharmaceutical companies to improve patient safety by detecting, characterizing and quantifying metabolites in early clinical studies.
To start the afternoon biotransformation session on drug–drug interactions (DDIs), moderated by Dr Vangala Subrahmanyam (Sai Advantium, India) and Dr Girish Gudi (Glenmark Pharmaceuticals, India), Professor Timothy Tracy (University of Minnesota, USA), delivered a presentation on ‘drug metabolism and its role in drug interactions’. Professor Tracy commented, that drug discovery and development efforts to assess drug interaction potential of new chemical entities must include a comprehensive kinetic analysis and considerations of potential confounding factors such as atypical enzyme kinetics and genetic polymorphisms. Next, Dr Vangala Subrahmanyam (Sai Advantium, India) presented some case studies on utilizing in vitro studies in the prospective prediction of DDIs in humans. Dr Charles Crespi (BD-Gentest, USA) presented strategies and tactics for implementing MS-based CYP-inhibition assays in a GLP-compliance environment with FDA recommended substrates and testing methods. Approaches to evaluate the bioactivation potential of new chemical entities at the discovery/lead optimization stages were discussed by Dr Amit Kalgutkar (Pfizer, Inc., Groton, CT, USA). While Dr Michael Sinz (Bristol-Myers Squibb, Wallingford, CT, USA) introduced the approach of using humanized PXR mouse and monkey models to help predict pharmacokinetic changes due to induction of CYP3A4, Dr Jasminder Sahi (Invitrogen, Ann Arbor, MI, USA) introduced approaches to evaluate transporter-mediated drug interactions and Dr Nimish Vachharajani (Advinus, India) introduced concepts behind clinical DDI. The final presentation of the conference, on the limits and possibilities of deuterated drugs, was delivered by Dr Alvin Vaz (Pfizer, Inc., CT, USA).
Short course
Applied Pharmaceutical Analysis-India events opened on Sunday with a 1 day educational forum entitled ‘Pharmaceutical bioanalytical short course’. The short course was opened following some remarks by the APA-India Conference Chairman Dr Olah. The objective of the short course was to build the foundation and educate the future generation of drug discovery and development pharmaceutical analytical scientists in the areas of ADME and MS applications. The short course, which was attended by more than 35 students and scientists from pharmaceutical, biotechnology, contract research and vendor industries from across India, was conducted by scientists from the USA (Timothy Olah, Ramaswamy Iyer, Ragu Ramanathan, W Griff Humphreys and Punit Marathe [all from Bristol-Myers Squibb, NJ, USA] and India (Shrinivas Savale [Clinigene] and Vinay Shedbalkar [PharmaEdge]).
Overall, the meeting was very successful and generated lots of excitement in the bioanalytical and biotransformation community in India. This meeting was the first attempt of its kind to bring together quality participation from scientists from the USA and India. The meeting also highlighted the newly found enthusiasm within the drug-discovery and development sector of the Indian pharmaceutical industry. Planning for the 2011 meeting is already underway, which is proposed to be held in Hyderabad, India in February 2011.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.