4th Jerusalem Conference
Quality by Design (QbD)
and Pharma Sciences
Book of Abstracts
May 20-22nd, 2014
The Edmond Safra Campus
The Hebrew University of Jerusalem
4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
Program
Day 1: May 20th, 2014
8:30
Registration
9:00
Opening: Prof. Simon Benita, Head School of Pharmacy Institute for Drug
Research
9:10
Keynote: Attaining and Sustaining Pharmaceutical Product Quality A Quality Culture Approach
Louis W. Yu, Ph.D. Executive V.P. Quality Control, Perrigo
1. A Pharmaceutical Quality
Chairperson: TBD
9:50
(2) A1 Sustaining Quality Compliance - Strategies to arrest "drifting
from good"
Claudio Pincus, President of the Quantic Group, USA
10:20
(3) A2 Pharmaceutical Quality and Clinical Research Quality: The
interaction
Dr. Yafit Stark, Teva, Israel
10:40
Coffee Break
2. B Analytical Methods
Chairperson: TBD
11:00
(1) B1 Analytical Method Development - A Life Cycle Quality by
Design
Dr. Rosario LoBrutto, Sr. Director, Head of Research and
Development (Parenterals), TEVA Pharmaceuticals, Pomona,
New York, USA
11:30
(2) B2 Estimation of Uncertainty of Analytical Methods
From Validation Data in the Pharmaceutical QC Lab
Dr. Raphael Bar, Ph.D., BR Consulting, Israel
12:00
(3) B3 Statistical Models for GR&R (Gauge Repeatability and
Reproducibility) Studies
Professor David Steinberg, Tel Aviv University, Israel
.
12:30
Lunch
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
3. C DOE and QbD in Pharmaceutical Research
Chairperson: TBD
14:00
(1) C1 QbD in Liposome Development
Professor Yechezkel (Chezy) Barenholz, Hebrew University,
Medical School, Jerusalem, Israel
14:30
(2) C2 Regulatory landscape changes for the generic industry and
Statistical methodologies as enabling tools to efficiently cope with
new requirements
Inna Ben-Anat,Teva
15:00
(3) C3 Definitive Screening Designs
Ian Cox, JMP Division of SAS
15:30
Special Invited Speaker - TBD
16:30
Q&A Session – Moderator: Prof Mel Weinswig
17:30
Day 1 closure
18:00
Conference Dinner
Day 2: May 21st, 2014
8:30
Registration
9:00
Keynote: Rapid Screening Methods for FDA Pharmaceutical Surveillance
Dr. Lucinda (Cindy) Buhse, Director, FDA Division of Pharmaceutical
Analysis, FDA St. Louis, USA
4. D Regulatory Updates and the use of data
Chairperson: Louis W. Yu, Ph.D. Executive V.P. Quality Control, Perrigo
9:40
(1) D1 Pharmacovigilance in Israel-The Way Forward
Grainne Quinn, M.D., VP, Global Head of Patient Safety, Perrigo
10:10 (2) D2 Pre-competitive gains from data sharing across sponsors: the
power of big data and collaboration
Professor Jonathan Rabinowitz, Bar Ilan University, Israel
10:40 (3) D3 International Quality Operations: Approaches to Quality
Metrics and Continuous Improvement
Stacy Berkshire, Perrigo
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
11:10
Coffee Break with light meal
5. E QbD in Pharmaceutical Development
Chairperson: TBD
12:00
(1) E1 A Design of Experiments (DoE) Approach to Optimized
Fabrication of Magnetic Maghemite Nanoparticles for Imaging and
Gene Silencing
Professor J-P. Lellouche, Bar Ilan University, Israel
12:30
(2) E2 QbD development of topical products
Michal Arnon, Perrigo
13:00
(3) E3 QbD in developing semisolid formulations
Haim Barsimantov, COO, Sol-Gel
6. F Quality Challenges in 2020 Drug Products
13:30 Panel – Moderator: Prof Philip Lazarovici
Dr. Yafit Stark, Teva
Prof. Louis Yu, Perrigo
Prof. Mel Weinswig, UW, USA
Prof. Ron Kenett, KPA, Hebrew Univ. and Univ of Turin
Rosario LoBrutto, Research and Development (Parenterals), TEVA
Pharmaceuticals, USA
Dr. Lucinda Buhse, FDA Central Laboratories, USA
Claudio Pincus, Quantic Group, USA
14:30 Day 2 closure
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
Day 3: May 22nd, 2014
A Special Introductory Workshop on:
Statistical Tools Supporting the New Process Validation Guidelines
Presenters: Prof Ron Kenett and Prof David Steinberg
The FDA new Process Validation Guidelines cover 3 stages in the lifecycle of the product.
The first phase is the design of the product and production process, the second phase is
qualification of the process and the third phase is ongoing monitoring of the process. The
January 2011 guidelines on process validation offer new possibilities and challenges and
require the application of various statistical methods. The new approach is scientific based
and builds on all quality by design guidelines. The guideline is driving industry to move
from an inspection focus, where things are inspected and the output of an inspection is
pass/fail, to a deeper understanding and a more in-depth analysis of what is going on. The
three stages and the corresponding main statistical tools supporting them are listed below.
Stage 1: Process Design; Development through submission – Statistical Design of
Experiments (DOE).
Stage 2: Process Qualification; Submission through launch - Acceptance Sampling
Plans
Stage 3: Continued Process Verification; During the commercial manufacturing of the
product – Statistical Process Control (SPC).
This introductory workshop is designed to provide participants with a guided tour through
the statistical design of experiments (DOE), acceptance sampling and statistical; process
control (SPC).
The material presented in the workshop is based on the second edition of:
Modern Industrial Statistics with applications in R, MINITAB and JMP by Kenett and
Zacks, Wiley 2014 (http://eu.wiley.com/WileyCDA/WileyTitle/productCd1118456068.html. Real life examples and simulations will be provided using JMP.
Workshop agenda:
9:00
Introduction to QbD and the New Process Validation Guideline
9:30
Design of Experiments (DOE)
11:15
11:45
Coffee Break
Acceptance Sampling
14:00
Lunch Break
14:45
Statistical Process Control (SPC)
16:30
Closure
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
Abstracts
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
Day 1 Keynote: Attaining and Sustaining Pharmaceutical Product
Quality - A Quality Culture Approach
Louis W. Yu, Ph.D. Executive V.P. Global Quality, Perrigo
Recently, FDA CDER Director, Dr. Janet Woodcock, along with the Director of Strategic
Programs, FDA Center for Drug Evaluation and Research, Dr. Theresa Mullin, are
preparing an update to the FDA/CDER's "Evolving Approach to Product Quality". In
essence, after more than 10 years and major efforts to realize the 21st Century
Pharmaceutical Quality Vision, CDER senior management acknowledged that there is a
need to revamp the program. Central to this revised approach is the recognition that there is
room to improve to attain and sustain pharmaceutical product quality for US Consumers.
In examining why the industry and the regulators are not quite there yet, the FDA
identified several opportunities. Among these is the formation of a super Office of
Pharmaceutical Quality to replace the Office of Pharmaceutical Science. Among the new
programs to be promulgated by OPQ is the implementation of a surveillance initiative
which will require the regulated industry to submit metrics on a regular basis to the FDA
OPQ so that it could assess how products and firms perform over the product lifecycle post
approval. While collecting and reviewing performance metrics are important tools to drive
continuous improvement, a more holistic approach to attaining and sustaining product
quality and continuity of supply is to assess if firms have all the ingredients in place to
promote and sustain a quality culture. "
A1: Sustaining Quality Compliance-Strategies to Arrest "drifting from
good"
Claudio Pincus, President, The Quantic Group, Ltd.
Sustainability from a compliance perspective can be defined as the highest level on an
organizational capability continuum. It correlates with increases in knowledge, learning
and capability, while at the same time decreasing risk and failures. Organizations should
actively and deliberately progress on an improvement journey, from reactive to proactive;
proactive improvements yield greater sustainability. Sustainability requires that companies
have appropriate change management processes, along with a risk management and
governance process. Organizations may be faced with challenges that result in a negative
journey, for example, from proactive to reactive. If this journey is a gradual process, it is
referred to as organizational “drift.” Case Studies highlighting improvement journeys and
“drifting” journeys are presented and examined.
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
A2: Pharmaceutical Quality and Clinical Research Quality: The
interaction
Dr. Yafit Stark, Teva Pharmaceutical Industries, Ltd., Israel
The medical community is raising some concerns regarding the safety of medical products.
There are also reports that the general public is losing confidence in clinical trials.
The complexity of clinical trials is increasing in terms of protocols, size, international sites,
number of patients/sites, increasing cost of traditional monitoring, but the efficiency of
clinical trials is reduced. We have recognized that we need to be able to effectively and
efficiently answer the intended questions about the benefits and risks of medical products
(therapeutic or diagnostic), or procedures, while ensuring protection of human subjects.
Practices adopted throughout development have to be identified and implemented, thus
increasing the quality and efficiency of clinical trials. We must generate evidence on how
to improve the clinical development strategy, followed by study design and execution.
Quality by Design (QbD) is a practice long used in the manufacture of medicinal products,
and the notion of building QbD into all clinical trials is now being considered. There is no
doubt that building quality prospectively into the process of drug/medical device
development, including into clinical development, is more effective than overhauling of
processes, changing SOP's and resources retrospectively. Building in quality from the start
and improving on-going studies to ensure quality clinical trials has to have the following
elements:

Scientifically valid and ethically sound experimental design.

Adequate protection of subject rights, safety and welfare.

Qualified trained personnel.

"Adequate" monitoring.

Current complete and accurate data.
Since no clinical trial is perfect, therefore no data set is perfect. However, "high quality
data" – data strong enough to support conclusions and interpretations – is equivalent to
those derived from error free data. Moving forward for the patient's benefit requires:

Methods based on understanding, knowledge and good science.

Selection/application of the right tool for the right clinical purpose in clinical
studies.
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin

Clinical trials based on and developed with QbD principles.

Design and implement innovative clinical design protocols during clinical
development.

Quality should be built in by design.

Information from clinical development as the basis for quality risk management.
B1: Quality by Design for Analytical Methods - A Lifecycle Approach
Dr. Rosario LoBrutto, Ph.D., Senior Director, Teva Pharmaceuticals
Implementation of Quality by Design in development allows for improved understanding
of the analytical method focusing on robustness and ruggedness designed with end user in
mind thereby facilitating methods transfer and provides opportunities for continual
improvement. This allows for reduced chance of method failures during release/stability
testing, aids OOS investigations, and ultimately increases quality and reduces costs. By
integration of elements of Analytical Quality by Design, into the development strategy the
critical sources of analytical variability (continuous and discontinuous) are identified thru
risk assessments, measured and understood so that they can be controlled with the
appropriate control strategy. Quality by Design implementation is aligned with a risk and
science based approach to methods development and methods validation. The outcome of
the risk analysis allows for the identification of the potential critical analytical method
variables that could be evaluated using a statistical design of experiments. Design of
experiments (DOE) is used to provide the most efficient and statistically sound approach to
evaluate multiple method variables and their responses (critical method attributes). This
provides an excellent opportunity for determination of optimum conditions generated from
a limited number of experiments used in the DOE study. Also, statistical design facilitates
an in-depth understanding of the method and justifies the choice of ranges for method
variables and finds a robust (optimum) region for the final method. Finally an analytical
method design space could be developed encompassing the operable ranges for the
potential critical analytical method variables and their interactions and suitable control
strategies can be implemented. Implementation of Analytical QbD, can provide a
structured approach aligned with a risk and science based approach towards methods
development and methods validation and continual verification. Implementation of such
an approach, can allow for significant reductions in working capital requirements, resource
costs and non value added time (ie due to replications, due to poor knowledge preservation,
knowledge exchange and transfer).
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
B2: Estimation of Uncertainty of Analytical Methods
From Validation Data in the Pharmaceutical QC Lab
Dr. Raphael Bar, Ph.D.BR Consulting, Israel
All measurements are subject to error and the Analytical Chemist is essentially always on
the quest for the true value of the attribute tested in a pharmaceutical drug. Thus, while
reporting a test result with its uncertainty is a requirement in ISO-compliant testing labs
and is in line with a QbD approach, the pharmaceutical QC laboratory usually neither
estimates nor includes uncertainty in reportable test results. This presentation will
introduce the two main approaches for estimating an uncertainty: a) the mathematical
model approach which combines all uncertainty sources and b) the approach based on
derivation of uncertainty from method validation experiments. The latter approach utilizes
the best available estimate of overall method precision and the best available estimate(s) of
overall method bias and its variability to evaluate the uncertainty of a final test result . The
validation experiments as commonly practiced in the pharmaceutical industry will be
discussed in view of explaining why uncertainty of test results is not estimated. In
contrast, the newly USP suggested approach for validating analytical methods will be
presented in relation to its accounting for measurement uncertainty in the validation
process. Finally, this presentation will address the question whether the pharmaceutical
industry is ready to report test results with uncertainty.
B3: Statistical Models for Gage R&R Studies
Prof. David Steinberg
Department of Statistics and Operations Research, Tel Aviv University
The standard format for a GR&R study is to take a random sample of 10 parts and to ask 3
operators to independently measure each part 3 times. Simple formulas (available in
spreadsheet format) are used to estimate the repeatability (intra-operator variation), the
reproducibility (inter-operator variation) and the process variation. This talk will discuss
the statistical models that underlie the analysis. I will describe the difference between
fixed effects and random effects and the implications for the analysis. I will also comment
on implications for the standard design format, including both sampling method and
sample sizes. If time permits, I will discuss more complicated settings, in which additional
features may affect the measurement process or in which the sampling is hierarchical.
Much of the talk will be based on articles by Vardeman and Van Valkenburg
(Technometrics 1999) and by Steiner and colleagues (e.g. Browne, MacKay and Steiner,
Technometrics 2009; Stevens, Browne and Steiner, Journal of Quality Technology 2010;
Steiner, Browne, Stevens, MacKay, IIE Transactions 2012).
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
C1: QbD in Liposome Development
Yechezkel (Chezy) Barenholz, Laboratory of Membrane and Liposome Research, IMRIC,
Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
C2: Regulatory landscape changes for the generic industry and statistical
methodologies as enabling tools to efficiently cope with new requirements
Inna Ben-Anat, Director, Quality by Design and Product Robustness, Teva USA
Regulatory landscape in Pharma is changing at rapid pace, especially for generic industry.
The regulatory environment is much more focused on process robustness and product
quality today than ever before. For Teva, this means understanding the products,
formulations, and processes in depth, and submitting appropriate applications to the
authorities using a more systematic development approach. During the past year several
new guidance documents were published by the agency, as part of the focus on products
(and submitted files) quality and robustness (New Stability Requirements, Guidance on
Size and Shape, Refuse to Receive Standards) in addition to Quality by Design initiative
(ICH Q8, 9, 10, 11) and New Validation Guideline. This presentation will provide an
overview of how to implement QbD in generic industry effectively and efficiently
throughout the product lifecycle and how various statistical methodologies (DOE, MonteCarlo Simulation, Stability Trending, ANOVA, SPC etc) provide an enabling tool to
efficiently cope with new regulatory requirements.
C3: Definitive Screening Designs
Dr, Ian Cox, JMP Division of SAS
The notion of cycles of learning is at the heart of QbD philosophy, and in practical
application this often means conducting a series experiments. By tradition, sequential
experimentation distinguishes between designs aimed at factor screening and
optimisation. However the recent introduction of definitive screening designs (DSD)
provides a hybrid approach: Not only can these new designs separate the vital few
factors that have a substantial effect on a response, they can correctly identify
influential factors with curvature that might be missed by other screening designs, and
also allow the correct identification of two factor interactions without the need for
additional runs to resolve confounding. This non-technical presentation shows an
example of a DSD to motivate you to learn more about the topic.
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
Keynote Day 2: Rapid Screening Methods for FDA Pharmaceutical
Surveillance
Lucinda (Cindy) Buhse, Ph.D., Acting Director, FDA Office of Testing and Research
Historically, FDA surveillance of pharmaceutical products and ingredients has involved
sampling, sending to a laboratory, and waiting for results from extensive testing such as
that in the United States Pharmacopeia. An ever increasing percentage of products and
ingredients are now coming from overseas, potentially increasing consumer exposure to
poor quality, counterfeit and adulterated pharmaceutical products. In response to this
situation, the FDA has developed rapid and portable screening methods to assess the
quality and safety of pharmaceutical products at ports of entry and other locations. This
presentation will briefly describe the current spectroscopic methods being utilized by the
FDA for field surveillance of pharmaceutical products including Raman, near infrared
(NIR), x-ray fluorescence (XRF) and ion mobility (IMS) spectrometries. Experiences with
method development, chemometric data analysis, and field deployment will be discussed.
D1: Pre-competitive gains from data sharing across sponsors: the power
of big data and collaboration
Prof. Jonathan Rabinowitz, PhD
Bar Ilan University
I will discuss my experiences as heading two cross sponsor data sharing initiatives,
NewMeds and DupCheck. The NewMeds (New Methods for Drug Discovery for
Depression and Schizophrenia) repository contains patient level data on over 30,000
patients from 77 randomized controlled trials of antidepressant and antipsychotic
medications. This repository is the result of a private-public colloboration funded by the
Innovative Medicines Initiative in colloboration with EFPIA. The data included was
contributed by AstraZeneca, Eli Lilly, Janssen, Lundbeck, Pfizer and NIH. NewMeds is
possibly the largest such precompetitive colloboration. Using this data we were able to
show that drug discovery trials could be conducted more efficiently by making them
shorter, by using enriched populations, by increasing proportion of patients on placebo, by
using interim analysis to re-estimate sample sizes, excluding centers with high placebo
response and by screening for duplicate or professional patients. DupCheck is a web based
data sharing initiative consisting of DupCheck-CT, clinical trials, and DupCheck-PV
pharmacovigilance. DupCheck-CT is used to screen, in real time, for duplicate enrolment
of patients in clinical trials within and across sponsors, trials and indications. These are
patients who participate in more than one trial at a time or more than once in the same trial.
DupCheck-CT reduces the damaging effects of duplicately enrolled patients in clinical
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
trials that has been shown to reduce efficacy results and increase misattributed adverse
events. DupCheck-PV is used to identify duplicate reporting of adverse events, primarily
post-marketing. This includes events reported by different reporters and attributed to
different compounds. DupCheck-PV reduces misattributed or multiply reported adverse
events.
D2: Pharmacovigilance in Israel-The Way Forward"
Grainne Quinn MD, Vice President, Head of Global Patient Safety, Perrigo, Dublin,
Ireland.
This session reviews the important legislative requirements present in Israel for the
pharmacovigilance of marketed products. Application of sustainable quality systems for
the collection, collation, review and reporting of safety data is critical in today's
environment. The speaker intends to outline the requirements in Israel and globally to
achieve this.
D3: An overview of elements for a sustainable Quality culture in a global
environment as well as outcomes that can be expected.
Stacy Berkshire, Vice President of International Quality Operations, Perrigo
How can we build and instill a Culture of Quality in our Pharmaceutical Operational sites
across the globe? How can we do this in a complex regulatory environment and under the
requirements of multiple Competent Authorities? What are the inputs into a culture that
owns quality and continuous improvement and what kind of outcomes can we expect?
And, most importantly, how do we do all of this not just for a moment in time but for
sustainable results?
E1: A unique podium for highlighting applications of quality by design
(QbD) to the Pharma Sciences
Prof. Jean-Paul (Moshe) Lellouche
Department of Chemistry & Nanomaterial Research Centre - Institute of Nanotechnology
& Advanced Materials (BINA), Bar-Ilan University
Iron oxide nanoparticles (NPs) have been quite widely used in numerous biotechnology
applications (magnetism-driven cell separation, magnetic field-guided drug/gene delivery,
non-invasive tissue MRI, anti-cancer hyperthermia). Serious drawbacks dealing with NP
fabrication, i.e., both detrimental NP aggregation and controlled NP surface
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
functionalization versatility are extremely challenging issues calling for innovative
solutions.
Scheme. 6.50±2.15 nm-sized PEI-Ce3/4+-doped -Fe2O3 NPs as innovative gene
delivery/silencing nanoparticulate system
Our recent work in the field led to the discovery of a novel method/concept for the (i)
aggregation control of ultra-small hydrophilic super-paramagnetic maghemite (-Fe2O3)
NPs and for (ii) its successful use for NP functionalization as a novel particulate system for
siRNA-mediated gene delivery/silencing (Scheme above). In contrast to common
knowledge, this novel nanofabrication method does not make use of any surfacepassivating organic species. Indeed, the ultrasound-assisted metal Ce(III/IV) cation doping
of the surface of 45/50 nm-sized (DLS) maghemite NPs strongly modified the NP surface
charge to a highly positive unexpected value (+41.0 mV) of their 
3/4+
cation-doping process enabled (i) an effective charge-control of NP aggregation, (ii) the
full NP water compatibility for biological applications, and finally (iii) the development of
a quite versatile surface coordinative attachment chemistry using the known rich Ce3/4+
complex coordination chemistry for any biomolecule or organic species binding (Scheme).
Influential parameters of this new NP ”inorganic” stabilization and NP surface
functionalization method towards optimized (i) ultra-small core Ce3/4+-doped -Fe2O3 NPs
and (ii) functional 25kDa b-PEI polymer-based decorated NPs for siRNA delivery (several
examples) have been investigated using Design of Experiments (QbD - MINITAB 16®
v16.2.4 software, Minitab Inc.). Subsequently, quite effective gene silencing for related
DoE-optimized polycationic NPs has been demonstrated at a level of effectiveness even
superior to the well-known lipofectamine™ gold standard and at much lower cellular
toxicity.
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
E2: QbD Development of Topical Products
Michal Arnon, BPharm, R&D Formulation Manager, Perrigo Israel Pharmaceuticals
The use of QbD in the development of extended topical products has become a second
nature in Perrigo. From the first stage of the development, throughout the entire
development process, risk management followed by DOE studies to assess the risk effect,
and finding a solution to this risk, is taking place. Examples from the development process
of ointment drug products, foam and a nasal spray will be presented. These examples will
focus on the risk evaluation process, and the followed experiment designs that led to the
manufacturing and packaging processes. How to work with a new API? What will the
effect of process temperature be on the product CQA's? How to fit the packaging process
to the product CQA's? These are some of the questions that are raised during the
development of a drug product and will be presented here.
E3: Quality by Design in developing semi-solid drugs
Haim Bar-Simantov, Sol-Gel Technologies
The presentation will describe the considerations which can be employed during the
development of a semisolid topical product including a discussion on the implementation
of quality by design concepts during development to ensure the drug product has the
desired quality attributes and ensuring batch to batch consistency. The presentation will
also address the concept of utilizing in vitro skin permeation studies as a tool to justify
product specifications and changes in the composition and manufacturing process to ensure
successful development . The emergence of quality by design as a new systematic science
and risk-based approach has added a new dimension to pharmaceutical development and
manufacturing. The presentation discusses the quality by design elements and concepts
applied for topical semisolid products. Quality by design begins with defining a quality
target product profile as well as critical quality attributes . Subsequently, this is followed
by risk identification/risk analysis/risk evaluation to recognize critical material attributes
and critical process parameters, in conjunction with design of experiments or other
appropriate methods to establish control strategies for the drug product. Few examples of
designs of experiments are included as practical strategies for the development and
optimization of formulation and process for topical drug products.
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
Speakers and Panelists
(in alphabetical order)
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
Michal Arnon is a Manager at the Formulation R&D at Perrigo Israel Pharmaceuticals
and in charge of the R&D improvements projects. She is a six sigma black belt (SSBB,
KPA certified). Michal has a B Pharm degree from the Hebrew University of Jerusalem
and has a Science Teaching Diploma from Lewinsky College. After four years of serving
as a community pharmacist (1995-1999) she switched to the industry and since September
1999 she works at Perrigo R&D (formerly Agis). During 2005-2006 Michal has worked at
Abbott Laboratories, Abbott Park, IL as a clinical Supplies Coordinator. Since she is back
in Israel she is back in Perrigo's R&D.
Raphael Bar is presently a pharmaceutical consultant at BR Consulting for the Pharma
and bio-Pharma industries. He provides consulting services on pharmaceutical
development and analytical support to investigational, new, and generic drugs as well as
medical devices and combination products. R. Bar is a member of the organizing
committee of Israel Analytical Chemistry Society since 1996 and past president of Israel
Chapter of the Parenteral Drug Association (PDA) during 2006 – 2009. He is now a board
member of the PDA Chapter of Israel and since Jan 2009, he is also a board member of the
Scientific Advisory Board of global PDA (USA). He received his Ph.D. in Chemistry
from The Hebrew University after combined graduate studies in Applied Chemistry and
Chemical Engineering from Virginia Tech, USA. Following this, Dr. Bar has also
completed a 3-year post-doctoral training in Biochemical Engineering at UVA, USA,
which he taught as a Lecturer in the Hebrew University. Dr. Bar joined Teva
Pharmaceuticals, Israel in 1995 and for three years, he was Head of the Analytical
R&D Laboratory. He was involved in preparation of ANDA files and underwent preapproval FDA inspections. In 1998, he joined Pharmos where he managed the Quality
Control and R&D laboratory for about ten years. As Senior Director of Analytical
Development, Dr. Bar was actively involved in preparation of CMC packages for Phases 1,
2 and 3 clinical trial studies. The main interests of Dr. Bar revolve around analytical and
bioanalytical method development and validation, stability studies, statistical evaluation of
laboratory data and bioassays, sterile production of parenterals and QA/RA issues. He
particularly developed an expertise in stability studies, from initial testing to final
statistical analysis of stability data. R. Bar conducted formal stability studies of drug
substance and product according to ICH/FDA guides. He also conducted and oversaw GLP
studies of metabolites identification and quantitation in biological matrices, while being
involved in IND/NDA files preparations. Dr. Bar has been teaching courses to QC and
R&D personnel from pharmaceutical companies for more than ten years both in Israel and
overseas. Dr. Bar authors over 40 peer-reviewed papers, of which the last two papers
address statistical analysis of drug stability data.
Chezy Barenholz is the Daniel G. Miller Professor in Cancer Research, head of Liposome
and Membrane Research Lab is on the faculty of Hebrew University Jerusalem Israel
since 1968 and a Professor there since 1981, a visiting Professor at the University of
Virginia School of Medicine, Charlottesville VA, USA (1973 to 2005); a Donder’s Chair
Professor at The Faculty of Pharmacy, University of Utrecht, The Netherlands on 1992; the
University Kyoto University (Kyoto, Japan, 1998), La Sapeinza University (Roma, Italy,
2006) Jaiotung University (Shanghai, China, 2006), Kings College (London, UK, 2006),
the Technical University Of Denmark (Copenhagen 2010) . His current research focuses
on the development of drugs based on drug delivery systems (DDS) best exemplified by
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
the anticancer DOXILTM the first nano liposomal and the first FDA approved (1995) nanodrug used world wide. Professor Barenholz is an author of more than 360 scientific
publications having altogether more than 10,000 citations. He is a co-inventor in more
than 30 approved patent families. He was an executive editor of Progress in Lipid
Research, an editor of 4 Special Issues, and is on the editorial board of 5 scientific journals.
Professor Barenholz is a founder of NasVax LTD, Mobeius Medical LTD, Lipocure LTD,
and Doxocure LTD all are in advanced stage of development of liposomal drugs based on
Professor Barenholz inventions and knowhow. Professor Barenholz was awarded: The
Donder’s Chair, twice the Kaye award (1995 & 1997), Alec D. Bangham (the Liposome
research "father") award (1998), Teva Founders Prize (2001), an Honorary Doctor degree
from the Technical University of Denmark (DTU) in 2012, and the international
Controlled Release Society’s (CRS) CRS Founders Award for 2012. On 2003 Professor
Barenholz founded (from DOXIL royalties) the "Barenholz Prize" to encourage excellence
and innovation in applied science of Ph.D. students in Israel. Professor Barenholz is
married to Dr Hanna Barenholz. Together they have 4 daughters and 12 grand children.
Haim Bar-Simantov, Chief Operating Officer at Sol-Gel Technologies
Mr. Bar-Simantov leads Sol-Gel’s pharmaceutical development, manufacturing, supply
and commercialization processes. An inventor of several patents related to semi-solids
drug products with 14 year of experience in this field.
Inna Ben-Anat is a Director, Global Quality by Design (QbD) and Product Robustness in
Teva Pharmaceuticals USA. In this role, Inna has implemented global QbD training
program, and is supporting R&D teams in implementing Quality by Design methodology,
optimizing formulations and processes and assisting develop robust product specifications.
Additionally, Inna supports Process Engineering group with process optimization during
scale-up and supports Operations in identification and resolution of any technical issues.
Inna has extensive expertise in process development, design of experiments for process
and product optimization, and statistical data analysis, and has near 15 years of
pharmaceutical development experience. Inna received her BSc degree in Chemical
Engineering and ME degree in Quality Assurance and Reliability in Engineering from
Technion-Israeli Institute of Technology.
Simon Benita is a Professor at The Hebrew University of Jerusalem, where he
received his Ph.D. in Pharmacy in 1980. His research is focused on polymeric nanoand
microparticulate drug delivery systems aimed at improving the therapeutic
performance of active ingredients. As a result of his research activities, Prof. S. Benita
formed and supervises a group of 32 M.Sc., 27 Ph.D. students, and 15 post-doctoral
students in pharmaceutical sciences. He has published 149 research articles and 19 book
chapters, edited or co-edited 5 books and been issued 16 patents and 9 patent applications.
He was selected to be a recipient of The Hebrew University Kaye Innovation Award in
2000 and again in 2005, and is an AAPS Fellow. He is the Founder of the company
Novagali Pharma that received in 2009 the “91 d’or” Award from the French Business
Confederation and the Siemens “Health Award”. Frost & Sullivan recognizes Novagali
Pharma for Innovation in Ophthalmic Therapies and grants the 2009 Best Practices Award.
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4th Jerusalem Conference on Quality and Pharma Sciences
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Novagali has been listed in the Euronext in 2010 and acquired by Santen Japan in
2012. Chevalier dans l’Ordre National du Mérite (Knight in National Order of Merit),
France, May 2012. Israel Controlled Release Society Chapter Prize for Outstanding
Achievements in Controlled Release, September 2012. He is actually the Director of the
Institute for Drug Research and Head of the School of Pharmacy, Faculty of Medicine, The
Hebrew University of Jerusalem.
Stacy Berkshire is currently Vice President of International Quality Operations at Perrigo
Company. She received her BA degree from Aquinas College and an MS in Regulatory
Quality and Compliance from Purdue University as well as her certificate in Lean Six
Sigma Black Belt from Villanova University. In her current position she is responsible for
effective, efficient and compliant Quality pharmaceutical operations and supplier quality
for all of Perrigo’s International Sites. This includes drug and API operations in 7 countries
(Mexico, UK, Israel, China, Australia, India and Canada). Dosage forms and drug
deliveries include: solid and liquid orals, creams, ointments, patches, gums, powders and
injectibles. Focus areas include building organizational and human capability and
performance including instilling a culture of Quality and continuous improvement.
Outcomes include improved performance in operational right-first-time, laboratory and
QA efficiencies, employee engagement, shop floor ownership for Quality and strong
compliance performance from regulatory inspections .
Lucinda (Cindy) Buhse, Ph.D., Acting Director, FDA Office of Testing and Research .
Dr. Buhse joined DPA in 2001 as Deputy Director of the Division of Pharmaceutical
Analysis for Center for Drug Evaluation and Research in the FDA. She was promoted to
Division Director in June, 2004 and has been acting director for Office of Testing and
Research since June 2013. Dr. Buhse received a B.A. in Chemistry from Grinnell College
and a Ph.D. in Physical Chemistry from the University of California, Berkeley under the
direction of John H. Clark and George C. Pimentel. Before joining FDA, Dr. Buhse
worked in management positions in Production, Validation and Analytical Services at
Sigma Aldrich Corporation and as a Senior Research Scientist for Rohm and Haas
Company. She leads a laboratory based office in the Center for Drug Evaluation and
Research (CDER) responsible for supporting FDA review, investigation and enforcement
actions and for conducting research programs to advance the science needed to regulate the
quality of human drugs .
Ian Cox currently works in the JMP Division of SAS. Before joining SAS in 1999, he
worked for Digital, Motorola, and BBN Software Solutions Ltd. and has been a consultant
for many companies on data analysis, process control, and experimental design. A Six
Sigma Black Belt, he was a Visiting Fellow at Cranfield University and is a Fellow of the
Royal Statistical Society in the United Kingdom. Cox holds a Ph.D. in theoretical physics.
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
Ron S. Kenett, Ph.D. is Visiting Professor at the Hebrew University Institute for Drug
Research, Chairman and CEO of the KPA Group and KPA Ltd., Research Professor at the
University of Turin, Italy and International Professor Associate at the Center for Research
in Risk Engineering, NYU-Poly, New York, USA. He has over 25 years of experience in
applied statistics in scientific, industrial and business applications. His 170 publications are
on topics in biostatistics, industrial statistics, quality and risk management. Ron is coauthor of 10 books including Modern Industrial Statistics: with applications in R,
MINITAB and JMP, 2nd edition (with S. Zacks and D. Amberti), John Wiley and Sons,
2014, Modern Analysis of Customer Surveys with Applications using R (with S. Salini),
John Wiley and Sons, 2011, Statistical Methods in Healthcare (with F. Faltin and F.
Ruggeri), John Wiley and Sons, 2012, Modern Industrial Statistics: Design and Control of
Quality and Reliability (with S. Zacks), Duxbury Press, 1998, Spanish edition 2000, 2nd
paperback edition, 2002, Chinese edition 2004 and Multivariate Quality Control: Theory
and Applications (with C. Fuchs), Marcel Dekker Inc., 1998. Ron's Ph.D. is in
Mathematics from the Weizmann Institute of Science. He is a Fellow of the Royal
Statistical Society, elected member of the International Statistical Institute, Past President
of the Israeli Statistical Association and Past President of ENBIS, the European Network
for Business and Industrial Statistics. In 2013 he was awarded the Greenfield Medalist of
the Royal Statistical Society for excellence in the application of Statistics. His biotech
consulting customers include Teva, Perrigo, Serono, Kamada, BTG and SolGel. He has
published in the American Journal of Human Genetics, the Annals of Allergy,
Immunogenetics, the Israel Journal of Medical Science, Pediatric Pulmonology , the
European Journal of Allergy and Clinical Immunology and the Journal of Trombosis and
Haemostasis.
Jean-Paul (Moshe) Lellouche (born in Constantine, Algeria in 1955) received his diploma
of Engineer in Organic Chemistry from the Ecole Supérieure de Chimie Industrielle de
Lyon (ESCIL, Lyon, France) in 1978. Thereafter, he joined the Commissariat à l’ Energie
Atomique (Gif-sur-Yvette, Saclay, France) to earn his PhD degree in 1981 (multi-step
syntheses of 14C-/3H-labeled organic molecules - radio-isotopic chemistry field). In 1997,
he moved to Israel to the Ben-Gurion University of the Negev (BGU, Beer-Sheva, Israel)
as an Associate Professor in Organic Chemistry (Guastella fellow stipend from the Rashi
Foundation). Having joined the Department of Chemistry of Bar-Ilan University in 2000,
he was nominated as a Full Professor in Organic Chemistry/Nano(bio)technology in July
2008. Having a very strong record in multi-step organic synthesis, he is currently
developing nanofabrication methodologies based on pyrrole/carbazole/thiophene-based
conducting polymers (CPs) and related nanosized composites as well as on functional
nanoscale colloids for diverse bio- and immuno-sensing applications. His current R&D
activity includes R&D developments at the cutting-edge Materials Science level
interfacing with nano(bio)technology He has authored 105 peer-reviewed papers, 12
patents, and 3 book chapters in organometallic, organic/fluorine, and materials science
chemistries/engineering.
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
Rosario LoBrutto is currently Senior Director, Head of Development for Sterile Products,
at TEVA Pharmaceuticals, in Pomona, New York. He is an active member of the global
analytical leadership team and Analytical QbD Champion and also serves on the USP
expert council for Methods Validation and Verification. Rosario has over 19 years of
experience in development of active pharmaceutical ingredients and drug products
including small molecules, proteins, and peptides for a variety of dosage forms (solid oral
dosage forms, transdermals, parenterals, films, etc). Prior to joining Teva Rosario worked
with Novartis Pharmaceuticals and Merck Research Laboratories. At Novartis he had
positions of increasing responsibility as project leader for API/drug product, Global QbD
Network Leader, and leading Global QbD training program, Global Specification Setting
Strategy team and global team for streamlining processes for CMC aspects of small
molecules/ biologics development projects for IND/IMPD to NDA/MAA/BLA. Rosario
received his Ph.D. in analytical chemistry from Seton Hall University.
Lazarovici Philip, Ph.D., is a member of the Institute for Drug Research of the School of
Pharmacy, The Hebrew University of Jerusalem. An acclaimed neuropharmacologist, he
graduated in pharmacology and toxicology at the Hebrew University, post graduated on
neurobiology at the Weizmann Institute of Science and conducted neurochemical and
molecular research at the National Institutes of Child Health and Human Development,
NIH, as a visiting scientist, which all set the stage for his lifelong career on
neuropharmacology. His groundbreaking work provided Israeli scientific community with
neurotrophins, neurotoxins and neuronal models. Prof. Lazarovici is a member of 10
academic societies, published more than 200 scientific articles and reviews, edited six
books and made more than 350 presentations at national and international conferences. He
is most proud of his graduate students, which are active in the Israeli community
pharmaceutical practice, academia, hospitals and institutions of teaching and research.
Claudio Pincus is Founder and President of The Quantic Group, Ltd., a consulting firm
that provides strategies for and implementation of technical, regulatory compliance and
quality programs for the pharmaceutical, vaccine, biotechnology, chemical and medical
device industries. Claudio has developed and directed major initiatives including
consulting & certification for FDA Consent Decrees; global manufacturing & sourcing
strategies; merger integration; quality systems deployments; organization design; and
reengineering development, quality & manufacturing activities. Claudio has presented to
The Harvard FDA Compliance and Regulatory Symposium, The Princeton Pharma,
Biotech and Device Colloquium, and The Pharmaceutical Regulatory and Compliance
Congress in Washington, DC; as well as to PhRMA, ISPE, CHPA, Project Management
Institute and AAPS. He has been published in industry journals and received a Fulbright
scholarship to attend Georgia Institute of Technology, where he received his Master’s
Degree in Engineering, which followed his engineering degree from The Catholic
University of Chile. He was Vice President of Operations for Davey McKee Engineering
& Construction.
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
Grainne Quinn, MD, is currently Head of Global Patient Safety at Perrigo PLC. Prior to
joining the pharmaceutical industry Dr. Quinn practised general internal medicine and
moved into the field of pharmacovigilance and medical patient safety over 10 years ago.
She was Head of the Safety Physician Group at Quintiles and Head of Global
Pharmacovigilance at Elan PLC before moving to Perrigo.
Jonathan Rabinowitz, PhD is The Elie Wiesel Professor and a former Department
Chairman at Bar Ilan University. He also holds a visiting professorship in the Department
of Psychiatry at Mount Sinai School of Medicine in New York. His current research
focuses on understanding and minimizing placebo response in antipsychotic and
antidepressant trials and developing statistical and methodological ways of improving
efficiency of drug trials. His research has been supported by NIH, BMBF, Innovative
Medicines Initiative, European Commission European Union, NARSAD and major
pharmaceutical companies. He serves as a member of the editorial board of European
Neuropsychopharmacology and is a member of the International Biometric Society,
International Society for Schizophrenia Research and the European College of
Neuropsychopharmacology. He serves on the Clinical Expert Review Committee for the
FDA (Food and Drug Administration) data standards development initiative that will
standardize clinical data elements for regulatory submission. He served on the Advisory
Group on Promoting Good Analysis Practice in relation to European Medicines Agency
Clinical Trial Data and Transparency which was set up to inform the EMA policy on
clinical trial data transparency. He is a member of the DIA (Drug Information
Association) scientific working group on missing data in clinical trials. He has published
over 150 scientific papers.
Yafit Stark holds a Ph.D. degree in Pathology from the Sackler School of Medicine, Tel
Aviv University, and a Post-Doctorate in Immuno-Histopathology from Tel Aviv
University and the Weizmann Institute of Science. She served as a member of the
academic staff of the Sackler School of Medicine and continues to lecture on Pathology
and Oncology Drug Development in the School of Medicine’s College for Advanced
Degrees. Yafit joined Teva in 1987 and from 1991 to 1994 was based in the US, where
she established the Innovative R&D Division of Teva USA, being responsible for the
clinical development of Copaxone®. Yafit then established and managed the Innovative
R&D Division’s global clinical research and clinical development of all innovative
products at Teva. Today she holds the position of Chief Clinical Officer, Innovative R&D
Division and is in charge of the clinical development strategy and implementation of new
methodologies in both innovative and biogeneric product development. Yafit is a member
of the Board of Trustees (ABOT) of the Association of Clinical Research Professionals
(ACRP) and also serves on the Global Conference Planning Committee of this global
organization. Yafit is an active member of “Tnufa”, the Project Funding Evaluation
Committee of the Chief Scientist’s Office at the Israeli Ministry of Industry, Trade and
Labor. She serves on the Board of Directors of the Israeli Research Association for Eye
Health and Blindness Prevention and the International Association for Fighting Best
Disease, and on the Advisory Board of Xenia Venture Capital, an investment company
operating a technological incubator in support of high-technology start-up companies in
Israel. In addition, Yafit is serving on the Board of Directors of two Israeli-based biotech
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4th Jerusalem Conference on Quality and Pharma Sciences
May 20-22nd, 2014, The Hebrew University of Jerusalem and University of Wisconsin
companies, Andromeda and Polypid. In April, 2011, Yafit became a member of the
Coalition Against Major Diseases Consortium (CAMD).
David M. Steinberg is Professor of Statistics and Chair of the School of Mathematical
Sciences at Tel Aviv University and a Senior Statistical Consultant at KPA Ltd. He has a
Ph. D. in statistics from the University of Wisconsin-Madison. Prof. Steinberg’s primary
research area is experimental design, with an emphasis on the design and analysis of
industrial experiments. From 2008-2010 he was Editor of the leading journal
Technometrics. In 2013 he was awarded the George Box Medal by the European Network
for Business and Industrial Statistics.
Melvin H. Weinswig is Emeritus Dean and Professor of Pharmacy in the School of
Pharmacy, University of Wisconsin Madison. He is a native of Massachusetts and
received the B.S. (1955) and M.S. (1957) degrees in pharmacy from the Massachusetts
College of Pharmacy, and the Ph.D. (1961) degree in pharmaceutical chemistry from the
University of Illinois. He served on the faculty of the College of Pharmacy at Butler
University before coming to Wisconsin in 1969. He has received awards for teaching and
service while serving on the faculty of both institutions, and has been extremely active in
various professional organizations. Dr. Weinswig has authored research articles dealing
with synthetic and analytical procedures of drugs, continuing pharmaceutical education
and drug abuse education.
Louis W. Yu, Ph.D. is the Executive Vice President, Global Quality & Compliance at
Perrigo, with responsibility for directing the company’s quality initiatives world-wide.
Prior to joining Perrigo, Dr. Yu was the VP, Quality at CV Therapeutics. Over the years,
he was head of global quality and compliance for Forest Laboratories and VP Quality for
Solvay Pharmaceuticals as well as VP and Chief Scientific Officer for Par
Pharmaceuticals. Earlier in his career in the pharmaceutical industry he served long term
leadership roles in the R&D and Quality organizations at Johnson & Johnson. Dr. Yu
earned a bachelor of science in chemistry from the University of Wisconsin in Madison,
Wisconsin and a Master of Science and Ph.D. in analytical chemistry from Rutgers
University. His professional affiliations include AAPS, ASQ, PDA, CHPA and Sigma Xi
organizations. He has served as an Adjunct Professor of the School of Pharmacy,
Extension Services in Pharmacy at the University of Wisconsin in Madison. He currently
serves as a member of the USP Committee of Experts for small molecules, and as a
director on the Board of Directors of the Product Quality Research Institute.
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