1. Rosario LoBrutto, Novartis Presentation Title - Quality by Design - Candidate Declaration to Marketed Product

Presentation Abstract -
Quality by Design (QbD) is a drug development framework proposed by several regulatory authorities in conjunction with the pharmaceutical industry. The framework emphasizes a systematic approach to drug development with focus on product and process understanding based on sound science and quality risk management. This understanding will enable more efficient drug development, with a high level of assurance of meeting pre-defined quality requirements and the potential for regulatory flexibility to operate within a design space.

The advent of QbD has shifted the paradigm from a retrospective to a prospective, systematic, and risk-based approach to develop enhanced process understanding. The QbD process starts with the selection of the desired performance attributes or Quality Target Product Profile (QTPP). The QTPP is then used to develop a list of measurable Critical Quality Attributes (CQA). During early development, the CQAs are then used to guide the development of qualitative risk matrices for API salt screening/selection, formulation principle selection and technology platform selection for formulation development of the intended dosage form. During later phases of development, more detailed quantitative risk analysis using fishbones and Failure Mode Effect Analysis (FMEA) is performed where the main focus is on the process and formulation optimization.The risk management tools that could be used during the development lifecycle from candidate inception to process scale up will be discussed.
The risk analysis allows the identification and prioritization of process parameters for further assessment. The designation of critical parameters and the critical method attributes allows for a systematic approach on demonstration of quality which is commensurate with efficacy of the product and safety for the patient. There is an inherent need to understand the main effects of critical process parameters and material attributes and their mutual interactions, on the critical quality attributes defined for a drug product. Moreover, since there are many variables a scientist must consider when developing or validating a robust process, statistical experimental design and analysis allows for an efficient and effective means for execution. This will lay the basis for defining the design space boundaries at small scale and ultimately verification at full scale. The design space reflects the product understanding as a multivariate area where processing parameters and/or material attributes can be varied with known impact on product quality. In essence, the multivariate design space replaces the Proven Acceptable Ranges (PARs) elaborated in the past for processing parameters; e.g., mixing times, etc. However, PARs lack an understanding of interactions among other parameters throughout the drug product manufacturing process. QbD also requires the establishment of a control strategy which ensures compliance of the drug product processing parameters and material attributes to areas within the design space. The application of these QbD elements during the development process will be discussed.

Biographical sketch of Rosario LoBrutto -
Rosario LoBrutto is a Project Leader (Senior Fellow) in the Product Development Unit at Novartis Pharmaceuticals Corporation, East Hanover, NJ leading project teams responsible for development of active pharmaceutical ingredient finishing steps, drug product, manufacturing and analytics for multiple early to late stage potential drug candidates, and is responsible for teaching in-house HPLC method development training. He is also the global Quality by Design/PAT network leader for pharmaceutical and analytical development.

Rosario received his Ph.D in Analytical Chemistry from Seton Hall University and his BS in Chemistry from Drexel University. Rosario worked in the Analytical Research Department (active pharmaceutical ingredient) at Merck for nine years, most recently as Project Leader managing early to late stage potential drug candidates. This included methods development and validation, in-process testing support (scale up from milligram to kilo scale to production scale and tech transfer to manufacturing facilities), release of clinical supplies and managing drug substance and raw material stability studies.

He has taught many HPLC method development short courses nationwide, has taught as visiting professor at Seton Hall University, has served as an adjunct professor at Stevens Institute of Technology since 1999, and as a short course lecturer for the University of Wisconsin-Extension Pharmacy program since 2006 and has chaired numerous sessions at various symposia.
He is an internationally recognized scientist, and an author/co-author of 28 research publications, 45 oral presentations and 30 poster presentations and 14 book chapters in various disciplines of analytical/physical chemistry. His most recent accomplishment is serving as a co-editor and contributor for a book entitled, “HPLC for Pharmaceutical Scientists” published by Wiley in January 2007. This book provides a unified approach to HPLC with an equal and balanced treatment of the theory and practice of HPLC in the pharmaceutical industry (from drug candidate inception to marketed drug product).

2. Steve Reich, Wyeth Presentation Title – Integrating Quality Risk Management and Operational Excellence – Concepts and Case Study

Presentation Abstract
Progressive organizations in the pharmaceutical industry are beginning to reap the rewards of integrating Quality Risk Management (QRM) and Operational Excellence (OE, also referred to as Process Excellence) methodologies to drive key transformation initiatives in cGMP environments. The combination of Lean/Six Sigma tools and techniques with the QRM philosophies and methodologies espoused in ICHQ9 has generated impressive results within efforts that have been focused on the elusive goal of improving product quality while concurrently increasing manufacturing efficiency. This presentation will emphasize the conceptual and technical synergies amongst QRM and OE and will include at least one detailed case study that showcases the achievements that are possible when merging QRM and OE.

Biographical sketch of Steve Reich –
In his role as Risk Management Principal, Mr. Reich leads Wyeth’s Quality Risk Management community of practice, and facilitates development and harmonization of Quality Risk Management best practices across a global network of locations. He also provides organizational leadership, project management, training, and facilitation for risk management programs and initiatives across Wyeth’s sites.

Mr. Reich’s leadership of pharmaceutical risk-based initiatives has included diverse topic areas such as quality systems, multiproduct facilities, manufacturing operations, engineering & maintenance, finished product AQLs and packaging, and the integration of QRM with Six Sigma operational excellence (OE) initiatives. Mr. Reich has acted as a primary contributor to several successful risk-based submissions to the FDA and has frequent interactions with members of the agency on the topic of quality risk management.

Mr. Reich’s background also includes nearly a decade of experience in validation and qualification of biopharmaceutical facilities, equipment, and processes. His expertise includes extensive knowledge in the areas of cleaning, sterilization, and contamination controls.

Mr. Reich frequently represents Wyeth at professional conferences, university lectures, community outreach forums, and within industry working groups. He is a graduate of Cornell University with a B.S. in Chemical Engineering and also holds a Master’s degree in Quality Assurance and Regulatory Affairs from Temple University.

3. Gary Hollenbeck, UPM Pharmaceuticals Presentation Title – Science-Based Decision-Making Tools in Early-stage Product Development

Presentation Abstract
Formulation and manufacturing processes and controls in early-stage drug product development are “Quality by Design” (QbD) driven activities which require a balance of business and science management. These activities occur within a context of regulatory requirements for a selected approval pathway (i.e., NDA, 505(b) (2), ANDA). Specific requirements for approval generally dictate expected product attributes, target R&D outcomes, dosage form(s), final product specifications, manufacturing processes and selection of formulation components. Pharmaceutical scientists involved in all aspects of this venture must have a broad understanding of drug delivery and unit operations, and be able to match project and product objectives with system capabilities. Early-stage constraints such as limited API, limited knowledge about the API, evolving analytical methodology, aggressive development timelines and limited funds generally preclude the kind of process analytical technology and statistical design of experiments associated with QbD. Case studies will be used to demonstrate how experience and good science can be balanced to make well-informed strategic decisions associated with early-stage product composition and manufacture.

Biographical sketch of Gary Hollenbeck -
Dr. Hollenbeck is Chief Scientific Officer at UPM Pharmaceuticals, Inc., formally assuming this position January 1, 2006. Prior to that he was most recently Professor of Pharmaceutical Sciences at the University of Maryland School of Pharmacy. He received his B.S. degree from Albany College of Pharmacy in l972 and his Ph.D. in Industrial and Physical Pharmacy from Purdue University in l977. As a former member of the American Association of Colleges of Pharmacy, he has served on the joint AACP/AAPS Commission On Graduate Education in Pharmaceutical Science, as chairman of the Teachers of Pharmaceutics Section, as a member of the Focus Group on Liberalization of the Curriculum, as chairman of the Academic Affairs committee, and as a presenter and facilitator at multiple AACP Institutes. Hollenbeck was Associate Dean for Academic Programs at the UM School of Pharmacy from 1991 to 1996, and was one of the principal architects of the School's nationally recognized Doctor of Pharmacy program. During that period, he was also co-principal investigator on the UMAB/FDA Collaborative Agreement; a joint education, research and computer database effort aimed at establishing a scientific basis for review of new and amended drug applications. In this capacity, he and his associates received a Special Recognition Award for the SUPAC IR Training Program, from the Center for Drug Evaluation and Research, FDA, PHS, DHHS. Hollenbeck also served as a member of the Advisory Committee on Pharmaceutical Science, Office of Pharmaceutical Science at FDA and in 2003 received a DHHS, FDA Commissioner’s Special Citation for his work with the Center for Veterinary Medicine. Since 1997, Hollenbeck has been involved in the formation and development of UPM Pharmaceuticals, Inc.

4. Richard Lostritto, FDA
Presentation Title - FDA Update on Quality by Design (QbD)

Presentation Abstract –
The background, elements, and current concepts of the QbD paradigm are presented followed by related updates which address gaps and challenges for the implementation of QbD; and those initiatives which are helping help meet those challenges. These initiatives include ICH Q8R1, ICH Q9, and summary results of the FDA's Pilot Program. These are discussed with examples and suggestions for next steps.

Biographical sketch of Richard Lostritto –
Richard (Rik) Lostritto, Ph.D., joined the FDA in 1995 and currently serves as Director of Division-III in the Office of New Drug Quality Assessment (ONDQA). His areas of CMC (chemistry, manufacturing, and controls) responsibility include drug products indicated for oncology, hematology, and medical imaging as well as manufacturing science which serves all Divisions within ONDQA. Before joining the Agency, Dr. Lostritto worked at Boehringer Ingelheim Pharmaceuticals where he led a medical aerosol formulations group after serving as Assistant/Associate Professor of Pharmacy at The University of Connecticut. He received his M.S. and Ph.D. Degrees in Pharmaceutical Chemistry and Pharmaceutics from the University of Michigan and his B.S. Degree in Pharmacy from The University of Connecticut.

Back up

Chris Moreton, Ph.D, FinnBrit Consulting, Waltham, MA

Presentation Title - Incorporating excipient variability into Quality by Design

Presentation Abstract -
Excipients are an important part of almost all pharmaceutical formulations, and excipient variability can impact pharmaceutical product variability. Quality by Design (QbD) in pharmaceutical product development, and Design Space in particular, promises many benefits. However, unless we can understand how the different parameters from the API, excipients and process influence product performance, QbD will not succeed. This presentation will consider ways in which we can incorporate excipient variability into our design of experiments (DoE) to establish our Design Space efficiently, and thereby deliver the robust formulations required for QbD submissions.

Biographical sketch of Chris Moreton –
Dr Moreton received his B. Pharm from the University of Nottingham, UK, his M.Sc from the University of Strathclyde, UK, and his Ph.D from the University of Wales, Cardiff, UK. He is a registered Pharmacist in the UK. Dr Moreton has over thirty years’ experience in the pharmaceutical industry. He has worked as a formulation scientist developing a variety of different dosage forms, and also in QA/QC and Technical Support in excipients and drug delivery. Prior to starting FinnBrit Consulting, Dr. Moreton was most recently Vice President, Pharmaceutical Sciences at Idenix Pharmaceuticals, Cambridge, MA where he was responsible for the design, development, scale-up, technical transfer and validation of all drug products and associated analytical methods, both during clinical development and eventual transfer into commercial manufacture, working with licensing partners and contractors.

He is a past chair of Chair of IPEC-Americas, and still active on several IPEC committees including GMP, QbD and Excipient Composition. Dr Moreton is also a past Chair of the AAPS Excipients Focus Group. He is a member of the International Steering Committee of the Handbook of Pharmaceutical Excipients, a member of the Editorial Advisory Board of Pharmaceutical Technology, and a member of the USP Expert Committee—Excipient Monograph Content 2. Dr Moreton has authored and co-authored scientific papers and book chapters, and lectured extensively in the areas of excipients, drug delivery, formulation and QbD at universities, training courses and symposia in the U.S. and Europe.

1. Dr. Lian-Feng Huang, J&J Presentation Title - Solubility Studies in Developability Assessment and Preformulation Studies

Solubility is one of the most important parameters studied during the development assessment and preformulation studies after the candidate selection. Yet it is also the parameter most difficult to understand because of the fact that there are multiple ways to determine the parameter and to interpret its meaning. Despite of the availability of various ways to estimate the solubility requirement, such as Maximum Absorbable Dose (MAD) and BCS classification, it is still difficult to have a clear answer to the question: how soluble is enough? This presentation will analyze the various methods of studying solubility and compare different ways of defining solubility criteria in developability assessment. Case studies will be discussed to suggest that additional in vitro and in vivo screening together with the solubility studies may be necessary to ensure the successful selection and development of drug candidates.

Dr. Huang is currently an Associate Director in Pharmaceutical Sciences department at Johnson & Johnson Pharmaceutical Research & Development, L.L.C., US. In this role, her responsibilities include ensuring pharmaceutical developability for Discovery compounds, developing formulation for drug candidates to support preclinical and FIH studies, performing polymorph/salt screening, and providing physical pharmacy support to the compounds at all development stages. Prior to joining Johnson & Johnson in 2002, she was a Research Leader in the Pharmaceutical Development Division of GlaxoSmithKline, Research Triangle Park, North Carolina. She has been a frequent invited speaker at various national and international meetings on the topics of preformulation including solid-state characterization, polymorphism and solubilization of poorly water-soluble compounds. Lian received her B.S. degree (1982) in Pharmacy from Shanghai Second Military Medical University (China). She then received her Ph. D. degree (1993) in Pharmaceutics from the University of Iowa. 2. Rose-Mary Dannenfelser, Novartis Presentation Title - Strategies for Early Formulations for Toxicological and Animal DMPK Studies

Early formulations for toxicological and animal PK studies are important to enable the selection of the most promising NCEs for further development. Many of the NCEs in research / development are poorly soluble and thus present additional challenges to the preformulation/formulation scientist.
For these compounds, identifying the most appropriate formulations will require the assessment of multiple formulation approaches with minimal amounts of compound. Additional considerations in identifying the most appropriate formulation include stability (physical, solution), availability of API, quality of API, selection of excipients (acceptability and tolerability for the species of interest and appropriateness for the administration route).
The most effective way to achieve high exposures from oral formulations needed in toxicological studies is to use a formulation where the compound is already solubilized eliminating the need for the compound to undergo a dissolution phase. However the use of a solubilized oral formulation for early development is debated since it may not be reflective of the final formulation used in clinical studies or commercially feasible, thus hurdles may potentially be encountered during later development.
Solubilization techniques (including the use of buffers/salt formers, cosolvents, surfactants, complexing agents, lipids and combinations) to help enhance solubility and exposure and thus aiding to identify potential toxicity will be discussed.

Dr. Dannenfelser is a project leader in technical research and development interfacing with research and development at Novartis Pharmaceuticals Corporation. Prior to becoming a project leader, she was in the clinical formulation group for seven years where she was responsible for parenteral and oral formulation development, and the manufacture of clinical supplies. She has served on the planning committee for the International Industrial Pharmaceutical Research Conference for over five years and was chair for the 2002 conference. She was also a member of the AAPS steering committee for the sterile products focus group. Rose received her Ph.D. in 1997 in Pharmaceutics at the University of Arizona. From 1983 to 1997 she worked in the laboratory of Dr. Samuel H. Yalkowsky at the University of Arizona during which time she was responsible for preformulation and parenteral formulation development of new chemical entities, developing predictive methods to evaluate physico-chemical properties, and overseeing the compilation of the AQUASOL dATAbASE. Her research interests include bioavailability enhancement of poorly water soluble compounds, pain upon injection, and early formulation development.

3. Dr. M. Sherry Ku, Wyeth

Presentation Title - Food Effect and Poorly Soluble Compounds: Can we predict it? Can we overcome it?

Food can change the rate and extent of drug absorption and influence the bioavailability in terms of Tmax, Cmax and AUC. The mechanism that food can alter bioavailability includes: 1)Delay gastric emptying, 2)Stimulate bile flow, 3)Change gastrointestinal (GI) pH, 4)Increase splanchnic blood flow, 5)Change luminal dissolution, 6)Change luminal metabolism, 7)Change drug permeability, 8)Physically or chemically interact with a dosage form or a drug substance. The degree of food effect is dependent of the solubility and permeability properties of the drug. BCS class 4 drugs tend to have the greatest positive food effect.
Food effects can have clinically significant consequences when the effect is large and dependent of the nutrient and caloric contents of the meal. Since meals that are high in total calories and fat content are more likely to affect the GI physiology, FDA generally requires food effect studies be conducted with a high fat meal. However, patient is usually on normal diet with less fat content so that when a large food effect is found, a second study with different types of meals follows suite. A large and meal type dependent food effect contributes to overall PK variability which is a barrier to further development of the drug or future commercialization due to impossible complicated meal, dosage and labeling requirements.
Understanding the importance, we conduct food effect studies for all new drugs and drug products in the first-in-human (FIH) single ascending dose study when the drug exposure reaches the level of therapeutic effect. The project Go-No-Go criteria can be as tight as not more than 2-fold food effect depending on therapeutic area. Several compound case studies encompassing various BCS classes with different food effects will be presented.

Dr. M. Sherry Ku is currently Senior Director of Pharmaceutical Development, Wyeth Research, a division of Wyeth Pharmaceutical Company. Her responsibilities encompass pharmaceutical development activities starting from discovery support, lead selection, phase 0 and IND submission to Clinical Phase 1 and 2 studies until clinical proof of concept. With the recent trend of new clinical leads becoming less soluble with poor oral bioavailability, Sherry’s emphasis has been in drug delivery technology. Since 2001, her group is responsible for the development of over 100 new clinical leads resulting in 79 initial IND filings. Sherry developed seven (7) commercial products including Suprax, Zosyn/Tazocin, Zebeta, Isovorin, Thioplex, Sonata and most recently Tygacil. In this process, her department has become one of the key engines in the generation of intellectual properties (IP) for Wyeth. She currently holds 25 published patents and 15 active invention disclosures. She received a Ph. D. Degree in Pharmaceutics and Pharmaceutical Chemistry from The Ohio State University. Sherry has published over 50 papers in the areas of Biopharmaceutical Classification System (BCS), discovery pipeline optimization, drug delivery, particle technology, polymorphism, salt selection, solubilization, controlled release dosage forms, pKa determination, partition coefficient, hygroscopicity, complexation, solubilization, chemical kinetics, solid-state stability, stabilization, lyophilization, formulation optimization and process validation. She is a member of AAPS, APhA PhRMA, NJphast and PDA.

4. Dr. Michael Pelekis, Simulations Plus, Inc.
Presentation Title - Application of Modeling and Simulation in Drug Product Development

The presentation will describe the development of an in silico model for in vitro dissolution of a low solubility drug in an aqueous surfactant media. The model will be applied to:
1. Predict in vitro dissolution for different concentrations of surfactants and particle sizes
2. Recommend a media composition to develop a discriminating test
3. Recommend dissolution apparatus and media composition to predict in vivo plasma concentrations in dogs and humans

Dr. Pelekis received his Bachelor’s of Science degree in Biochemistry and a Graduate Diploma in Ecotoxicology from Concordia University in Montreal. His Ph.D. in Pharmacokinetics was from the University of Montreal and his MBA from Temple University, in Philadelphia. He has 20 years of experience in the environmental toxicology and pharmaceutical industries. Most recently he held the position of Principal Scientist with a top five pharmaceutical company. His experience includes a broad spectrum of pharmaceutical and environmental research and development as well as business planning and strategy implementation, including serving as a senior research pharmacokineticist/toxicologist in the Toxicology Division of the Air Force Research Laboratory at Wright-Patterson AFB, Ohio. He’s an experienced user of Simulations Plus’ state-of-the-art GastroPlus™ and ADMET Predictor™ software programs, and has hands-on knowledge of other key pharmaceutical research software tools.

5. Dr. Neil Mathias, BMS
Presentation Title - In vitro/in vivo models in predicting bioavailability: evaluation of biorelevant dissolution methodologies in drug absorption

With the emergence of more selective and potent compounds from drug discovery, the number of poorly soluble drugs entering the development pipeline has grown tremendously. Consequently, using appropriate methodology to study the dissolution process is critical to realistically gauge dissolution in the GI lumen and predict the drug’s performance (absorption) in vivo. Over the last decade, a plethora of experimental methodologies, dissolution media, and biorelevant models have been proposed along with a suite of simulation software options to suggest prediction of in vivo exposure. While some methodologies tend to be simplistic and practical for rapid throughput in assessing exploratory formulations, others can have increased complexity as they attempt to mimic the in vivo situation. This talk will cover and contrast a handful of methodologies that study dissolution of poorly water soluble compounds under biorelevant conditions. Examples will be presented to highlight the utility of specific models to understand dissolution of conventional and non-conventional (amorphous) dosage forms and their representation of absorption in the GI tract.

Dr. Neil Mathias received his Bachelor’s degree in Pharmacy in 1989 from the Pune College of Pharmacy, India, and Ph.D. in Pharmaceutical Sciences from the University of Southern California in Los Angeles (1997) under tutelage of Dr. Vincent H.L. Lee. Prior to USC, he did a short stint in generic pharma in the manufacture of tablets and injectables. Currently, Neil is a Principal Scientist at Bristol-Myers Squibb Co., in the Biopharmaceutics Dept. in New Brunswick, NJ, working on drug delivery, exploratory clinical formulations, and biopharmaceutical assessment of dosage forms at the Discovery-Ph1-2 clinical development interface. His research interests include mechanistic understanding of drug absorption across mucosal tissues, application of non-invasive alternate routes of administration for problematic oral compounds, and application of drug delivery technologies to maximize the therapeutic impact of a drug product. He has published more than 15 articles and several abstracts/poster presentations in these research areas. He is a member of AAPS and a reviewer for several pharmaceutical journals.

6. Dr. Kieran Crowley, Catalent
Presentation Title - Rapid Disintegration….And more: Applying Orally Disintegrating Tablet (ODT) technologies to solve specific PK challenges

Historically, ODTs have been considered as product life-cycle management tools, offering niche advantages of improved patient compliance and fast-onset. These product advantages can be viewed as nice-to-have product attributes and not necessarily product-enabling attributes. Recent advancement in the ODT platform technologies, coupled with pharma’s drive for more innovative and effective products, have resulted in the emergence of ODT products that exhibit fast-disintegration and also solve specific PK challenges. This dual-role for ODTs (fast-dissolve AND drug delivery) will be examined in this presentation.
PK challenges that can be addressed using ODTs include:
- Improved drug delivery of an acid-labile molecule that degrades in gastric conditions
- Bioavailability enhancement of a molecule that undergoes significant first-pass metabolism
- Improved dissolution and bioavailability of poorly soluble compounds
Two reasons can be identified for rapid progress in applying ODTs to PK challenges. Firstly, a broad range of processing technologies are used to manufacture ODTs (lyophilization, loose-compression, particle coating), many of which are well-suited to solving PK challenges. Secondly, the methods used in ODTs to solve taste masking problems often involve manipulation of API dissolution, so an ODT formulator is keenly aware of the importance and relationship between Disintegration and Dissolution. For all case studies described in this presentation, a specific set of scientific principles and processes have been applied to Disintegration (critical for an ODT), then additional scientific principles and processes have been applied to the Dissolution aspect of product performance (critical for dual-role ODTs). This presentation will focus on the PK advantages available through control and modification of Dissolution using ODT technology platforms.

Dr. Kieran Crowley manages preformulation and formulation R&D groups supporting oral dosage form development at Catalent Pharma Solutions in Somerset NJ. His main responsibility is developing ODT products with the proprietary Zydis® dosage form, which uses freeze-drying to achieve the target product characteristics.
Kieran holds an undergraduate degree in pharmacy from the University of London UK and a doctorate from the University of Bradford UK. He completed post-doctoral research at the University of Wisconsin-Madison, followed by 10 years pharma experience. He has published numerous peer-reviewed articles in the fields of amorphous state characterization / stabilization, and lipid-based formulations.

7. Biopharmaceutical Properties and Considerations for Progression of Poorly Soluble Candidates - Round Table Discussion Moderators: Dr. Thomas Lee (Celgene) & Dr. Esteban Bornancini (GSK)

Round Table Discussion Topics:
1. Decision tree on using special delivery systems
2. Decision tree on moving a poorly soluble compound into development
3. Decision tree on FIH formulation for Poorly Soluble Compounds
4. How to conduct risk assessment on poorly soluble compounds