4th Annual Conference 2018
22nd – 23rd October 2018
Boston, Massachusetts, USA


07:00 - 08:00
Breakfast & Registration
08:00 - 08:45
Sunrise Session – Lexington-Concord Meeting Room

Introduction to the Accelerated Stability Assessment Program (ASAP)

Kenneth Waterman, Ph.D.
President at FreeThink Technologies, Inc
08:45 - 09:00
Coffee Break
09:00 - 09:10
Session I – ASAP and Its Applications

Session Chair Opening Remarks & Invitation to FreeThink Open House

Kenneth Waterman, Ph.D.
President at FreeThink Technologies, Inc
09:10 - 09:50
Feeling the Crunch: Accelerated Stability in the Land of OTC Drugs/Dietary Supplements

The global over-the-counter (OTC) drugs and dietary supplements markets are expected to be valued at $450B by 2024 with a compound annual growth rate (CAGR) of 9%. With the addition of novel dosage forms, such as chewable gels, and specialty nutraceutical/botanical blends, the speed of innovation and new product development is as important as the speed to market. Furthermore, regulatory bodies across the world are instituting ever more stringent regulations for these products. In this fast-paced environment, deep understanding of the products and their stability profiles is critical. And the analytical and stability scientists must play an essential role during development.

In this pursuit, Procter & Gamble has adopted tools such as ASAPprime® as well as internally developed solutions for accelerated evaluations of stability profiles for a wide variety of active ingredients. These tools are utilized throughout the development cycle to aid in formulation development, specification limit settings, packaging options evaluations, and accelerating product launch. Several case studies will be presented wherein these tools were employed to provide critical insights in the stability of OTC drugs, vitamin supplements, and probiotics in varying dosage forms, such as tablets, capsules, chewable gels, and powders. Moreover, novel analytical approaches and experimental execution strategies will be discussed.

Freneil Jariwala, Ph.D.
Senior Scientist, P&G Healthcare, R&D
09:50 - 10:30
Application of Accelerated Stability Assessment Programs to Facilitate Market Formulation Development of a Small Molecule Drug Product

Accelerated Stability Assessment Programs were extensively utilized to evaluate the stability of a small molecule drug product during market formulation development. The formulation contained a key acidic excipient as pH modifier to improve drug solubility and bioavailability, but it also increased the level of a degradant that is stability limiting. The effects of critical material attributes, formulation and process parameters, and packaging configurations on stability were investigated. The particle size of the excipient and the surface area of the API were found to have a major impact. When and how the excipient was introduced in the manufacturing process was also important. The final parameters were optimized to balance the stability, bioavailability, and manufacturability of the market formulation.

Dawen Kou, Ph.D.
Senior Scientist, Genentech
10:30 - 10:40
Morning Break
10:40 - 11:20
ASAP for Parenteral Formulation Development – Solution and Lyophilisate
Sabine Thielges, Ph.D.
11:20 - 12:00
Validating ASAP Predictions with ICH-compliant Stability Data and Implementing GMP ASAP Studies

The application of ASAP studies during pharmaceutical development has been increasing within AstraZeneca over the last 5 years. As such just under one hundred ASAP studies have been completed during that time frame on our development portfolio, across drug substance, starting materials, intermediates and a range of drug product types. Over this ever-growing data set, real time ICH compliant stability data is now available for a number of the drug substances and products tested. Comparison of the ASAP predictions with the real-time stability data will be presented across a range of drug substances and products. Drug substances that are chemically stable and do not degrade during an ASAP study offer a particular challenge when setting an initial retest period. Real time ICH data for such drug substances will be presented, demonstrating that an initial retest period of at least 12 months can be supported when no degradation is observed during an ASAP study. A brief overview of the procedures followed to introduce GMP ASAP studies will also be presented.

Helen Williams, Ph.D.
Associate Principal Scientist, AstraZeneca
12:00 - 13:25
13:25 - 13:35
Session II – Accelerated Stability beyond ASAPprime®

Session Chair Afternoon Remarks

Helen Williams, Ph.D.
Associate Principal Scientist, AstraZeneca
13:35 - 14:15
Improving the Accuracy of Accelerated Stability Modeling
Donald Clancy
Modeling Lead at GlaxoSmithKline
14:15 - 14:55
Some Product Stability Findings When There is Little or No Degradation in Accelerated Stability Tests

Accelerated stability studies can help companies quickly quantify stability risks. Although little or no degradation during an accelerated test provides evidence that a product is stable, it does not discharge the risk of a low Ea mechanism. In addition, it can be difficult to estimate shelf life when some or even all of the accelerated test data are below the quantification limit. A Bayesian approach with weakly informative priors and zero order degradation kinetics allows one to make probabilistic statements about the degradation when stored at specified conditions for such situations. This Bayesian approach will be described and applied to hypothetical examples. Further, general implications for the design of accelerated tests will be given. Finally, an analagous Bayesian approach will be used to show how the stability of related drug substance campaigns can be compared and aggregated to provide more precise stability estimates and guide risk-based real-time stability tests.

Meng J. Zhao, Ph.D.
Research Advisor at Eli Lilly
14:55 - 15:10
Afternoon Break
15:10 - 15:50
Prediction of the Long-Term Dissolution Performance of an Immediate-Release Tablet using Accelerated Stability Studies
Garry Scrivens, Ph.D.
Senior Principal Scientist at Pfizer
15:50 - 16:30
ASAPprime® Version 6 Algorithm-Based Data Analysis

ASAP employs isoconversion (time to hit the specification limit at each condition) with designed temperature/RH conditions (based on a humidity-corrected Arrhenius equation) to build a model for degradant formation or potency loss for drug products and drug substances. Once the model is built, the shelf-life inside packaging can be determined based on the calculated RH inside the packaging. These methodologies provide for far better predictions of shelf-life (expiry) than previously possible at a significantly reduced time frame (2-3-weeks). ASAPprime® employs this science in combination with statistical tools to enable accurate estimations of shelf-life with many factors determined computationally (e.g., packaging, storage conditions, storage excursions).

Kenneth Waterman, Ph.D.
President at FreeThink Technologies, Inc
16:30 - 18:30
FreeThink Sponsored Networking Event, Poster Session, and Exhibitor Expo – Winthrop Room
07:00 - 09:00
Breakfast & Registration
09:00 - 09:10
Session III – Accelerated Stability and Global Regulatory

Session Chair Opening Remarks

Darren Reid, Ph.D.
Director Process Development at Amgen
09:10 - 09:50
IQ Update: Lean Stability Perspectives Across Industry and Current Regulatory Feedback
Megan McMahon, Ph.D.
Associate Director, Global Regulatory CMC, Pfizer
09:50 - 10:30
Regulatory update: IQ Risk-Based Predictive Stability Regulatory Sub-team

Accelerated Predictive Stability (such as ASAP) can be used for a variety of applications during drug development. While some companies primarily use this approach for product development, many companies have been submitting Accelerated Predictive Stability data in regulatory submissions. The benefits of submitting Accelerated Predictive Stability data is twofold, it not only saves time which in turn can accelerates the clinical trial timeline and potentially shorten the time to deliver new therapies to patient, but also provides a more accurate prediction of the product stability than conventional approaches such as ICH approach. However, because Accelerated Predictive Stability is still relatively new, and has not been considered fully accepted by global regulatory agencies. It is for the benefits of both the industry and patients, the early adopters in the industry to work with agencies and each other to advance the acceptance of Accelerated Predictive Stability data in regulatory filings. This presentation provides an overview of the recent activities of the IQ RBPS regulatory sub-team in promoting the use of Accelerated Predictive Stability data in regulatory submissions, examples of success submissions, and at last the opportunities and challenges ahead of the industry.

Fenghe Qiu, Ph.D.
Senior Research Fellow at Boehringer Ingelheim Pharmaceuticals Inc.
10:30 - 10:45
Morning Break
10:45 - 11:25
The Remarkably Complex Degradation Chemistry of Drug X: Solving a Stubborn Mass Balance Problem
Steven Baertschi, Ph.D.
Baertschi Consulting, LLC
Session IV – Degradation Chemistry
11:25 - 12:05
Passivation of Carbohydrate -Containing Excipients via an Innovative Formulation Strategy: Proof of Concept

Thorough knowledge and control of impurities is an expectation for the registration of pharmaceuticals. It’s also well known that formation of API related impurities within formulated drug product are often related to decomposition of the excipients themselves. As an example formaldehyde and formic acid appear to be ubiquitous in many common excipients. Unfortunately these and other reactive species within formulations can lead to increasing impurity profiles which are often managed by the addition of additives. This presentation will report on a recent approach towards “passivating” carbohydrate based excipients in an effort to minimize not only the impact of excipient generated formaldehyde but also Maillard related impurities.
Shane Eisenbeis1*, Todd Zelesky1, Greg Sluggett1, Robert North1 and Steven Baertschi 2
1. Pfizer Pharmaceuticals, Groton CT., 06340 USA
2. Steven Baertschi Consulting, LLC, Carmel, IN., 46033 USA

Shane Eisenbeis, Ph.D.
Associate Research Fellow at Pfizer
12:05 - 13:25

Exhibitor Tables Open and Poster Viewing in the Winthrop Meeting Room

13:25 - 13:35
Session Chair Afternoon Remarks
Steven Baertschi, Ph.D.
Baertschi Consulting, LLC
13:35 - 14:15
Transition Metal Catalyzed Chemistry in Solid Oral Dosages

Oxidative degradation of API (Active Pharmaceutical Ingredient) is one of the common degradation pathways in drug products, and transition metal ions often play an important role in this process. Iron(III) is one of the most abundant metal ion impurities present in excipients and buffers. In drug degradation literature, iron(III) has been primarily shown as a catalyst in the oxidative process when hydroperoxides are present. However, the example of iron(III) in the absence of peroxides, acting as an oxidant is less common. This presentation will highlight the benzylic oxidation of drug molecules/drug fragments in the presence of iron(III) only. The formation of an aromatic cation radical is postulated as the key intermediate for the downstream oxidation.
Kausik K. Nanda, William D. Blincoe, Paul Harmon, Leonardo R. Allain, W. Peter Wuelfing

Kausik K. Nanda, Ph.D.
Associate Principal Scientist, Merck Research Laboratories
14:15 - 14:55
Forced degradation studies: an essential tool for the formulation development of vaccines

Forced degradation studies are typically conducted during the early development phase of vaccine candidates to obtain information on potential degradation pathways, support analytical methods development, and identify potential vaccine stabilizers and optimal conditions for long-term storage. The regulatory guidelines for forced degradation regarding biologics have few to no procedural instructions on how to approach forced degradation studies. In my presentation, I will provide an overview of methods used to study forced degradation in vaccines, mechanisms of degradation, analytical methodology, forced degradation examples conducted for vaccine products.

Manvi Hasija
Scientist, Sanofi Pasteur
14:55 - 15:10
Afternoon Break
15:10 - 15:50
Zeneth knowledge-based system for the prediction of forced degradation of organic compounds

Zeneth is an expert, knowledge-based system for the prediction of forced degradation of organic compounds. Features include the ability to predict the structures of degradants and the degradation pathways they undergo as well as a likelihood level for each degradant. The system generates predictions by using a library of chemical transformations. These transformations are researched and implemented by knowledge scientists using (mainly) publicly available literature. Zeneth can be used to aid the analysis of forced degradation experiments as well as to provide information to guide development of stability-indicating methods. The program is currently undergoing a period of redevelopment with the aspiration of providing faster and more accurate predictions. This is being achieved through implementation of new scientific features. Predicted degradants will now be given a ‘score’, which will be used in place of likelihood levels. This scoring system will add a level of granularity to predictions with the aim of generating fewer false positives. Plans to validate this methodology, a key aspiration, are in motion. The new software will also benefit from enhanced stereochemical behaviour. Calculating physicochemical properties is going to be an important part of the new software. A pKa calculator has been developed (in-house) and implemented with the aim of improving the accuracy of predictions for epimerisation reactions at various pH’s and a bond dissociation energy calculator is also in development.

Rachel Hemingway, Ph.D.
Senior Scientist, Lhasa Limited.
Session V – Stability Indicating Method Development
15:50 - 16:30
Developing Stability Indicating Methods: Case Studies

HPLC method development is an arduous and time-consuming process particularly for stability-indicating methods for drug substances and drug products. This seminar describes short cuts and tricks-of-the-trade to the separation scientist in rapid development of (u)HPLC methods (potency and ICH-compliant stability-indicating assays) using a 3-pronged method template approach and a universal generic gradient methodology. Method development case studies in pharmaceutical development including those for quality control of drug candidates with multiple chiral centers are used to illustrate these approaches.

M. W. Dong and K. Zhang, UHPLC in method development, Trend in Anal. Chem., 63, 21-30, 2014.
M.W. Dong, A Three-Pronged Template Approach for Rapid HPLC Method Development. LCGC North Am. 31(8), 612-621, 2013.

Michael Dong, Ph.D.
Principal Consultant, MWD Consulting
16:30 - 17:10
Complex Solid-State Study: Challenging Analytical Case Study – An Analytical Quality by Design (AQbD) Approach

AeroVanc is dry-powder inhalation product under development for the treatment of methicillin resistant S. Aureus (MRSA) infections in the lungs of cystic fibrosis patients. AeroVanc contains the antibiotic, vancomycin hydrochloride and L-leucine. Vancomycin, which is listed on the WHO’s List of Essential Medicine, is a complex glycopeptide derived from N. orientalis with significant analytical challenges, including the presence of at least 12 identified impurities and a similar number of unknown impurities1,2. Various HPLC methods are listed in USP, EP and the BP monographs for the assessment of vancomycin impurities; however, none of the compendial procedures provide acceptable separations for the determination of the impurities in vancomycin drug substance and in AeroVanc. Vancomycin has six ionizable groups and some of the impurities have seven. This presentation discusses the importance of design-of-experiments (DoE) combined with a good understanding of the physico-chemical properties of vancomycin (especially the relationship between the charge of the molecule and mobile phase pH) in the rational development of a robust analytical method for the separation of complex mixtures in a solid dosage form. A reversed HPLC column packed with a perfluorophenyl-C18 bonded phase from Phenomenex proved to be particularly suitable due to its high functional group selectivity and its ability to separate positional isomers. Design-of-experiments (DoE) involving the investigation of pH (2.5 – 7.0), and organic solvent composition (acetonitrile, THF and methanol) and concentration (0-100%) identified the optimum conditions, which involved isocratic elution for the separation of the peaks eluting before vancomycin and gradient elution for the peaks eluting after vancomycin. A DoE approach also proved very useful in defining the multi-dimensional relationship between the resolution of three critical pairs of peaks and the intrinsic variables (instrument type, flow rate, temperature, column age) and extrinsic variables (pH, solvent type and solvent composition).
1. CM Harris, H Kopecka and TM Harris, J.Am.Chem.Soc., 1983, 105, 6915-6922
2. AS Antipas, D Vander Velde and VJ Stella, Int.J.Pharm, 1993, 261-269

Christopher Riley, Ph.D.
President at Riley and Rabel Consulting
17:10 - 17:50
Predicting Stability of Lyophilized Formulations from Molecular Mobility Measurements in Solid
Marc Caporini, Ph.D.
Scientist at Amgen
17:50 - 18:00
SOS 2018 – Closing Remarks
Kenneth Waterman, Ph.D.
President at FreeThink Technologies, Inc
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