Process Validation Lifecycle

NEXUS
Vol. I, Issue 1 | April 2014
Process
Validation
A Life Cycle Approach
A collaboration between the Southern California PDA chapter

and its affiliate student chapter at the Keck Graduate Institute
Click on a page number to jump to its respective article
TABLE OF CONTENTS
Southern California PDA Chapter Section
Focus Theme: A Lifecycle Approach to Process Validation
A Lifecycle Approach to Process Is Your Environmental Monitoring
10 Validation: Interpreting the 2011 FDA
Process Validation Guidance
26 Program Risk-Based?
Marsha Stabler Hardiman, Senior Consultant
Ravi Samavedam, General Manager Concordia ValSource, LLC
BioSPEQ, Inc.
Risk and Statistics Serve as Tools for Application of Risk Management in

16 Solving Variation Riddles and Creating
Robust Processes
30 the Process Validation Lifecycle for
Biopharmacuetical Manufacturing
Dr. Mike Long, MBB, Sneha Deshpande, Engineer II
Concordia ValSource, LLC BioSPEQ, Inc.
Cleaning Validation - Points to Consider Lifecycle Approach to Validation of Water

22 Dean Isildakli, Engineer I
BioSPEQ, Inc.
34 Systems
Igor Gorsky, Senior Consultant
Concordia ValSource, LLC
Recent Technical Advances

Thermo Fisher Scientific TruScan Innovative Technologies to Build
42 RM Instrument: Anti-Counterfeiting,
Detecting Counterfeit Drugs
45 Partnerships and Protect Human
Subjects
Robert Brush, Business Development Manager Debra Reed, Vice President
Thermo Fisher Scientific Liberty IRB
Subject Matter Experts

The Use of Disulfide Reducing Agents in BPOG’s Extractables Protocol
46 Biotechnology - A Technical Overview
Clarke A. MacDonald, Technical & Product Support
52 Standardization Efforts - A Step Forward
to Facilitate Implementation of Single-
Specialist Use Technologies (SUT)
BioVectra, Inc. Weibing Ding, Ph.D., Principal Scientist, Materials
Roger L. Lundbald, Ph.D., Independent Consultant Science
Amgen, Inc.
The NEXUS is a non-peer reviewed publication

Click on a page number to jump to its respective article
Company Spotlight
Skingenix, Inc. Prolacta Bioscience, Inc.
57 Shaleen Parekh, General Manager and Prinicipal
BioSPEQ, Inc.
59 Ruchika Raval
Vice President, PDA Southern California Chapter
President, Global BioPharm Regulations
PDA Event Highlight

Southern California Chapter Q1 Educational Program: Making Sense
62 of the New Extractables & Leachables Best Practices for Parenteral

Products... A Blueprint for Success
John Holmgren
President, PDA Southern California Chapter
Director Quality/Validation
Global Pharmaceutical Services, Irvine
Allergan, Inc.
Dr. Michael Ruberto, President
Material Needs Consulting, LLC
KGI-PDA SoCal Student Chapter Section

Focus Theme Student Event Highlight
66 Process Validation Guidance: Legacy
Products
73 PDA Student Chapter Professional Events at
KGI Set Foundation for Lasting Relationships
Steve Speer, Associate Director, West Region between BioScience Students and Industry
ProPharma Group Leaders
Joanna D. Naymark, President
Focus Theme SoCal PDA Student Chapter, Keck Graduate Institute
69 Process Validation, No More Sleepless

Nights
Michael Jarpe, Ph.D.,
Academic Partnerships
Advisory Council, Keck Graduate Institute
Vice President, Biopharmaceuticals
Allergan, Inc.
78 Keck Graduate Institute: At the Intersec-
tion of Science and Commerce
Paige Stein, Manager of Media Relations
Student Initiative Keck Graduate Institute
71 PDA SoCal Student Chapter Mentorship

Program
April Yang, Co-Leader of Mentorship Program
SoCal PDA Student Chapter, Keck Graduate Institute
The NEXUS is a non-peer reviewed publication

NEXUS Vol. 1 Issue 1
Meet the Nexus

EDITORIAL
TEAM BRIAN UNDERHILL
CO-EDITOR-IN-CHIEF,
SoCAL PDA CHAPTER,
BIOSPEQ, INC.
VARANT SHIRVANIAN
CO-EDITOR-IN-CHIEF,
SoCAL PDA STUDENT CHAPTER,
KECK GRADUATE INSTITUTE
DAPHNE DARMAWAN
WEB EDITOR,
SARA HERRMANN
ASSOCIATE EDITOR,
JOEL GREGGAIN
ASSOCIATE EDITOR,
KEKOA IOBST
ASSOCIATE EDITOR,
Contributors
AUTHORS JOANNA D. NAYMARK
President, SoCal PDA Student Chapter
ROBERT BRUSH Keck Graduate Institute
Business Development Manager
Thermo Fisher Scientific SHALEEN PAREKH
General Manager and Principal
SNEHA DESHPANDE BioSPEQ, Inc.
Engineer II
BioSPEQ Inc. RUCHIKA RAVAL
Vice President, SoCal PDA Chapter
WEIBING DING, Ph.D. President
Prinicpal Scientist, Materials Science Global Biopharm Regulations
Amgen, Inc.
DEBRA REED
IGOR GORSKY Vice President
Senior Consultant Liberty IRB
MICHAEL RUBERTO, Ph.D.
MARSHA STABLER HARDIMAN President
Senior Consultant Material Needs Consulting, LLC
RAVI SAMAVEDAM
JOHN HOLMGREN General Manager
President, SoCal PDA Chapter BioSPEQ, Inc.
Director Quality/Validation
Global Pharmaceutical Services, Irvine STEVE SPEER
Allergan, Inc. Associate Director, West Region
ProPharma Group
DEAN ISILDAKLI
Engineer I PAIGE STEIN
BioSPEQ, Inc. Manager of Media Relations
Keck Graduate Institute
MICHAEL JARPE, Ph.D.
KGI Advisory Council APRIL YANG
Vice President, Biopharmaceuticals Co-leader, SoCal PDA Student Chapter Mentorship Team,
Allergan, Inc. Keck Graduate Institute
MIKE LONG, Ph.D.

MBB
Concordia ValSource, LLC DONORS
ROGER L. LUNDBALD, Ph.D. SHELDON M. SCHUSTER, Ph.D.
Independent Consultant President
CLARKE A. MacDONALD
Technical & Product Support Specialist
Biovectra, Inc.
Letters from the

Editors
The NEXUS is a non-peer reviewed publication, which developed out of a collaboration between
the PDA Southern California Chapter and the PDA Student Chapter. Working with the students from
Keck Graduate Institute (PDA Student Chapter) on the vision and execution of the NEXUS Journal
has been a privilege and great inspiration. I feel extremely blessed to have had the opportunity to
work alongside so many young, driven and exceptionally intelligent people. The college is a very
forward-thinking and entrepreneurial institution and the support and energy has played a key con-
tributor to the NEXUS initiative.
This initiative was undertaken to serve the following: (1) provide a tool that expands upon tech-
nical topics and enhances knowledge among PDA members and our industry, (2) provide a vehicle
that allows the opportunity for professionals at various levels in their career to publish and expand
the industry, (3) promote and strengthen the awareness of resources to enhance this network in
our industry, and (4) create a platform for highlighting aspects in our industry and among our
professionals that lend to collaboration and professional development. We feel proud of our first
publication, as we believe that these objectives have been successfully met.
Sustainability… This has obviously taken a significant amount of time for all that have been in-
volved in this exciting initiative. In order to sustain this journal, the NEXUS PDA Committee needs
volunteers that have passion for directing and contributing to the evolution of this publication. If
you want to learn about what is involved in volunteering for this exciting initiative, please contact
me: brian@biospeq.com, (909) 714-3155.
We’ve had a lot of fun working on this publication. We truly hope that you enjoy it, and in some
way help us in supporting its sustainability.
Thank you,
Brian Underhill
General Manager and Principal
BioSPEQ, Inc.
Letters from the

Editors
On behalf of the Southern California PDA Student Chapter and the NEXUS team, I’m proud to
present the inaugural issue of the NEXUS Journal. When I started this initiative in July of 2013
with Brian Underhill, NEXUS co-editor, our vision was to create a valuable resource of information
for life science professionals, strengthen the relationships between the future life science profes-
sionals at KGI and industry professionals of the PDA Southern California Chapter, and expose life
science graduate students at KGI to current and relevant issues in the Life Sciences industry today.
After nine months of hard work and determination by all those involved, we are proud to say we
have realized that vision.
Creating the NEXUS Journal as its founding co-editor has truly been a unique experience. It has
taught me valuable lessons in leadership and teamwork, enriched my professional development,
and helped me establish lasting friendships and professional relationships that I will take with me
into my professional career in the Life Sciences. As I prepare to graduate from KGI this May, I’m
confident that the KGI NEXUS team will strive to perpetuate this journal to new heights on the way
to maximizing its value potential for the Life Sciences industry.
I must thank my editorial team: Daphne Darmawan, Joel Greggain, Sara Herrmann, and Kekoa
Iobst whose diligence and dedication have made the vision of the NEXUS Journal a reality. I’d like
to thank Joanna Naymark (President, PDA SoCal Student Chapter) and the PDA Student Chapter
officers for their contributions and support throughout this project. Also, I want to thank the authors
of this inaugural issue for sharing their valuable experiences and insights with our readers. Finally,
I’d especially like to thank Brian Underhill, for his mentorship and direction. Working with him has
taught me that the magnitude of success is limited only by one’s drive and imagination, and I feel
very fortunate to have worked with him on the NEXUS.
Thank you,
Varant N. Shirvanian
News & Media Project Leader
PDA SoCal Student Chapter
Call for
Authors
Each NEXUS Journal issue will contain a focus theme, which will have multiple
articles surrounding this topic. In addition to the “focus theme,” each issue will also
contain other sections (subject matter experts, recent technical advances, company
spotlight, PDA event highlight, Highlighting Industry Professionals, etc.).
If you would like to EITHER contribute an article to the NEXUS, or volunteer on

the NEXUS Team to research and outreach into our industry for topics and articles,
please contact:
brian@biospeq.com or (909) 714-3155.
Advertising
Opportunities
The NEXUS Journal Team is also accepting advertisements for each issue. If you
or your organization would like to advertise in the next issue of the NEXUS, or learn
more about our media package, please contact:
Brian Underhill: brian@biospeq.com or (909) 714-3155

OR
Varant Shirvanian: vshirv13@students.kgi.edu or (248) 974-8906.
Keck Graduate Institute Team Master’s Projects offer a cost-effective,
professional option for outsourced bioprocessing projects.
With a KGI Team Master’s Project (TMP), For more information:
your organization can outsource a problem http://www.kgi.edu/tmp_corp_partners
or opportunity that might otherwise be To schedule an introductory phone
conversation, contact:
back-burnered. A team of KGI graduate
Diana Bartlett
students works on your project for nine Assistant Vice President, Corporate Partnerships
months under the supervision of a KGI Diana.Bartlett@kgi.edu
faculty member and company liaison. 909-607-9864
TMPs can be
Projects are being accepted now through June
· Laboratory-based projects – downstream 2014 for a start in September 2014.
or upstream processing, process design, etc.
· Market research www.kgi.edu
· Technology assessment
· Economic modeling
· Contact KGI for other possibilities
10
TABLE OF CONTENTS
Focus Theme
BY RAVI SAMAVEDAM
GENERAL MANAGER
BioSPEQ, INC.
A Lifecycle Approach
to Process Validation
I
n January 2011, the FDA Guidance for In-
dustry - Process Validation: General Prin-
INTERPRETING ciples and Practices, was released. This

guidance is relevant for human and veterinary
THE 2011 FDA drugs, biological and biotechnology products,
API and Drug Substances as well as combi-
PROCESS VALIDATION nation products. Companies have since had
the need to evaluate their existing validation
GUIDANCE programs against the lifecycle approach rec-
ommended by this guidance document. For
companies that have been following the tra-
ditional process validation approach of “three
runs and done” are now forced to evaluate the
11
impact of this guidance. The increased empha- quality products, via extensive characterization
sis on process knowledge and understanding the and development studies. Process knowledge
variability, underscores the need to understand and understanding sources of variability is critical
the inter-dependencies of various activities that to this effort. Design of experiments (DOE) ap-
encompass the commercialization process of
proaches is often used at this stage to understand
drugs.
multivariate interactions between inputs and
Process Validation (PV) is defined per the outputs. Risk analysis tools are recommended to
2011 FDA guidance on PV as “the collection and screen potential variables for DOE studies to re-
evaluation of data, from the process design stage duce the number of studies performed, yet maxi-
throughout production, which establishes scien- mizing process understanding. It is not a regulato-
tific evidence that a process is capable of consis- ry expectation that the process be developed out
tently delivering quality products”. to failure, but rather developed to establish the
operating space for ongoing manufacturing.
A lifecycle approach to process validation
with enhanced focus on process knowledge and Studies performed at this stage need to be
understanding is recommended per this guid- based on sound scientific principles and should
ance. Specifically, the guidance refers to three follow good documentation practices, but do not
inter-related stages as being the components of necessarily need to be conducted under cGMP
the lifecycle approach to PV: conditions. Certain studies such as impurity and
viral clearance studies, however, are considered
Stage 1 – Process Design: The commercial man- critical enough that they require quality oversight
ufacturing process is defined during this stage and should be treated separate from other early
based on knowledge gained through characteri- process design experiments. Process design typ-
zation, development and scale-up activities. ically also includes pilot or large scale studies, in
Stage 2 – Process Qualification: During this stage, addition to bench scale experiments. This is es-
the process design is evaluated to determine if pecially true when scale dependent parameters
the process is capable of reproducible commer- exist, that cannot be adequately studied using
cial manufacturing. small scale models. It is important at this stage to
understand the capability and limitations of large
Stage 3 – Continued Process Verification: Ongo- scale equipment for routine manufacturing to en-
ing assurance is gained during routine production sure control strategies recommended at the end
that the process remains in a state of control. of stage 1 are appropriate.
The following sections provide some important

concepts and activities during each stage in the THE FOCUS IS ON DESIGNING A ROBUST
PV lifecycle. PROCESS CAPABLE OF CONSISTENTLY
DELIVERING QUALITY PRODUCTS VIA
STAGE 1: PROCESS DESIGN EXTENSIVE CHARACTERIZATION AND
During stage 1, the focus is on designing a DEVELOPMENT STUDIES.
robust process capable of consistently delivering
12
At the end of stage 1, it is expected that the

STAGE 1 - PROCESS DESIGN ACTIVITIES
operating space for stage 2 and 3 is adequate-
• Risk Assessments
ly defined, ensuring consistent product quality.
• Small scale characterization studies
Sources and extent of variability and the control
• Robustness studies
strategy for each unit operation is expected to be
• Engineering/Scale up/Shakedown runs
defined. The description of the manufacturing • Clinical Lots
process along with the operational parameters • Historical Experience
(inputs) and performance parameters (outputs)
are typically defined at the end of stage 1 as part STAGE 1 – PROCESS DESIGN OUTPUTS
of process development documents. Acceptable • Commercial Process Description
and/or operational ranges for process parame- • Control Strategy for Unit Operations
• Categorization of Process Parameters
ters are also defined at the end of stage 1. It is
• Parameter Range definitions
common for companies at this stage to categorize
• Sampling strategy for Routine Mfg, Stage 2
such process parameters for each unit operation,
and Stage 3
based on their impact to product quality and pro-
• Process Monitoring Strategy
cess consistency. For example, input parameters
that are found to be product quality impacting during stage 2 and 3. Inadequate or unclear pro-
may be categorized as critical. Such critical pa- cess definition often leads to issues downstream
rameters are typically included, at a minimum, in the commercialization process. For example, if
during stage 2 and 3. Certain parameters that the impact of a certain parameter is not clearly
may not impact product quality, but are indicative understood and hence appropriate ranges not de-
of process consistency, are also typically includ- fined, excursion during stage 2 and 3 cannot be
ed as part of stage 2 and 3. Risk analysis tools adequately investigated.
may be employed at this point to assist with pa-
rameter categorization. Several approaches to STAGE 2:
parameter categorization exist, which makes this PROCESS QUALIFICATION
activity prone to subjectivity and internal debate.
It is imperative that the category definitions and Process Qualification consists of two ele-
approach be clearly understood and agreed upon ments (a) Facility, utilities and equipment design
by all parties and let the development data gov- and qualification and (b) process performance
ern the output. qualification (PPQ).
Due to the inherent dependency of stage 2 Successful completion of Stage 2 is required

and 3 on stage 1 outputs, it is important that a prior to commercial distribution, expect in certain
cross functional team, consisting of members circumstances, where concurrent release of PPQ
responsible for all three stages, are involved in batches are possible. Concurrent release require-
the planning and strategy development for var- ments are discussed later in this article. Adher-
ious stages. Robust process design is central to ence to cGMPs is required at stage 2, since lots
a successful process validation program as this is produced at this stage are considered commer-
the basis for the activities and control strategies cially viable.
13
STAGE 2A - FACILITY, UTILITIES AND EQUIP- STAGE 2 - PROCESS QUALIFICATION

MENT DESIGN AND QUALIFICATION ACTIVITIES
During stage 2a, activities such as design, • Risk Assessments
commissioning and qualification are performed • Facility Design
to ensure that facilities, utilities and equipment • Equipment Design
are suitable for their intended use and perform • Commissioning and Qualification of
properly. Majority of stage 2a activities are com- Equipment
pleted prior to stage 2b, process performance • Qualification of sterlization/sanitization
qualification. processes
• Process Performance Qualification
Design and installation of systems are veri-
fied for compliance with the design specifications, STAGE 2 – PROCESS QUALIFICATION
including material of construction, capacity, func- OUTPUTS
tionality etc. It is critical that systems are tested • Facility and equipment qualified
to ensure process requirements, specifically op- • Process performance qualification complete
erational ranges, are able to be met taking into • Data available for regulatory submissions
consideration unforeseen circumstances such as (BLA, MAA, etc.)
interventions, stoppage etc. Stage 2a activities
should be outlined in a plan or several plans that takes into consideration the level of risk involved with
each system and prioritize activities commensurate to risk. The plan(s) should at a minimum include
the extent of testing performed, schedule of activities, roles and responsibilities, success criteria, eval-
uation of changes and the reference source documents governing various activities. The completion
of all activities outlined in the plan should be documented in report(s) that should be reviewed and
approved by the quality unit.
STAGE 2B – PROCESS PERFORMANCE QUALIFICATION

During stage 2b, process knowledge gained during the process design stage is qualified via commer-
cial scale testing and evaluation of resulting data. These commercial scale runs are performed based
on the defined process established during stage 1 and testing is performed for various product quality
attributes to establish a qualified process, suitable for ongoing commercial manufacturing. It is recom-
mended in the guidance document that knowledge gained from all studies during stage 1, including
characterization/development studies in the lab, engineering runs at scale, historical experience with
similar products etc., be taken into account to establish the conditions for the PPQ runs. During these
PPQ batches, it is not expected that the range of various operating parameters be explored, as long as
sufficient data exists based on stage 1 activities that support these ranges. The level of sampling and
testing during the PPQ batches is expected to be higher than routine batches to adequately demon-
strate acceptable product quality throughout the process. Data yielding from manufacturing lots man-
ufactured during stage 2 is typically included in regulatory submissions to demonstrate a qualified
process that is capable of delivering consistent product quality.
14
Protocols that are prospectively approved by PPQ protocol. In addition, such batch should be
appropriate departments and the quality unit is put on stability and be highly scrutinized for any
a requirement for PPQ batches. These protocols customer complaints and defect reports.
should contain the manufacturing conditions,
process parameters and ranges, as well as PPQ For companies employing process analytical
success criteria, based on sampling and testing technologies (PAT) for real time monitoring and
for product quality and process consistency. It is control of process parameters, the approach to
expected that the sampling plan is adequate to stages 1 and 2 should focus more on the mea-
address inter-batch and intra-batch consistency. surement systems and control aspects of the at-
In addition, the protocol should contain instruc- tributes.
tions for addressing excursions against the proto-
col requirements, status of stage 2a activities as
STAGE 3: CONTINUED
PROCESS VERIFICATION
well as the status of the analytical methods to be
used for testing the PPQ batches. The conditions The objective of stage 3 in the PV lifecycle is
during PPQ batch should be representative of a continual assurance that the validated state of
normal operations expected for routine commer- the manufacturing process and related systems is
cial manufacturing. The results of the execution maintained. During this stage, process parame-
of the protocols should be summarized in final re- ters that are indicative of product quality and pro-
ports analyzing the testing results, discussion of cess consistency are expected to be monitored
any excursions observed and the overall conclu- and analyzed. It is recommended that a statistical
sions of the PPQ effort. approach to process control be established in or-
der to adequately measure the level of process
The guidance document provides the provi- control and variability of the manufacturing pro-
sion for potentially releasing PPQ batches prior cess. In addition, stage 3 activities could serve as
to the completion of the PPQ activities. Majority an early warning system of adverse variability in
of the time, it is expected that all PPQ activities
are completed prior to release and distribution STAGE 3 – CONTINUED PROCESS
of product. In certain circumstances, such as or- VERIFICATION ACTIVITIES
phan drugs, drug with short half lives or those in • Monitoring and analysis of process parame-
limited supply (causing limited number of batch- ters and quality attributes
es produced), concurrent release of PPQ batches • Estimation of process capability and process
may be accomplished. This requires that the PPQ control
protocol provide the rationale and criteria for re- • Ongoing maintenance and calibration
lease of such batches prior to the completion of • Re-qualification activities
all PPQ activities (e.g. minimum number of suc-
STAGE 3 – CONTINUED PROCESS
cessful runs required to be completed for the pro-
VERIFICATION OUTPUTS
cess to be considered qualified). The data from
• Verification of process control
the batches in questions must meet standard
• Process improvement opportunities
cGMP requirements, any regulatory approval cri-
• Maintenance of qualified state for facilities,
teria and the lot release criteria established in the
equipment and utilities
15
the process and can help identify potential pro-

THE OBJECTIVE OF STAGE 3 IS A CONTINUAL
cess improvement opportunities. Scrutiny of in-
ASSURANCE THAT THE VALIDATED STATE
tra-batch as well as inter-batch variation is part of
a comprehensive continued process verification
OF THE MANUFACTURING PROCESS AND
program. RELATED SYSTEMS IS MAINTAINED.
The starting point for the extent of monitor-

ing and analysis during stage 3 are the process
parameters and quality attributes that are part of
stage 2b. As and when sufficient data is available,
the frequency and type of sampling may be ad-
justed based on process variability. The data ana-
lyzed as part of stage 3 should be reviewed by the
quality unit on a periodic basis. Any changes to
the process resulting from stage 3 activities must
be pre-approved by the quality unit and must in-
clude a rationale and an implementation plan.
In addition to the manufacturing process, the

facilities, utilities and equipment qualification
should also be maintained in a qualified state to
assure process control. Maintenance of the qual-
ified state is often achieved via routine activities
of maintenance and calibration. The qualified REFERENCES
state of these systems should be assessed peri-
1. Guidance to Industry, Process Validation: General
odically to determine the need for re-qualifica-
Principles and Practices, Food and Drug Administra-
tion activities. tion, 2011
2. ICH Q7 Good Manufacturing Practice for Active Phar-
Process validation is now defined as a three
maceutical Ingredients, guidance for industry, Au-
stage lifecycle that is an ongoing activity rather gust 2001.
than a pre-commercialization activity consisting 3. ICH Q8(R2) Pharmaceutical Development, guidance
of a snapshot of the manufacturing process. Sci- for industry, November 2009.
ence and risk-based methodologies focusing on 4. ICH Q9 Quality Risk Management, guidance for in-
dustry, June 2006.
establishing process knowledge throughout the
product and process lifecycle is a major recom- 5. ICH Q10 Pharmaceutical Quality System, guidance
for industry, April 2009.
mendation in the FDA guidance document. Stage
2 and 3 activities are highly dependent on the
activities and outputs of stage 1, increased the
need for enhanced collaboration between vari-
ous groups in the commercialization process.
TABLE OF CONTENTS
16
TABLE OF CONTENTS
Focus Theme
Risk and Statistics Serve as Tools for
Solving Variation Riddles and Creating
Robust Processes
This article was originally published in the April 2013 PDA Letter and is
republished with permission.
BY DR. MIKE LONG, MBB

in assisting to solve variation riddles and

help drive knowledge management so indus-
try can:
• Understand the product

• Understand the process
• Understand the variables
Have confidence before going into com-

mercial manufacture (1) as discussed in Tech-
nical Report 60: Process Validation: A Lifecycle
Approach, control of variation is one aspect
of the application of the enabling system of
H
ow much variation is acceptable in risk management. For it to be effective, risk
our products and processes? For such tools need to be introduced early in Stage
a simply stated question, the answer 1. This initial application will better help in-
can be quite complex, especially when ap- dustry understand and control the amount of
plied to drug product Stage 2 testing (Pro- variation in its products and processes, the
cess Performance Qualification, or PPQ). It is source of its origin and its ultimate impact
a question industry needs to begin answer- on the patient. In essence, we are trying to
ing at the initiation of Stage 1 activities, with create a means by which we can develop,
risk management as the key tool and driver and ultimately measure, the robustness of
17
our products and processes. But first we must define the maximum amount of variation we
are willing to accept in our product attributes for these robust products and processes to be
developed. This requires a full embrace of the new lifecycle approach to process validation.
How do we get there? “Line of Sight” is how we can describe the manner in which varia-
tion can be assessed along the lifecycle. The amount of testing we perform during Stages 2
and 3 needs to have a clear path back to the attributes of the products we wish to deliver. It
must also have a risk-based statistical justification (2).
Why employ this approach? When we can measure, reduce and control variation, gains
will be seen on both the operational and quality assurance sides of the business. Production
and process yields will increase with reductions in variation. As yields increase, profitability
advances will be seen. From a quality-system standpoint, reduction in variation will correlate
to reductions in events like deviations, OOS, and CAPA (Figure 1).
The following steps, embedded

within Stages 1 and 2, provide the
basis for this Line of Sight approach
(Figure 2):
• Initial definition of Critical Quality
Attributes (CQAs)
• Criticality analysis of CQAs (also
known as Continuum of Criticality)
• Criticality-based statistical ap-
proach for sample sizes
• PPQ sample size justification
The initial step in the process is

Figure 1. Effects of decreased variation on operations and to identify the product CQAs. There
quality metrics. are different approaches used in in-
Source: M. Long, PDA Annual Meeting, San Antonio, TX 2011 “Intro-
dustry when determining CQAs. An
duction to QbD for Suppliers: The first steps.” example of a risk tool that can be
CQA Risk Based PPQ

CQA Critically
Identification Statistical Sample Size
Assessment
Assessment Sampling Plan Justification
Figure 2. Line of Sight: CQA Identification to PPQ Sample Size Justification

Sources: Technical Report 60: Process Validation: A Lifecycle Approach, 51-55, and Long, M. Baseman, H. and Henkels, W.D. “FDA’s
New Process Validation Guidance: Industry Reaction, Questions, and Challenges,” Pharmaceutical Technology, Volume 35, Sept
2011.
18
utilized is shown in Table 1. While there are different manners in which product quality at-
tributes are identified as “critical,” the answer eventually comes down to a “yes or no” for
criticality. The attribute simply is or is not a CQA with “Potential CQAs” moving up to critical
or down to noncritical as product and process knowledge increases.
Table 1. Example of Quality Attribute Criticality Assessment
Source: Technical Report 60: Process Validation: A Lifecycle Approach, Page 53.
IDENTIFY RISKS WITH ASSESSMENTS

After the initial CQA Assessment, the relative risk of the individual CQAs needs to be de-
termined. Not all CQAs are equivalent from a risk standpoint. The impact of the failure of a
CQA is on a continuum. Some will have a minor impact on patient safety, while others will
have a major impact. The relative difference needs to be assessed with a method called the
“Continuum of Criticality,” which will eventually provide the basis for PPQ sample size justi-
fication (3).
The Continuum of Criticality assessment is simple from a conceptual standpoint. CQAs

that have a high severity rating should have a higher standard of testing applied to them as
compared to those CQAs that have been determined to have a low severity. For discussion, we
19
can look at three product attributes for a large molecule being filled into a syringe (potency/
bioactivity, plunger glideability and pH). All have all been classified as CQAs. A simple risk
assessment has been performed to determine the relative criticality for each (see Table 2).
The analysis of this product example shows that we must test and assess potency/bioactivity
to a higher level than pH. This is the point at which we are starting to determine the maximum
amount of variation we will allow in our product and process, which creates a baseline mini-
mum amount of robustness. It is now something we can target and begin to measure.
Table 2. Example CQA Contin-

uum of Criticality Analysis with
Relative Statistical Sampling Re-
quirements
Sources: Technical Report 60: Process

Validation: A Lifecycle Approach, 51-
55, and Long, M. Baseman, H. and
Henkels, W.D. “FDA’s New Process Val-
idation Guidance: Industry Reaction,
Questions, and Challenges,” Pharma-
ceutical Technology, Volume 35, Sept
2011.
As the relative criticality has been assessed, there should be standard methods within or-
ganizations to tie these severity rankings to a statistical level. Using a typical confidence of
95%, we have applied 99%, 95% and 90% minimum population acceptance levels to high,
medium and low severity bands respectively (see Table 3). What this means, practically, is
the three CQAs in our example must meet at the least, with 95% confidence, the population
levels shown. We now have assigned the minimum level of robustness we will allow for the
CQAs.
Table 3. Example CQA Contin-
uum of Criticality Analysis with
Detailed Statistical Levels As-
signed.
Sources: Technical Report 60: Pro-

cess Validation: A Lifecycle Approach,
54, 84, and ISO 16269–6 Statistical
interpretation of data–Part 6: Deter-
mination of statistical tolerance in-
tervals.
Although we have assigned statistical levels that tie Line of Sight back to the relative risk levels of
the CQAs, we have not determined their risk-based sample sizes. The number of samples will be de-
termined by the manner in which the data the CQA is presented. If the data is continuous, we will have
20
to take fewer samples than if the data is discrete (pass/fail). An example of how to select sample sizes
using ISO 16269–6 is provided in Table 4 (4).
Table 4 . CQA Criticality Based PPQ Sampling for Drug Product, Combination Products, or Medical Devices
Sources: Technical Report 60: Process Validation: A Lifecycle Approach, 54, 84, and ISO 16269–6 Statistical interpre-
tation of data–Part 6: Determination of statistical tolerance intervals.
The amount of testing performed during development and clinical batches may assist in pooling of
the samples. For example, if a given CQA output is shown to be substantially equivalent batch to batch,
samples can be taken across each batch and pooled together, rather than performing the testing by just
sampling within each batch. For a high severity CQA, Figure 3 provides a decision tree that shows the
difference in samples required if the data collected is discrete or continuous, pooled or not. As you can
see, the range can be significant (Note, the decision to pool should not be taken lightly, care must be
taken to justify this action). But, the earlier in the lifecycle this analysis is performed and understood,
the easier it is to plan.
Moving backwards in the lifecycle…the samples sizes we selected were based upon standard statis-
tical methods using the type of data and variation seen in development, and tied to a relative severity
level of the product quality attributes assessed to be critical to quality. This is our Line of Sight – this is
how we begin to control variation and create robust products and processes.
STATISTICAL METHODS CONTROL VARIATION

Robust processes require the identification and control of variation. This control begins
the initiation of Stage 1 activities with the identification of preliminary CQAs, and executed
with a Line of Sight approach tying sampling in PPQ directly back to CQAs through a method-
ical use of risk management and statistics.
21
Product Attribute with High

Severity from Criticality
Analysis
NO Data Normal? YES
Descrete Data Method Continuous Data Method

N=299, 0 Defects Per Batch (N=30*) Use ISO 16269-6
Allowed *example
NO Pool Data? YES NO Pool Data? YES
N=300 N=100 N=30 N=10

Per Batch 3 Batches Per Batch 3 Batches Per Batch 3 Batches Per Batch 3 Batches
897 total samples 299 total samples 90 total samples 30 total samples
Figure 3. Example of Decision Tree for PPQ Sample Size Justification
[Editor’s Note: This article is based upon REFERENCES

content being presented by the author at
1. Long, M., Baseman, H. and Henkels. FDA’s New Pro-
the 2013 PDA/ FDA Process Validation Work- cess Validation Guidance: Industry Reaction, Ques-
shop, May 20-21 in Bethesda, Md.] tions, and Challenges. Pharmaceutical Technology;
2011, 35: s16-s23 www.pharmtech.com/pharmtech/
article/articleDetail.jsp?id=738387.
ABOUT THE AUTHOR 2. Guidance for Industry Process Validation: General

Principles and Practices, U.S. Food and Drug Adminis-
Mike Long has over 20 years of experience tration: January 2011 www.fda.gov/downloads/Drugs/
in the pharmaceutical and medical device GuidanceComplianceRegulatoryInformation/Guidanc-
industries. Currently, he is part of the man- es/ucm070336.pdf.
agement team at Concordia ValSource and a 3. Technical Report No. 60: Process Validation: A Lifecy-
member of PDA’s Science Advisory Board and cle Approach; Parenteral Drug Association: 2013. www.
the PDA Letter Editorial Committee. pda.org/bookstore (accessed March 14, 2013).
4. ISO 16269-6 Statistical interpretation of data–Part

6: Determination of statistical tolerance intervals, ISO:
2005 www.iso.org/iso/catalogue_detail.htm?csnum-
ber=38772.
TABLE OF CONTENTS
22
TABLE OF CONTENTS
Focus Theme
Cleaning Validation:
Points to Consider
BY DEAN ISILDAKLI
ENGINEER I
BioSPEQ, INC.
reduction of such residues to sufficient lev-

els, based on batch-to-batch carryover of the
same product or carryover to another prod-
uct, in the case of multi-product operations.
In addition, cleaning validation assures that
cleaning agents are sufficiently removed as
well as a state of microbial control, via ap-
propriate sampling and testing.
A robust cleaning validation program

includes several inter-dependent aspects,
some of which include – cleaning process/
cycle development studies, development of
sampling and testing methods (swab/rinse
recovery studies, assay development), es-
T
he objective of cleaning validation is tablishment of cleaning acceptance criteria,
to demonstrate that cleaning methods cleaning validation and ongoing monitoring.
employed for reusable Biopharmaceu- The following sections summarize some crit-
tical product contact equipment is effective ical points to consider for each of these as-
in removing residues from routine process- pects of a cleaning validation program.
ing operations. These residues are inherent
to the manufacturing process and insuffi- Small parts and disassembled equipment
cient cleaning processes pose the risk of tend to require detailed SOPs to describe
carryover to a subsequent batch/product. how they are cleaned, rinsed, dried, and
Cleaning validation is designed to ensure the stored. This may be done with a parts wash-
23
er, which is the preferred method, or with a ment is held after use and before start of
manual cleaning method, which is not gener- cleaning) etc. The output of the study should
ally recommended because of the potential be a preliminary assessment of cleanability
exposure to strong cleaning agents and the of the residue using the proposed cleaning
inherent variability in the cleaning method. solution. Such studies are typically followed
by at-scale studies to ensure scalability of
Tanks, chromatography systems, and fer-
the cleaning mechanism.
menters can be connected to Clean-in-place
(CIP) circuits that are either portable or part In order to claim sufficient cleaning, a ro-
of the manufacturing facility. The appropri- bust sampling and testing regimen needs to
ate cleaning and rinsing agents can also be be in place. The sampling and testing em-
bagged and attached to the skid or part of ployed should incorporate methods that can
a facility’s CIP storage system. Many tanks detect the soilant, cleaning agents and any
have spray balls connected to the top of microbial proliferation. Typical tests em-
the tank where cleaning and rinsing solu- ployed in the Biopharmaceutical industry in-
tions are sprayed into the tank. Spray balls clude visual inspection, Total Organic Carbon
“A robust cleaning validation program is necessary to

adequately comply with the regulatory requirements
and to ensure lack of product contamination.”
are usually designated for specific tanks and (TOC), conductivity, protein/product specific
have strategically placed holes in them that assays, bioburden and endotoxin. Rinse and
spray cleaning and rinsing agents into every swab samples are typically taken to demon-
crevice of the tank. This includes top/side strate sufficient cleanliness. For such sam-
ports that have sample valves, pH/conduc- ples, it is necessary to demonstrate that the
tivity probes, temperature gauges, pressure recovery of residues is adequate and any
gauges, and agitator blades. resultant recovery percentages are factored
into the acceptance criteria utilized during
Development studies for cleaning pro-
cleaning validation.
cesses typically are performed using coupons
of representative product contact materials Acceptance criteria utilized during clean-
at small scale. These studies should aim to ing validation must take into consideration
demonstrate that product residues (soilants) the possibility of carryover of residues from
can be adequately cleaned using the pro- one batch to another. This is especially crit-
posed cleaning agent. Such coupon studies ical for multi-product operations, where the
should try to mimic actual production condi- risk of carryover from one product to another
tions as close as possible, including but not exists due to potential insufficient cleaning
limited to, soilant concentration, cleaning processes. The acceptance criteria should
contact time, dirty hold time (time equip-
24
also take into consideration aspects of the lized to reduce the burden of performing
sampling technique, such as swab surface these studies. Examples of such approaches
area, equipment surface area, etc. It is not include performing studies on certain rep-
uncommon for companies to equate the ac- resentative or worst case equipment among
ceptance criteria to that of the attributes of a group/family of equipment that have the
the final rinse solution (for example, WFI), same soil and cleaning process. In such in-
such as TOC, bioburden, endotoxin, conduc- stances, the rationale should be based on
tivity etc. It is however still recommended science-based claims documented prospec-
that a carryover calculation be performed to tively in cleaning validation documentation.
ensure such limits employed are adequate
In cases in which the same equipment is
from a potential contamination risk stand-
utilized for either multiple products or soils,
point.
a worst case soilant approach may be uti-
Carryover calculations involve the high- lized. This is typically preceded by an eval-
est amount of a product from one batch that uation of all the soils for cleanability. Some
can get carried over into a batch of the next factors to be considered include solubility of
product and can potentially cross contami- the residues in the cleaning agent, routine
nate another drug. Several factors are in- manufacturing conditions such as dirty hold
volved in this calculation, including the av- times, ability of the sampling technique to
erage product contact surface area of that recover residues, etc. The output of these
specific piece of equipment, the highest evaluations typically include an establish-
possible batch of the next drug product that ment of a worst case soilant that can used as
flows through the piece of equipment, and a representatives of all the residues evaluat-
the largest effective dose of the first prod- ed as part of these studies.
uct.
After completion of cleaning validation,
Cleaning validation studies are typically it is required to implement a cleaning mon-
performed concurrent to manufacturing op- itoring program that is capable of assuring
erations, since such studies require an eval- adequate cleaning on an ongoing basis.
uation of the cleaning process after soiling Some important aspects of such as program
the tank with the relevant residue. During include periodic sampling and testing simi-
these studies it not uncommon to employ lar to cleaning validation. Review of clean-
worst case methodologies such as reducing ing failures/deviation, review of product
the cleaning agent concentration, incorpo- changeover events and any testing should
rating a target maximum dirty hold time pri- be summarized in periodic review documen-
or to start of cleaning, reducing the cleaning tation to demonstrate continued verification
duration compared to routine operations etc. of adequate cleaning. It is also necessary to
incorporate proper assessment of impact to
During cleaning validation, bracketing
cleaning processes are part of the change
and/or worst case approaches may be uti-
control program.
25
GMP Cleaning validation requires docu- limited to a robust cleaning development,

mentation of the results, procedures, and ra- sampling and testing method development,
tionale of all the criteria used. There typical- at-scale studies to demonstrate adequate
ly needs to be an initial cleaning validation cleaning, and ongoing monitoring.
master plan detailing the process equipment,
residues, the extent and type of sampling
to be performed to demonstrate sufficient REFERENCES
cleaning. Individual protocols are typically
written and executed for each type of equip- 1. Agalloco, James (1992). “Points to consider’ in the
validation of equipment cleaning procedures”. PDA
ment. In accordance with FDA standards,
Journal of Pharmaceutical Science and Technology
there are four steps involved in cleaning 46 (5): 163–8
validation that need proper documentation. 2. Walsh, Andrew; Cleaning validation of 21st century:
These standards are designing the system, Overview of new ISPE cleaning guide
developing it, qualifying the process, and 3. ICH Q9: Quality Risk Management
4. FDA Guidance for industry: Process Validation –
making the proper process verifications. The
General principles and practices
first two steps are initially scheming how the 5. 2009 Cleaning Memos, by Cleaning Validation Tech-
cleaning will be laid out and what samples nology
are needed. The third step demonstrates 6. 2011 Cleaning Memos, by Cleaning Validation Tech-
nology
that the cleaning is functional for that type
7. Institute of Validation Technology (IVT) Network
of system. The fourth step ensures continu- Blog titled as “5 Tactics for Cleaning Validation
al checks of the cleaning steps to make sure Compliance”
the cleaning system in place is performing 8. http://www.ivtnetwork.com/article/5-tactics-clean-
ing-validation-compliance
as needed.
9. h t t p : / / w w w . i j p r d . c o m /A N % 2 0 O V E R V I E W % 2 0
A robust cleaning validation program is O N % 2 0 C L E A N I N G % 2 0 VA L I DAT I O N % 2 0 O F % 2 0
API%20MANUFACTURING%20PLANTS.pdf
necessary to adequately comply with the
regulatory requirements and to ensure lack
of product contamination from batch-to-
batch or from one product to another. Clean-
ing validation requires well documented,
science based approaches including but not
TABLE OF CONTENTS
26
TABLE OF CONTENTS
Focus Theme
Is Your Environmental
Monitoring Program
Risk-Based?
BY MARSHA STABLER HARDIMAN
SENIOR CONSULTANT
A
s part of the product lifecycle, data
needs to be collected to ensure that
the manufacturing process remains in
control. Performing routine Environmental
Monitoring (EM) of your manufacturing pro-
cess allows for the collection and evaluation
of data about the contamination levels in
your controlled environments. EM of con-
trolled areas in healthcare manufacturing is The way that EM sample locations were
not a new concept. Healthcare companies selected has progressed over the years from
have been performing non-viable air partic- random sampling to grid sampling (where
ulate and viable air and surface particulate clean rooms were set up by dividing up a
monitoring for years. Global regulations re- room based on its area and selecting X num-
quiring EM for aseptic manufacturing pro- ber of sample locations). The most common
cesses are published in documents such as random sampling scenario looked something
the FDA Aseptic Processing Guideline, Annex like this: viable/non-viable locations were in
1 and the Japan Aseptic Processing Guide. the center of the room and in all four room
What is new in regards to EM is the applica- corners (maybe on a work bench near these
tion of risk to EM programs for the selection five locations). Floor contact plate samples
of sample site locations and for the determi- were likely in the center of the room and
nation of sampling frequencies. all four corners. Wall contact plate surface
27
samples were taken in the center of each their new cleanroom qualification protocols
wall. It was not uncommon to see ceiling and would then cut back the number of rou-
samples collected at lower frequencies than tine EM sample locations at the end of the
floors and wall samples. A move towards qualification based on results/data.
grid sampling occurred once ISO 14644-1,
Advance to current day. Healthcare has
“Cleanrooms and Associated Controlled En-
adopted risk management and risk-based
vironments – Part 1: Classification of Air
decision making. In regards to EM, compa-
Cleanliness” came into existence in 1999.
nies now need to ensure that their EM pro-
Some companies increased the number of
grams are risk based. Many EM programs are
routine EM samples (for both viable and
still set up in the random sampling or grid
non-viable) to match the required minimum
sampling format and companies are reas-
number of samples from the formula sup-
sessing their current EM programs in order to
plied in the standard:
develop risk-based ones. So how do you en-
“Companies now need to ensure that their EM

programs are risk based.”
N = square root area √A where A is the sure that an EM Program is risk-based? The
area of the room in square meters. approach is slightly different depending on
whether someone is setting up a brand new
This equation essentially makes a grid of
EM program, perhaps with a brand new fa-
each room and samples are collected in each
cility and has no prior EM data knowledge,
grid square. However, the above formula is
or whether they are reassessing their cur-
a requirement for the minimum number of
rent EM program and have lots of prior data/
non-viable particulate locations needed to
knowledge to use.
certify a cleanroom to ISO-14664-1 (annu-
al and bi-annual cleanroom recertification). NEW EM PROGRAM
This was never meant to be the number of
If a company is setting up a new EM pro-
locations required for routine environmental
gram, they need to assess the microbial state
monitoring including viable particulate mon-
of control for the proposed new products/
itoring locations. With that said, historically
processes and cleanroom design. If done
it was not a bad idea to use this formula to
correctly, this activity will take place during
determine the minimum number of samples
the conceptual design stage, prior to the de-
for both viable and non-viable sample loca-
sign freeze, so that any identified microbial
tions when setting up a new EM program and
risks that need mitigation can be addressed
wanting to assess a larger number of sample
before it’s too late or becomes something
locations to help determine the final loca-
a company now has to add extra controls
tions for the routine program. Some compa-
around that could have been designed out of
nies would use this formula to determine the
the process. A good first step is a cross-func-
minimum number of EM viable samples for
28
tional team brainstorming session to identify these activities. This floor assessment in-
potential microbial risk factors for the new formation coupled with the known microbi-
products and processes. A fishbone (Ishi- al contamination risks in the manufacturing
kawa) diagram is a great tool for this activ- process will allow for selection of sample
ity. At this stage, there is no need to assess locations to best address these risks. Once
current planned controls or mitigations. It these prior activities are complete, selection
simply helps to identify anything and every- of EM sample locations can be made based
thing that may cause a microbial contamina- on risk of microbial contamination. The ra-
tion concern. The next step is to perform a tionale for selection of each sample location
formal microbial contamination risk assess- should be documented. All above mentioned
ment (FMEA (Failure Mode and Effects Anal- activities are documented and remain living
ysis) or HACCP (Hazard Analysis Critical Con- documents that should be revised as needed
trol Points) are tools that can be used for this or when changes are made.
activity) to identify microbial contamination
risks and planned mitigations of these risks EXISTING EM PROGRAM – REVISING
for the products and production processes. SAMPLE LOCATIONS
This risk assessment shall be performed with If a company has been performing EM
a cross-functional team, utilizing the results with random or grid based sampling, then
of the brainstorming activity and identifying they will have prior knowledge and data that
all controls and mitigations that will be in was not available in the new EM program
place to address the potential failure modes scenario described above. Often times, com-
and determine if a control strategy is in place panies will have many years’ worth of data
for each one. and prior knowledge. This data and knowl-
Once the product and process microbial edge about product and process microbial
risks are identified and evaluated, the next contamination risk is very helpful and serves
step is to perform an assessment on the man- as an input into the risk evaluation process.
ufacturing floor to review the personnel flow, The first step in reassessing a current EM pro-
material flow, and production activities. This gram is performing a review of the current
assessment will utilize the knowledge gained EM program data to assess currently known
about contamination risks during the FMEA problem locations as well as low risk loca-
or HACCP. The most important part of select- tions which rarely detect any colony forming
ing risk based sample locations for your EM units. The company likely already has formal
program is understanding the people and risk assessments identifying the product and
material flows. In most cases, the people in process microbial risk areas; therefore, the
the controlled environments are the greatest fishbone diagrams and formal risk assess-
risk of introduction of microbial contamina- ments mentioned above do not need to be
tion; therefore, sample locations should be created. However, these assessments need
selected to reflect and capture data around to be reviewed for accuracy. If these assess-
ments of microbial contamination are not al-
29
ready in place, they need to be performed at Taking the time to fully understand the
this stage as per the new EM program section products and processes in relation to the mi-
above. These assessments will be used as an crobial risks will ensure that a company’s EM
input to the selection of risk based sample program is value added. Once sample loca-
locations. As in the first scenario, an assess- tions are selected, sampling frequency can be
ment of the production floor needs to take easily determined based on risk. One com-
place to observe personnel flow, material mon and useful took for this is a risk ranking.
flow and production steps so that areas of For example, if an FMEA was used to assess
highest microbial risk can be determined. microbial contamination risk, the resulting
The historical data from the current EM pro- RPN numbers can be divided up to reflect
gram will aid in the microbial risk determi- low, medium and high risk (highest scoring
nations. Also, data from bioburden or oth- numbers = highest risk, middle scored num-
er utility testing will add knowledge. This bers = medium risk, and low scoring numbers
information needs to be assessed together = lowest risk). The higher the risk, the more
to determine and justify the new risk-based frequent the sampling can be. The rationale
sample locations. Once the data review, risk for the sampling frequency should also be
assessment review and floor assessment ac- documented. Finally, once sample sites and
tivities are complete, selection of EM sam- frequencies are selected, it is very important
ple locations can be made based on risk of to ensure that proper training is given to the
microbial contamination. The rationale for Microbiologists responsible for EM to ensure
selection of each sample location should be that they fully understand the importance of
documented. Prior sample locations which risk in EM programs.
are low risk may be eliminated or moved to
other higher risk locations in the clean room
area. New sample locations may be added.
Each sample location for the prior and new
locations should have a detailed rationale
as to why it is being kept, removed, moved
or added based on risk. All above mentioned
activities are documented and remain living
documents that should be revised as needed
TABLE OF CONTENTS
or when changes are made.
30
TABLE OF CONTENTS
Focus Theme
Application of Risk Management in
the Process Validation Lifecycle for
Biopharmaceutical Manufacturing
BY SNEHA DESHPANDE
ENGINEER II
BioSPEQ, INC.
in the context of Biopharmaceutical manufac-

turing and compliance. Several examples exist
of regulatory guidance documents that include
utilization of risk management in the various
T
aspects of commercialization and continued
he ability to take calculated risks is crit-
manufacturing of drug products. The follow-
ical to the success of any organization.
ing table summarizes some of regulations and
Effective Risk management improves
guidance documents that are applicable to the
performance, reduces waste and is focused
process validation lifecycle for biopharmaceu-
on doing things right the first time. Managing
ticals and medical devices2. A large majority of
potential threats and failure modes provide a
these documents reiterate the importance of
competitive advantage to any organization1. A
quality risk management.
good risk management program requires con-
tinuous analysis and communication, irrespec- Risk is defined as the combination of the
tive of where it is applied. Utilization of risk probability of occurrence of harm and the
management tools in the process validation severity of that harm4. ICH Q9 provides some of
lifecycle for Biopharmaceutical manufacturing the risk management tools that could be utilized
is a regulatory expectation as well as a means in the Biopharmaceutical industry. Flowcharts,
for companies to focus on the right areas to en- Check Sheets, Process Mapping, Cause and
sure product quality and patient safety. Effect Diagrams are used to organize data and
facilitate identification of risk factors. Failure
Regulatory agencies have, over the years,
Mode Effects Analysis (FMEA) and Failure Mode
increased their emphasis on risk management
Effects and Criticality Analysis (FMECA) can be
31
used to analyze and evaluate potential failure other tools exist and can be utilized in lieu of
modes. Individual failure modes can also be those shown here.
analyzed using Fault Tree Analysis (FTA). Hazard
1. Establish a cross functional team involving
Analysis and Critical Control Points (HACCP)
subject matter experts and trained person-
Regulation Reference nel from stakeholders within the company.
21 CFR part 210 Current Good Manufacturing Practice Specific risk owner and risk facilitator should
in Manufacturing Processing, packing,
or Holding of Drugs be assigned at this point. It is important to
21 CFR part 211 Current Good Manufacturing Practice
for Finished Pharmaceuticals
FDA Guidance Document Process Validation: General Principles
and Practices3
GHTF Guidance Document Quality Management Systems: Process
Validation Guidance
ASTM E 2500-07 Standard Guide for Specification,
Design, and Verification of Pharmaceu-
tical and Biopharmaceutical Manufac-
turing Systems and Equipment
ICH Q9 Quality Risk Management4
Annex 15 to EU guide to GMP Qualification and Validation5
WHO Technical Report Series, Supplementary Guidelines on Good
No. 937, Annex 4 Manufacturing Practices: Validation6
PIC/S Pharmaceutical Inspection Co-opera-
tion Scheme
ISPE ISPE baseline guides and GAMP guides
PDA Technical Reports PDA Technical Reports for different
validations
ISO 14971:2007 (E) Medical devices -- Application of risk
management to medical devices
FDAAA 2007 Food and Drug Administration Amend-
ments Act of 20077
is another tool that is identified in ICH Q9 to identify objective and scope of risk assess-
analyze and evaluate risk. ments, and related roles and responsibilities
of the team in the early stage of planning.
The following diagram from ICH Q9 shows
the various aspects of a sound quality risk 2. Risk owner(s) should present the preliminary
management program. risk assessment methodology to the team for
buy-in and common understanding.
A sound quality risk management program
3. Process/product understanding is a critical
includes the following four broad aspects - Risk
pre-requisite to risk assessments. In order
Assessment, Risk Control, Risk Communication
to minimize subjectivity, science and data
and Risk Review.
based decision should be made. The data
Identified below are steps that can part of can be gathered from different sources such
the risk assessment aspect quality risk man- as historical batch data, standard operat-
agement. The example tables included8 are for ing procedures, control documents, product
a FMEA/FMECA type of exercise, however, many specifications, annual product reviews, pri-
32
or relative risk assessments if any, etc. The each risk based on the following example
evaluation of risk to quality should be based table. This interim score takes into account
on scientific knowledge and ultimately link two factors – Severity and Likelihood of oc-
to the protection of the patient. currence. The actual ratings and categories
4. Risk assessment worksheets should include used needs to be agreed upon and pre-de-
details of potential risk/harm, different termined prior to the risk assessment exer-
modes of failure, available controls/mitiga- cise. The example shown here has outputs
tions and potential severity, likelihood and that are qualitative, but can be used quan-
detectability of risk. Significant brainstorm- titatively as well by multiplying the rating
ing efforts lead to effective risk assessments. numbers.
5. Identification of risks can be based on a va- 8. Based on the above interim scoring and the
riety of sources such as product complaints, detectability for each risk, a final risk score
known critical points, historical or scientific can be assigned, such as in the example table
knowledge etc. Once identified, each risk below. The outputs shown here are qualita-
must be scored based on severity, likelihood tive, however a quantitative Risk Prioritiza-
of occurrence and detectability. tion Number (RPN) can also be generated by
multiplying the three factors – severity, like-
6. Internal standard risk rating scales for sever-
lihood and detectability for each risk. The
ity, likelihood and detectability of potential
various risks can then be categorized based
risk should be prepared and documented.
on an RPN threshold that is agreed upon as
Example of a risk rating scale is included in
the cut-off point for various risk levels.
the following table. It is important that all
participants of the risk assessment process 9. Once the risks are categorized based on lev-
agree to the same risk rating scale prior to els, the ones that are considered high risk or
evaluating risk factors. above a certain RPN threshold, risk control
needs to be applied. Risks that are consid-
7. An interim risk score can be developed for
ered low may be accepted as is.
Scale Type Value Defintion Potential to Cause Risk
Exceed specification limits. Reject lot because of potential to com-
10 Severe
promise patient safety
Severity 7 Exceed other non-specification limits. Lot-tied investigation Major
4 Observed trend with no limit excursion. Non lot-tied investigation Moderate
1 No limit excursion or trends. No investigation Minor
10 Expected to occur > 50% of the time Frequent
Occur- 7 Expected to occur > 10% to < 50% of the time Likely
rence/
Likelihood 4 Expected to occur > 1% to < 10% of the time Occasional
1 Expected to occur < 1% of the time Unlikely
10 No way to detect Absolutely uncertain
7 Not detectable until after current process step is complete Remote
Detection
4 Detectable during current process step Moderate
1 Detectable before next processing step High
33
Severity of Risk Detectability

1 4 7 10 1 4 7 10
Minor Moderate Major Severe High Moderate Remote Uncertain
Likelihood of Occurence
10 - High/ High/
Medium Medium High Low Medium High High
Frequent Critical Critical
Interim Risk Score

7- High/
Low Medium High High Low Medium High High
Likely Critical
4-
Low Medium Medium High Medium Low Medium Medium High
Occasional
1-
Low Low Medium Medium Low Low Low Medium Medium
Unlikely
Risk control consists of mitigation/reduc- throughout the process validation lifecycle of
tion of known high unacceptable risks. These Biopharmaceutical manufacturing is important
may include procedural controls, addition- to ensure that the focus is on the right areas.
al processing steps etc. The risk assessment
methodology allows for companies to deploy
REFERENCES
resources commensurate to risk. During the
risk control phase, it is necessary to ensure that 1. http://www.best-management-practice.com/man-
agementofrisk_demo/content.aspx?page=mor_18&-
any mitigation/reduction measures do not in-
showNav=true&expandNav=false
troduce new risks. 2. Presentation by Tomoney Nancy, Risk based valida-
tion and requalification of processes and equipment.
Risk communication needs to happen http://www.pda.org/Chapters/North-America/Metro/
throughout the risk assessment process and Presentations/Risk-Based-Validation-and-Requalifica-
tion-of-Processes-Equipment.aspx
needs to include all stakeholders, including 3. Guidance for industry: Process Validation – General prin-
but not limited to senior management, regu- ciples and practices. http://www.fda.gov/downloads/
latory bodies, patients, health care providers, Drugs/Guidances/UCM070336.pdf
4. ICH Q9: Quality Risk Management. http://www.ich.org/
CMOs etc. fileadmin/Public_Web_Site/ICH_Products/Guidelines/
Quality/Q9/Step4/Q9_Guideline.pdf
Risk review is another important aspect 5. European commission, Final version of Annex 15 to EU
of an effective quality risk management pro- guide to Good Manufacturing Practices. http://ec.europa.
gram. Risk assessment should be treated as eu/health/files/eudralex/vol-4/pdfs-en/v4an15_en.pdf
6. http://www.who.int/medicines/areas/quality_safety/
an ongoing process, rather than a one-time ex- quality_assurance/SupplementaryGMPValidationTR-
ercise. Review of risk factors, especially after S937Annex4.pdf
significant changes to manufacturing process- 7. Risk Evaluation and Mitigation Strategies (REMS) Under
FDAAA. http://cardinalhealth.com/beckloff/documents/
es, schedules etc., is critical to ensure current pdf/REMS-white-paper_final%20100509_website.pdf
state is factored into the understanding and 8. Sedor L, Lewus P, Validation & Compliance: Using Risk
mitigation of risks. Analysis in Process Validation; BioPharm International,
vol 20, Issue 2. http://www.biopharminternational.com/
biopharm/article/articleDetail.jsp?id=400869&page-
This step by step approach ensures under-
ID=4
standing of the harms/risks, informed deci-
sion making, and appropriate remedial actions,
TABLE OF CONTENTS
34
TABLE OF CONTENTS
Focus Theme
LifeCycle Approach
to Validation of
Water Systems
T
he key to control of any process lies in BY IGOR GORSKY
understanding of its variability. How SENIOR CONSULTANT
much do we know about variation of our Concordia ValSource, LLC
processes or systems and are we in the state
of control? These questions need answers to
pursue success in execution of our processes.
rigorous application of Risk Management tools
Understanding, detection, response and
during Stage 1 (Process Design Stage) that
control from input through output of variation
will help the industry to assess, understand
consumed a focus of recent revision to the
an ultimately control the level of variation in
FDA Process Validation Guidance to Industry1
systems and processes.
(Figure 12). So how does one go about control of
variation? To do that one has to enable a Risk A set of Risk Management tools which will
Management System3. To be highly effective a aid us in our pursuit of robust design is outlined
Risk Management System needs to be initiated in a “Line of Sight” first introduced by Dr. Mike
early on during the design of a process or a Long4. It is how we can describe the manner in
system. As shown in Figure 1 the lifecycle of which the variation can be assessed throughout
the process is divided into three stages. It is a the lifecycle.
1. Guidance for Industry Process Validation: General Principles and Practices, U.S. Food and Drug Administration: January
2011 www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070336.pdf
2. Basemen, H. Parenteral Drug Association (PDA) Process Validation Process Validation Training Course, 2013
3. Technical Report No. 60: Process Validation: A Lifecycle Approach; Parenteral Drug Association: 2013. www.pda.org/book-
store (accessed March 14, 2013)
4. Risk and Statistics Serve as Tools for Solving Variation Riddles, Mike Long, PDA Letter, April 2013.
35
Figure 1.
The “Line of Sight” methodology is Water System from the Process Design (Stage
comprised of the following steps5: 1), through Performance Qualification (PQ)
(Stage 2) to Continued Verification (Stage 3)
1. Define system’s or process Critical Quality
Attributes (CQAs) monitoring activities which we should use for
2. Analyze CQAs criticality to maintain, improve and optimize our system.
3. Establish statistically based sample sizes The following Figure 3 shows a typical flow of
per criticality of the CQA the Water System’s lifecycle documentation.
4. Justify sample size for Performance
Qualification (Stage 2) and Continued Next we identify Water System’s Critical
Verification (Stage 3) Process Parameters (CPPs) and Critical Quality
Attributes (CQAs). This is a necessary task to
The “Line of Sight” methodology applies
identify impact of CPPs on CQAs (Refer to
to any pharmaceutical process or system. We
Table A). This task is important for establishing
will see that it is well suited for such critical
a baseline of Purified Water testing results
utility system as Purified Water. The design of
(Stage 1), Performance Qualification testing as
typical Purified Water system is illustrated in
well as future Continued Verification (Stage 3)
Figure 2. To start a “Line of Sight” methodology
monitoring.
we should first outline the lifecycle of the
5. Technical Report 60: Process Validation: A Lifecycle Approach, 51-55, Long, M. Baseman, H. and Henkels, W.D. “FDA’s New
Pro¬cess Validation Guidance: Industry Reaction, Questions, and Challenges,” Pharmaceutical Technology, Volume 35, Sept
2011. Risk and Statistics Serve as Tools for Solving Variation Riddles, Mike Long, PDA Letter, April 2013.
36
Figure 2. Design of Typical Purified Water System
Figure 3.
37
Table A.
In addition to identification of CCPs, CQAs and their correlation during the design stage one
of the main decisions is one on the temperature at which system is operated, water is stored and
finally used. Table B is designed to aid in making an appropriate decision for the intended use of
the system. It also provides pros and cons of each system’s design so that appropriate procedures
could be properly drafted.
Table B.
Temperature Cold Hot Ambient

(2 to 8°C) ≈80°C ≈22°C
Low Microbial Count, Will Low Microbial Count, Will
Hot Sanitization is
Not Prevent Biofilm, Periodic Not Prevent Biofilm, Periodic
Storage Recommended at Least Once a
Chemical Sanitization is Chemical Sanitization is
Week
Recommended Recommended
Low Microbial Count, Will Low Microbial Count, Will
Hot Sanitization is
Not Prevent Biofilm, Periodic Not Prevent Biofilm, Periodic
Recirculated Loop Recommended at Least once a
Chemical Sanitization is Chemical Sanitization is
Week
Recommended Recommended
If Operation Requires Ambient
If Operation Requires Advantageous if Ambient
Temperature Water Need a Heat
Ambient Temperature Water Temperature Water is Used in
Exchanger or Several Heat
Need a Heat Exchanger or Operation, Heat Exchanger or
Points of Use Exchangers at the Points of Use
Several Heat Exchangers at Multiple Heat Exchangers are
if Different Temperature Water
the Points of Use if Different Required if Hot Water Required
is Needed. Advantageous if Hot
Temperature Water is Needed for Operation
Water is Needed.
38
After designing the system, it installation and operation needs to be qualified and sampling
regimen for Performance Qualification needs to be selected. Table C shows typical locations of
system sampling sites and Table D6 outlines Performance Qualification (Stage 2) strategy.
Table C. Examples of Sampling Locations
Location in the Process Flow CQA/CPP Measure

Multimedia Filter Pressure, Particulates
Distillation Systems
Softener Hardness
Oxidation/Reduction
Potential (ORP), Free
Carbon Bed
Chlorine, Ammonia, Total
Microbial Count
Conductivity, TOC, Total
Vapor Compression or Multi Effect
Microbial Count and
Still, Pretreatment with RO/CEDI
Endotoxin
Multimedia Filter Pressure, Particulates
Softener Hardness
Electrodeionization (EDI)
Reverse Osmosis and/or
pH Adjustment pH
De-Chlorination Oxidation Reduction
Potential (ORP), Total &
Carbon
Free Chlorine and Total
Bisulfite Microbial Count
Inlet and Outlet
Reverse Osmosis Conductivity, Flow Rate
and Total Microbial Count
Conductivity, TOC and
EDI
Total Microbial Count
Table D6.
Performance Qualification Phases
Duration Main Objectives Sampling
CPOP Operating Ranges Finalization
I 2-4 weeks Finalize SOPs Every Location, Every Day
Demonstrate Performance of the System
II 2-4 weeks Demonstrate Consistency with Finalized SOPs Every Location Twice a Week
Additional 10 to 11 Demonstrate Extended Performance, Establish Every Location Once a Week, One
III
months Continued Monitoring and Trending Location Daily
6. ISPE Commissioning and Qualification of Pharmaceutical Water Systems

39
After qualifying the system we should revised Guidance for Process Validation. FDA’s
utilize knowledge gained from Performance Guidance tells us that we should be assuring
Qualification (Stage 2) to continue measuring process stability and capability.
system quality attributes during Continued
First we should be plotting monitored
Verification (Stage 3) also called monitoring. The
attributes onto a run chart. Run charts or line
typical metrics for this stage not only include
graphs display any process performance over
analysis of CQAs but also review and analysis of
time. Upward and downward trends and large
other important pieces of information, such as
oscillations are easily spotted and could be
• Deviations, immediately investigated further. The run charts
• Change Controls, shows an attribute values on the vertical y-axis
• Preventative Maintenance and as they are plotted against given time period on
• Sanitization Cycles. horizontal x-axis.
In conjunction with review of testing results For example, two run charts in Figure 4 show
robust review and analyses of above metrics will performance of Purified Water system. Total
provide valuable information of system’s state Organic Carbon (TOC) and Conductivity are two
of control. In addition, this holistic review will major Purified Water Critical Quality Attributes
provide basis for future changes, improvements that are plotted on the timeline. In these charts
and optimizations. we can clearly see that the process normally
To facilitate proactive and rigorous oscillates. There are a number of statistical
monitoring of Purified Water system’s quality parameters we can observe on these charts
attributes we recommend using statistical but most importantly we can visually observe
process control much like it is discussed in FDA’s shifts in the process and predict future failures.
It helps us assessing process stability.
Run Chart of TOC Run Chart of Conductivity

0.0035
0.9
0.0030
0.8
Conductivity
TOC
0.0025 0.7
0.0020 0.6
0.0015 0.5
1 5 10 15 20 25 30 35 40 45 50 1 5 10 15 20 25 30 35 40 45 50
Observation Observation
Number of runs about median: 27 Number of runs up or down: 30 Number of runs about median: 28 Number of runs up or down: 36
Expected number of runs: 26.0 Expected number of runs: 33.0 Expected number of runs: 26.0 Expected number of runs: 33.0
Longest run about median: 8 Longest run up or down: 4 Longest run about median: 5 Longest run up or down: 3
A pprox P-Value for C lustering: 0.612 A pprox P-Value for Trends: 0.153 A pprox P-Value for C lustering: 0.716 A pprox P-Value for Trends: 0.847
A pprox P-Value for Mixtures: 0.388 A pprox P-Value for Oscillation: 0.847 A pprox P-Value for Mixtures: 0.284 A pprox P-Value for Oscillation: 0.153
Figure 4.
40
The capability of a process is a measure and standard deviation. The process capability
of the proportion of in-specification items is represented by a term Cpk. It calculates a
the process produces when it is in a state of difference between the target of the process and
statistical control. It should be noted, that the upper and lower specification limit divided
process capability and process performance by three (3) times standard deviation (σ). The
are two different things. When assessing Cpk is a measure of short term process capability
process performance we are interested in how while the long term capability is represented by
the actual performance measures against the the term Ppk. The long term process capability
specification (limit), while process capability accounts for a long term variation and is more
measures if the process is capable of producing predictive of how the process will perform over
when it is in a statistical state of control. For time. Generally a value of Ppk that is greater
a valid process capability calculations, the data than 1.33 is acceptable to represent a capable
being assessed must be from a process that is process and a Ppk value of greater than 1.5 is
in a state of control, with respect to its’ mean desirable. Figures 5 and 6 illustrate usage of
Run Chart of TOC (2nd System) Run Chart of Conductivity (2nd System)
0.0055 1.4
Conductivity (2nd System)
0.0050 1.3
1.2
TOC (2nd System)
0.0045
1.1
0.0040
1.0
0.0035
0.9
0.0030
0.8
0.0025
0.7
0.0020
0.6
1 5 10 15 20 25 30 35 40 45 50 1 5 10 15 20 25 30 35 40 45 50
Observation Observation
Number of runs about median: 14 Number of runs up or down: 30 Number of runs about median: 22 Number of runs up or down: 36
Expected number of runs: 26.0 Expected number of runs: 33.0 Expected number of runs: 26.0 Expected number of runs: 33.0
Longest run about median: 11 Longest run up or down: 4 Longest run about median: 8 Longest run up or down: 3
A pprox P-Value for C lustering: 0.000 A pprox P-Value for Trends: 0.153 A pprox P-Value for C lustering: 0.126 A pprox P-Value for Trends: 0.847
A pprox P-Value for Mixtures: 1.000 A pprox P-Value for Oscillation: 0.847 A pprox P-Value for Mixtures: 0.874 A pprox P-Value for Oscillation: 0.153
Figure 5.
Process Capability of TOC (2nd System) Process Capability of Conductivity (2nd System)
LSL USL LSL USL

P rocess Data Within P rocess Data Within
LS L 0 Ov erall LS L 0 Ov erall
Target * Target *
USL 0.5 P otential (Within) C apability P otential (Within) C apability
USL 1.3
S ample M ean 0.026 Cp 16.67 Cp 2.17
S ample M ean 0.7
S ample N 50 C PL 1.73 C P L 2.33
S ample N 50
S tDev (Within) 0.005 C PU 31.60 C P U 2.00
S tDev (Within) 0.1
S tDev (O v erall) 0.000820958 C pk 1.73 C pk 2.00
S tDev (O v erall) 0.1715
O v erall C apability O v erall C apability
Pp 101.51 Pp 1.26
PPL 10.56 PPL 1.36
PPU 192.46 PPU 1.17
P pk 10.56 P pk 1.17
C pm * C pm *
00 52 04 56 08 60 12 64
.0 0. 0 0. 1 0. 1 0. 2 0. 2 0. 3 0.3
-0 -0.00 0.24 0.48 0.72 0.96 1.20
O bserv ed P erformance E xp. Within P erformance E xp. O v erall P erformance O bserv ed P erformance E xp. Within P erformance E xp. O v erall P erformance
P P M < LS L 0.00 P P M < LS L 0.10 P P M < LS L 0.00 P P M < LS L 0.00 P P M < LS L 0.00 P P M < LS L 22.36
P P M > U S L 0.00 P P M > U S L 0.00 P P M > U S L 0.00 P P M > U S L 20000.00 P P M > U S L 0.00 P P M > U S L 233.91
P P M Total 0.00 P P M Total 0.10 P P M Total 0.00 P P M Total 20000.00 P P M Total 0.00 P P M Total 256.27
Figure 6.
41
run charts and process capability analyses as we recommend them for Continued Verification (Stage
3) of system’s validation lifecycle. As we can see in an example shown on Figure 5 the process had
shifted on approximately 10th day as the TOC and Conductivity readings started to climb. There
could be multiple reasons for this shift. What is the most important lesson is that the run chart
monitoring helps us initiating an investigation early on prior to encountering “out of specification”
readings. So the run chart monitoring allows for an early detection of upward shifts.
Additionally, when analyzing process capability charts (Figure 6) of the process shown in Figure
5 they exhibit dramatic increase in variability and we can also observe that Conductivity now is
shifted closer to the Upper Control Limit (USL). This is an example of the system not capable to
meet a specification. As to the reasons for the shift in process capability there could be many. The
point is to prevent this shift by monitoring, statistically plotting results and correlating CQA values
with preventative and routine maintenance events as well as performing sanitization and other
necessary activities.
By utilization of statistics we can predict failures, prevent lengthy investigations and product loss
as well as improve and optimize our systems. Table E summarizes post-Performance Qualification
activities which are aided be structured routine statistical control monitoring programs.
In conclusion, it is evident that Process Validation lifecycle approach is applicable to Purified

Water Systems validation. The “Line of Sight” methodology helps us understanding our process,
the products of the processes, our variables and ultimately gives us confidence during commercial
production. Finally utilization of statistical process control is essential to effective and efficient
Purified Water post-PQ monitoring programs.
Table E. Purified Water Systems Improvement and Optimization Activities
TABLE OF CONTENTS
42
TABLE OF CONTENTS
Thermo Fisher Scientific TruScan RM Instrument:
Anti-Counterfeiting, Detecting Counterfeit Drugs
BY ROBERT BRUSH ARTICLE PROJECT MANAGER:
BUSINESS DEVELOPMENT MANAGER MIKE SHELLY, WESTERN REGIONAL SALES MANAGER
LIFE SCIENCES, DOE & INGALLS
THERMO FISHER SCIENTIFIC
W
ith increasing regulatory pressures for real-time identification. Utilizing la-
and the drive toward lean manufac- ser-based Raman spectrometry, TruScan an-
turing, pharmaceutical manufactur- alyzers screen pharmaceutical materials in
ers need efficient ways to perform accurate the field while providing results as reliable
incoming raw material identification. The as a laboratory.
Thermo Scientific™ TruScan™ RM is a hand-
The TruScan device collects a “spectral
held chemical analyzer that enables phar-
fingerprint” of the medicine in seconds and
maceutical manufacturers as well as govern-
compares it to a reference spectrum of an
mental and non-governmental organizations
authentic sample from a validated, digital
to rapidly screen counterfeit pharmaceutical
library of medicines and pharmaceutical
substances on the spot, effectively “bringing
ingredients. TruScan analyzers utilize an
the laboratory to the field.”
embedded decision engine containing
Designed for users with interests in se- proprietary algorithms for the comparison.
curing the pharmaceutical supply chain all These sophisticated mathematical equations
the way from raw materials to finished prod- offer a pass or fail result in seconds based
ucts, the TruScan platform is an important upon the statistical consistency of the
advancement in handheld instrumentation “spectral fingerprint” with the authentic
43
reference. The digital library can also

be easily enhanced by the end user
through input of their specific materials
of interest. This automated decision-
making approach removes much of the
subjectivity classically associated with
authentication of medicines by non-
experts.
TruScan instruments are designed

for ease of use by someone who may
have only limited laboratory or scien-
tific experience. The device workflow
was intended to be simple enough that
novice users could be trained on ef-
fective operation within 15 minutes.
More advanced users developing li-
braries can be trained in a matter of
a few hours and typically utilize our
extensive standard operating protocol
(SOP) templates to customize the ex-
perience and instruction for others.
The portable spectroscopy concept

began with product protection teams
from some of the largest pharmaceu-
tical manufacturers, who identified
the benefit of a handheld instrument
that could provide high performance
pharmaceutical ingredient analysis. In
short, the application of counterfeit
screening grew organically out of our
extensive experience in authenticating
the raw materials used to formulate
medicines. Since the genesis of the
TruScan analyzer in December of 2006,
the instrument has since evolved into
a powerful tool used at regulatory and
donor agencies tasked with ensuring
the safety of medicines for the patients
in the countries they protect.
44
The current device is a second generation 2013. The new device, with its associated
analyzer; it was released three years ago. We workflow, streamlines many of the regulatory
strive to improve upon our software to make parameter choices required by multinational
the operator’s experience as easy, efficient pharmaceutical organizations in lieu of fixed
and effective as possible. Earlier this year, in controls to ensure Good Manufacturing Prac-
the latest software release for TruScan RM, tices (GMP). Point, shoot and identify is an
we enhanced our database performance to exciting and effective mode of operation.
handle over ten thousand reference signa- Simplifying the analyzer makes it easier to
tures. This was required by regulatory agen- implement and operate and has been well
cies desiring to catalog all the medicines received by early adopters who have experi-
being prescribed in their countries. We also enced the device in action.
improved the robustness of the automatic
Thermo Scientific TruScan analyzers are
report generation feature to more elegantly
bringing the laboratory to the field, enabling
handle slower electronic networks encoun-
commercial and regulatory users to rapidly
tered in many markets where the technology
identify counterfeit substances. Our TruScan
infrastructure may be weak.
instrument is part of the wider portfolio of
One of the many important applications our analytical testing instruments, which
for TruScan analyzers is screening of anti-ma- include bench top instruments like the
larial drugs in Africa, where malaria claims Thermo Scientific™ Nicolet™ iS™50 FT-IR
hundreds of thousands of lives every year. Spectrometer or the Thermo Scientific™
Substandard and fake drugs affect every- DXR™ Raman Microscope, which enable
one as drug resistant disease becomes more users to perform confirmatory sample
common due to the counterfeit epidemic. testing in the laboratory. Together, our
Screening programs based upon TruScan an- material identification instruments enable
alyzers and parallel laboratory verification users to first perform in field testing prior to
instituted in Nigeria claim to have reduced performing a more exhaustive analysis in the
the prevalence of fake anti-malarial medi- laboratory, as needed.
cines from the marketplace by 65% over the
Thermo Fisher Scientific is the world
past five years. Thermo Fisher Scientific is
leader in serving science. Our mission is to
working with global standard-setting bodies
enable our customers to make the world
to place analyzers in countries such as Gha-
healthier, cleaner and safer. With revenues
na to help further educate African authori-
of $13 billion, our scale and depth of capa-
ties and promote the quality of medicines
bilities enable Thermo Fisher to provide our
imported into as well as manufactured in
customers with the technology and support
Sub-Saharan Africa.
to solve complex analytical challenges, im-
We currently distribute the TruScan RM prove patient diagnostics and increase labo-
analyzer throughout Africa and just launched ratory productivity.
a more economical version called the Ther-
mo Scientific™ TruScan™ GP in November of
TABLE OF CONTENTS
45
TABLE OF CONTENTS

Innovative Technologies to Build
Partnerships And Protect Human Subjects
BY DEBRA REED, VICE PRESIDENT
LIBERTY IRB
Skype and EchoSign are just a glimpse of the

many innovative ways Liberty uses technology
to provide the most accurate review of clinical
studies, while protecting human subjects and
remaining fully compliant. The ability to con-
sult with an expert in the field, in real time, from
T
oday, an Independent Review Board (IRB) any location, has revolutionized study review.
is challenged more than ever before. The It promotes the most accurate, detailed and
challenge with accelerated innovation is cohesive review of a study. Liberty is able to
that there are far more protocol review, pa- tailor these in-depth reviews per their clients
tient safety discussions and ethics discussions needs, providing them with an unprecedented
than in the past twenty years. With multiple quality of service and personalized protection
weekly IRB board meetings, and an extensive for their research participants.
repertoire of expert board members, whose
Today, document transmission to board
attendance is often times a challenge to syn-
members and clients is immediate and secure
chronize, Liberty IRB has implemented several
through our Freedom portal. Pre-review of
innovative communication tools for connecting
the study begins the day we receive it. This
with such experts.
facilitates a faster turnaround time for quicker
Liberty IRB has implemented several in- results to our clients. Liberty IRB has also re-
novative communication tools for connecting duced use of paper 70% by providing review
with industry experts. Using innovative tech- of meeting materials electronically.
nologies like Skype and Adobe EchoSign allows
Liberty IRB, Inc. is a female owned and op-
board members to consult with these experts
erated central independent review board (IRB)
and specialists during meetings. Users are able
located in DeLand, Florida. Liberty has had full
to FaceTime into the board meeting to be un-
AAHRPP accreditation since 2009 and reviews
dertaken effectively. This is accomplished by
Phase I-IV pharmaceutical, device, biologic, be-
using smartphone, tablet, laptop or webcam.
havioral and psycho-social research. For more
Adobe EchoSign provides secure document
information on Liberty IRB, Inc. please visit
sharing, tracking and signing no matter where
www.libertyirb.com.
the IRB member is located. Technologies like
46
TABLE OF CONTENTS
Subject Matter Expert

The Use Of Disulfide Reducing
Agents In Biotechnology
A Technical Overview
BY CLARKE A. MacDONALD
TECHNICAL & PRODUCT SUPPORT
SPECIALIST, BioVectra, Inc.
& ROGER L. LUNDBALD, Ph.D.
INDEPENDENT CONSULTANT
ARTICLE PROJECT MANAGER:
MIKE SHELLY, WESTERN REGIONAL SALES MANAGER
LIFE SCIENCES, DOE & INGALLS
OVERVIEW OF THE REGULATORY

ENVIRONMENT
T
he manufacture of biopharmaceutical
products is performed under GMP (Good
Manufacturing Practice) procedures (1) .
The process must be designed (Quality by
Design, QbD) (2) to reproducibility provide a
safe and effective product; the process must Any substances in the API which are not
also be validated (3) . The biopharmaceutical API are either a contaminant or an impurity.
product is defined as an active pharmaceuti- An impurity is “any component present in
cal ingredient (API) which “…. Is any compo- the drug substance or drug product that is
nent that provides pharmacological activity not the desired product, a product-related
or other direct effect in the diagnosis, cure, substance, or an excipient including buffer
mitigation, treatment, or prevention of dis- components. It may be either process- or
ease, or to affect the structure or any func- product-related” while a contaminant is “any
tion of the body of man or animals.” (4) . The adventitiously introduced materials (e.g.,
API can be either a drug or a biologic and is chemical, biochemical, or microbial species)
formulated into the final drug product prior not intended to be part of the manufacturing
to use. process of the drug substance or drug prod-
47
uct.” There is considerable interest in the 1. The use of reducing agents in the man-
measurement of impurities in APIs and final ufacturing of immunoglobulin conjugates
(14)
drug products (5)(6) .
2. The processing of difficult to recover
Impurities and contaminants are always proteins, often, recombinant proteins ex-
of importance as such indicate the quality pressed in bacterial cells (15) .
of the manufacturing process but are of par-
ticular regulatory concern where there is an DISULFIDE REDUCING REAGENTS IN SULFHYDRYL
effect on product efficacy or safety. In the CONJUGATION
case of the two products discussed in the
In the case of the immunoglobulin conju-
current document, dithiothreitol (DTT) and
gates, there is, in addition to the reduction
tris(2-carboxyethyl)phosphine (TCEP), there
of disulfide bonds to cysteinyl residues, the
is little information to suggest concern for
necessity of the preservation of cysteine in
product safety. Dithiothreitol seems to have
the reduced state such that it is available for
an beneficial antioxidant effect in vivo and
formation of a covalent bond with a conju-
in isolated tissue culture system (7) (8) (9) but
gate which could be a drug or a chelate con-
was reported to enhance mercury toxicity (10) .
taining a radioisotope. Similarly, the preser-
“Disulfide reducing reagents, in the manufacture of biopharmaceuti-

cal proteins and associated bioconjugates, typically find utility in one
of two different, but closely related, applications“
There is no evidence to suggest that oxidized vation of a free sulfhydryl group is required
DTT is more toxic than DTT. As cited below, for reaction with a matrix such as a colloidal
the use of DTT in the reduction of inclusion gold particle. Free thiol (cysteinyl residues)
bodies is followed by extended dialysis for in proteins are susceptible to non-enzymatic
refolding of the protein which would remove oxidation to cysteinyl sulfenic acid and sub-
the DTT. Tris(2-carboxyethyl)phosphine is sequently to a disulfide (16) . This process can
considered to be relatively non-toxic (11) and be reversed with a thiol such as dithiothreit-
has been used in an in vivo study to prevent ol. An example is provided by human serum
oxidation of eye proteins (12) . Methods for albumin which has a single free sulfhydryl
the determination of DTT and oxidized DTT group which is present as a mixture of oxi-
in protein mixtures have been published (13) . dized and reduced cysteine (17) .
DISULFIDE REDUCING REAGENTS: Immunoglobulins can have free sulfhydryl

APPLICATIONS IN BIOTECHNOLOGY groups (unpaired cysteine residues) on the
Disulfide reducing reagents, in the man- native protein (18) (19) . Free sulfhydryl groups
ufacture of biopharmaceutical proteins and can result from issues during manufacturing
associated bioconjugates, typically find util- (20) and are a source of heterogeneity (21) .
ity in one of two different, but closely relat- While it should be possible, in some cases, to
ed, applications: label a cysteine residue on an antibody with-
48
out reduction of additional disulfide bonds, residues via protein engineering for modifi-
reducing agents such as dithiothreitol (DTT) cation by maleimides can markedly improve
or tris(2-carboxyethyl)phosphine (TCEP) are product quality (32) .
used to reduce disulfide bonds to provide
The individuality of monoclonal antibod-
more sites for bioconjugate formation. An-
ies and fragments thereof such as F(ab’) and
other possibility is the insertion of a cyste-
Fab can not be overemphasized. Thus, while
ine residue into a recombinant monoclonal
there are some general principles, each man-
antibody by genetic engineering (22) (23) . This
ufacturing situation must be addressed as
later approach may provide more specificity
unique. For example, the presence of a tri-
for the attachment of drugs but still would
sulfide in a monoclonal antibody has been
require the presence of reducing agents such
shown to require a higher amount of TCEP
as TCEP to maintain sulfhydryl groups.
to achieve satisfactory yield of a bioconju-
A reducing reagent such as DTT or TCEP gate (33) . This trisulfide modification can be
can be used for the cleavage of disulfide controlled by feeding strategies, particularly,
bonds in an immunoglobulin or immuno- cysteine concentration in the feed medium
globulin fragment to generate a cysteinyl was found to be directly correlated to trisul-
residue available for modification (24) . The fide level in the product (34) . It is clear that
interchain disulfide bonds are preferentially the development of monoclonal antibody
reduced compared to the intrachain disul- therapeutics will use QbD (35) (36) (37) (38) (39) .
fide bonds. Lyon and coworkers (24) ob-
served that the interchain disulfide bonds REDUCING REAGENTS IN INCLUSION BODY
are distal from both the CDR (complementar- RECOVERY
ity determining region) which interacts with The second major use of reducing agents
the antigen (25) and Fc domain which inter- in biotechnology is in the manufacture of
acts with effector cells such lymphocytes biopharmaceutical proteins in bacterial ex-
(26) . It is useful to note that 2-mercaptoetha-
pression systems such as Escherichia coli (40)
nol was used to distinguish between IgG and (41) . A highly productive method for the ex-
IgM antibody responses. An IgG response is pression of recombinant proteins in bacterial
not inhibited by 2-mercaptoethanol while expression systems involves inclusion bod-
an IgM response is inhibited (27) (28) (29) . The ies (42) (43) present in the periplasmic space.
reduction of monoclonal antibodies can be Inclusion bodies are insoluble, aggregated
effectively controlled (30) (31) and it is likely mass of proteins which need to be denatured
that the successful processing of monoclonal under reducing conditions and allowed to
antibodies to yield bioconjugate products slowly reoxidize into their native, biological-
will be a proprietary process. The leading ly active conformations (44) (45) (46) . Both the
functionalization for conjugation to a free chaotropic agent and reducing agent are re-
sulfhydryl is maleimide chemistry. Maleim- moved during the process of refolding which
ides are very specific for reaction with thiol usually uses dialysis. One advantage to this
groups and the rational insertion of cysteine approach is the relative ease of purification
49
of inclusion bodies (47) . This latter study also COMPANION REAGENTS – OXIDIZING
illustrates the ability of the method for puri- REAGENTS IN PROTEIN CHEMISTRY
fication of the inclusion body to remove tox-
ic materials; in this case, endotoxin. OXIDIZED DTT (DTTOX; TRANS-4,5-DIHYDROXY-1,2-
DITHIANE) – BIOVECTRA CAT#1364
A COMPARISON OF DTT & TCEP FOR USE IN
Oxidized DTT can promote the refolding
BIOTECH APPLICATIONS
of proteins that have been denatured and
TCEP and DTT appear to be the reagents reduced. It has been used to identify inter-
of choice for commercial biotechnology. mediates in the protein refolding process (55)
Tris-(2-carboxyethyl)phosphine (TCEP) is (56) (57) (58) .
substantially less reactive than dithiothreit-

DEHYDROASCORBIC ACID (DHAA; DHA) –
ol (DTT) with sulfhydryl alkylating reagents ONGOING DEVELOPMENT AT BIOVECTRA
such as maleimide derivatives therapeutic
payloads and is the reagent of choice for the Dehydroascorbic acid is an oxidizing re-
cleavage of disulfide bonds in immunoglob- agent gaining popularity as an oxidizing re-
ulins and immunoglobulin fragments prior to agent used for the reformation of interchain
conjugation procedures used in the genera- disulfides in antibodies with introduced
tion of Antibody Drug Conjugates (31) . Dith- cysteine residues (ecMabs/Thiomabs) after
iothreitol, due to the reversible nature of its using TCEP to remove blocking cysteines or
oxidation, may be more useful for the reduc- glutathiones from non-native cysteines (32)
tion and reoxidation of disulfide bonds in in- (23) . It is attractive in this application be-
clusion bodies. Both reagents are relatively cause: it occurs naturally in humans, so is of
easy to work with, being water soluble and lesser concern as an impurity than alterna-
active at pHs that are amenable to biotech tives; and, has been found to be effective in
applications. TCEP is somewhat more stable this application. This reagent may find addi-
than DTT in aqueous solution (48) (49) . TCEP tional utility in the stabilization of disulfide
shows a higher rate of reduction at acidic type cleavable linkers in formulated ADC
pHs (50) . DTT requires the deprotonation of drug products, although these products have
its thiol group to the thiolate anion to initiate not yet been commercially observed.
reduction (51) . This property reduces the rate
at which DTT can reduce disulfides as the pH
drops below the thiol-thiolate pKA (52) .
DTT TCEP
Irreversibly
No Yes
Oxidized
Redox Potential -0.33 (53) -0.29 (54)
Reactivity w/
Yes Limited (31)
Maleimide
Preferred Inclusion Body Thiol
Application Recovery Conjugation
pH Optimum Basic N/A
50
15. Use of the Design-of-Experiments Approach in the Development

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TABLE OF CONTENTS
52
TABLE OF CONTENTS
Subject Matter Expert

BPOG’s Extractables Protocol
Standardization Efforts
A Step Forward to Facilitate Implementation
of Single-Use Technologies (SUT)
BY WEIBING DING, Ph.D.
PRINICPAL SCIENTIST, MATERIALS SCIENCE
AMGEN, INC.
1 AMGEN CENTER DRIVE, THOUSAND OAKS, CA 91320
EMAIL: WDING@AMGEN.COM
ARTICLE PROJECT MANAGER:
VICKI SOUTHLAND, REGIONAL SALES MANAGER
EUROFINS LANCASTER LABORATORIES, INC.
INTRODUCTION tractables data is key to single-use systems (SUS)

Implementation and assessing risk to product
B
POG is a cross industry collaboration of quality and patient safety. Yet right now, there is
biopharmaceutical manufacturers with the no specific FDA guidance on how to perform ex-
aim of creating and sharing operational tractables study on single-use systems, leading to
best practices in drug substance manufacturing, inconsistency among individual end user submis-
process development and fill finish. In the Drug sions. User experience also shows that most sup-
Substance phorum, virtually every large biophar- pliers’ current extractables data packages are to-
maceutical company is represented and, over 600 day not technically adequate for most processes
subject matter experts work in 12 active work- evaluation and not consistent between suppliers.
streams, of which one is Disposables. BPOG’s For example, model solvents and testing condi-
mission is to accelerate the rate of the journey to tions are not representative enough for expected
industrial maturity. Although BPOG is not a stan- process conditions, and extractables data is not
dards body and is representative of users not comparable between suppliers and too often it is
suppliers, it works with and through other bodies not as comprehensive as users require. In addi-
to realize change. tion, the SUS Integrator has different extractables
data from different component suppliers, which
The BPOG extractables working group was
makes it impossible for the integrator to provide
set up in 2013 in recognition of the fact that ex-
53
consistent supplier data to the end users and in tent set of extractables data are readily available
a form that makes the extractables data easy to to biopharmaceutical end users. The protocol
use and comparable. This situation necessitates covers the methods used for extractables studies,
end users to perform additional studies resulting provision of extractables data for single use sys-
in the same components being tested multiple tems, sample preparation, reporting of test article
times. The implementation of SUS is also being sampling conditions, and data reporting. This data
slowed by increasing regulatory scrutiny with will enable end users to evaluate safety and per-
commercial applications because of the inconsis- form risk assessment, which is related to product
tency of extractables data available for a product. quality and patient safety. It will also enable com-
ponent selection with comprehensive extract-
A standardized extractables protocol (SEP)
ables data along with other validation package
would be a win-win situation for suppliers, end
information. The data may be augmented with
users and regulators. For suppliers, the benefits
leachables evaluation for regulatory submission.
include: a consensus industry end user require-
However, this does not replace stability studies
ment for extractables; having one extractables
for final product.
protocol to follow, which gives a clear and com-
mon reporting format; a solid starting point for SCOPE
the creation of future regulatory guidance; and
The protocol covers the methods used for ex-
increased sales through wider adoption and fast-
tractable studies, provision of extractable data
er implementation of SUS across the biopharma-
for single-use systems, sample preparation, and
ceutical industry.
reporting of test article sampling conditions. The
For end users, the advantages are: having a protocol applies to, but is not limited to, the fol-
consensus extractables protocol which enables lowing disposable components:
users to screen and select SUS products efficient-
• Bags used for storage, mixing and as bioreactors
ly and effectively; a solid starting point for risk • Tubing and tubing connectors
based assessment; consistent expectations with • Aseptic connectors / disconnectors
respect to the data that will be available from • Filters, both process and sterilizing-grade
suppliers; reliable/consistent extractables data; • Disposable sensors
and ability to make rapid early decisions to use • Filling needles
SUS in developmental path and sequential imple-
There are two ways to report extractables data
mentation for clinical and commercial production.
for an assembly, provide data for each individual
For regulators, a standardized extractables proto-
component, or perform the study on the assembly
col would help reduce their review time and set a
as a whole and report the data. This protocol
starting point for generation of pertinent regula-
is limited to the former because individual
tory guidance.
component is well defined.
OBJECTIVES
A Summary Extractables Statement to an end
The objective of this protocol is to support a user as part of the qualification data of an SUS
lifecycle approach being taken by SUS suppliers assembly or component will report materials of
and to ensure that a comprehensive and consis- construction of the test article and test article
54
sample conditions which include method of be reported. For extractables study on each
sterilization used (worst case), g irradiation component, it is recommended to test at least
conditions (dosimeter value and total cycles), two samples, each from a different lot.
autoclave conditions (time, temperature, and
TEST DESIGN
total cycles), thickness (bag and tubing), duration
from film manufacturing to sterilization, and The extractables study is specific to each
duration from sterilization to extraction. The part component. Samples will be prepared with
number and lot number of the test article must a minimum of 6:1 (cm2/ml) surface area to
Table 1. Recommended sample extraction conditions for single-use components

Single Use Component Recommended Sample Extraction Conditions
Type
Use a small bag (≤ 5L) that will provide an adequate volume of extract for analysis and fill to
meet 6:1 (cm2/mL) surface area to volume ratio. 2D bags can represent 3D bags. Shaking on an
Storage / Mixing / orbital shaker is recommended.
Bioreactor bags
Express analytical results in µg/cm2.
Use tubing with ½’’ ID and fill to meet 6:1 (cm2/mL) surface area to volume ratio. Shaking on
an orbital shaker is recommended.
Tubings
Express analytical values in µg/cm and µg/cm2.
Use filter with effective filtration area (EFA) equal to or greater than 0.1 m2 for study and
maintain at least 1:1 (cm2/mL) EFA to volume ratio. Either recirculating solvent through the
Sterilizing-grade/ Process filter or filling the filter and shaking on an orbital shaker is recommended.
Filters Express the analytical values in µg/cm2.
Use cassette with EFA equal to or greater than 0.1 m2 for study and maintain at least 1:1 (cm2/
Tangential flow filtration mL) EFA to volume ratio. Recirculating solvent through the cassette is recommended.
(TFF) cassettes Express the analytical values in µg/cm2.
Use connector with ½’’ ID and fill to meet 6:1 (cm2/mL) surface area to volume ratio. To
generate enough fluid for analysis, multiple connectors are used and the fluids are pooled for
Aseptic connectors/ analytical purpose. Shaking on an orbital shaker is recommended.
disconnectors
Express the analytical results in µg/connector and µg/cm2.
Use connector with ½’’ ID, submerge the connectors in solvent and shake on an orbital shaker.
Maintain 6:1 (cm2/mL) surface area to volume ratio.
Tubing connectors
Express the analytical values in µg/cm2.
Use sensors or valves with ½’’ ID and fill to meet 6:1 (cm2/mL) surface area to volume ratio.
To generate enough fluid for analysis, multiple sensors or valves are used and the fluids are
Disposable sensors / valves pooled for analytical purpose. Shaking on an orbital shaker is recommended.
Express the analytical values in µg/sensor or µg/valve, and µg/cm2.
Use needle with smallest inside diameter; submerge the needles in solvent and shake on an
orbital shaker. Maintain 6:1 (cm2/mL) surface area to volume ratio or use the highest possible
Filling needles inner surface area to volume ratio.
Use coupons that are the same as the finished column or moulded parts of mixer, submerge
Chromatography column / the coupons in solvent and shake on an orbital shaker. Maintain 6:1 (cm2/mL) surface area to
volume ratio.
moulded parts of mixer
55
volume ratio as a worst case [1] except for filters, There are four tables to detail the recom-
which should have a minimum of 1:1 (cm2/ mended analytical instruments and detectors
mL) effective filtration area to volume ratio. For conditions, which serve as starting points.
other special products that could not practically
1. Table I: LC-PDA-MS
meet 6:1 (cm2/ml) surface area to volume ratio,
• Column, mobile phases, gradient, UV range
the highest possible surface area to volume (200-400 nm), standards, reporting limit
ratio should be used and justified based on the • Criteria: LOQ, LOD, spiked recovery, precision
product’s intended use. Table 1 summarizes the
2. Table II: GC-MS
recommended extraction conditions. • Column, scan range (30- 400 amu), standards,
internal standards, reporting limit, liquid-liq-
For each test, a negative control is obtained as
uid extraction solvent and procedure
the background. When the negative control study
• Criteria: LOQ, LOD, spiked recovery, precision
is performed, the same test set up is used but
without the test article. 3. Table III: HS-GC-MS
• Column, scan range (30- 600 amu), standards,
The model solvents include 0.5N NaOH, 5M internal standards, reporting limit, liquid-liq-
NaCl, 50% Ethanol, 0.1M Phosphoric acid, 1% uid extraction solvent and procedure
• Criteria: LOQ, LOD, spiked recovery, precision
Polysorbate 80, and WFI neutral.
4. Table IV: ICP-MS or OES
The time points and temperatures include • LOQ, LOD, and suggested elements for screen-
less than 30 minutes at 25oC, 24 hours at 40oC, ing.
and 7 or 21 or 70 days at 40oC.
For full content of the protocol, please contact
The above extraction solvents, times and
BPOG via email at gerry@biophorum.com or
temperatures to be used in extractables studies
tony@biophorum.com.
have been established, via surveys to end users,
to cover the range of biopharmaceutical process-
es and have been set in accordance to the ASTM
F1980 Standard Guide for Accelerated Ageing of
Sterile Medical Device Packages [2] to bracket
worst-case situations.
ANALYTICAL METHODS
The analytical techniques include:
• pH measurement
• Conductivity
• TOC (when feasible)
• Metal ions: ICP-MS or OES
• Volatiles: HS-GC-MS
• Semi-Volatiles: GC-MS
• Non-Volatiles: LC-PDA-MS
56
ABBREVIATIONS REFERENCES:
BPOG: BioPhorum Operations Group 1. USP<88> Biological reactivity tests, in vivo, USP 37 –
NF32, http://www.usp.org
SUT: Single-Use Technologies
2. ASTM F1980-07(2011) Standard Guide for Accelerated
SUS: Single-Use Systems Ageing of Sterile Medical Device Packages, http://www.
SEP: Standardized Extractables Protocol astm.org/Standards/F1980.htm
WFI: Water For Injection
TOC: Total Organic Carbon
ICP-MS or OES: Inductively Coupled Plasma – Mass
Spectrometry or Optical Emission Spectrometry
HS-GC-MS: Headspace Gas Chromatography Mass
Spectrometry
LC-PDA-MS: Liquid Chromatography Photodiode
Array Detector Mass Spectrometry
LOQ: Limit of Quantitation
LOD: Limit of Detection
ACKNOWLEDGEMENT TABLE OF CONTENTS
The author would like to thank the BPOG program

directors and all the participating team members
of the BPOG extractables working group, espe-
cially the ones who contributed to the review of
the manuscript.
57
TABLE OF CONTENTS
Company Spotlight
Skingenix, Inc.
BY SHALEEN PAREKH
GENERAL MANAGER AND PRINCIPAL
BioSPEQ, INC.
M
any of you have undoubtedly met Eric
Wang, MD, CCRP, RAC at one of the PDA
chapter events or other trade events in
Southern California. This is, in fact, how we (Bio-
SPEQ, Inc.) met Dr. Wang, Executive Vice Presi-
dent of Skingenix, Inc., a company focused on
the development of wound healing pharmaceu-
tical products. Over the past couple of years, we
have been able to support Skingenix operations
by creating a basis of design for new construc- Pictured: Eric Wang, M.D., CCRP, RAC,
tion at their facility in Ontario, CA. Executive Vice President, Skingenix, Inc.
Skingenix was established in 2001. As an in-

novative and mission-driven company, Skingenix stantial medical burden in the developed coun-
pursues a standard of excellence in the regen- tries. Of the nearly 26 million people with diabe-
erative medical industry with an emphasis on tes in the U.S., 15% to 25% will develop DFUs
developing organ in situ regenerative products in their lifetime, which is estimated at 900,000
for improving human health and quality of life. new DFU cases each year in the United States.
Their product may promote regenerative cells to Up to 20% of DFU patients will require amputa-
heal wounds. Skingenix is currently pursuing a tions. The 5-year mortality rate of 45% is higher
number of indications under an Investigational than that of many cancers. DFUs consume about
New Drug Application (IND) in the U.S. A Phase II $60 billion in direct healthcare expense each
randomized and controlled clinical trial to assess year in the U.S.
the safety and efficacy in patients with Diabetic
DFUs are a significant health care problem
Foot Ulcers (DFUs) has recently been successful-
and represent a huge unmet medical need. The
ly completed. The company is currently in the
standard care for DFUs include offloading (re-
planning stages of Phase III confirmatory clinical
duction of pressure to the foot ulcer), debride-
trials for this indication.
ment (removal of necrotic or infected tissue),
Chronic wound such as DFUs impose a sub- and maintenance of a moist wound environment.
58
Growth factor therapy and bioengineered tis- when those roles are only sporadically required.
sues are considered as advanced wound care for When outsourcing, he has found that the steep
those unhealed wounds. However, in the last 20 learning curve is also financially cumbersome.
years, the healing rate remains very low (15%, Another disadvantage of outsourcing is the loss
25%, 30% at 8, 12, and 20 weeks of treatment, of in-house knowledge or “company memory”.
respectively). As consultants in the regulated industries, we
have found other clients with similar challenges
Skingenix’s investigational new drug for
in balancing contractor vs. FTE.
DFUs, a topical use ointment product, contains
a complex of botanical extracts, which can pro- A unique challenge that botanical drug mak-
mote self-healing in various kinds of wound. The ers face is that their raw materials are procured
recently completed multicenter Phase II study from farms in the United States. Although other
showed that, compared to standard of care, the regulatory bodies (e.g. WHO, EU) have regula-
new drug doubled the healing rate in 8 weeks tions and guidelines for Good Agricultural and
of treatment. Another advantage is that the new Collection Practices (GACP), the FDA has not
drug is very easy to use at home by patients or yet provided guidance for pharmaceuticals that
a caregiver. source raw materials from farms. Specifically,
this hinders the industry to easily obtain their
Dr. Wang started with Skingenix in late 2006.
raw materials from local farmers.
As Executive Vice President, he is responsible
for leading strategic business development ini- When asked how the PDA could further sup-
tiatives as well as the assessment of the compa- port companies like Skingenix, Dr. Wang men-
ny’s product development strategy and perfor- tioned a more formal training program, poten-
mance. In addition, his current responsibilities tially including a certification process, would be
have stretched from medical (clinical study helpful. In addition, he wishes that focus groups
design, planning and monitoring) to regulatory be created for non-mainstream products (like
(FDA submissions and interactions) and quality topical drugs). These Subject Matter Experts
(chemistry, manufacturing and controls). (SME) groups could potentially help him to navi-
gate the requirements of sterility procedures for
Previously, Dr. Wang had been in medical
topical medications. These focus groups could
practice as a clinician and academic researcher
also help Dr. Wang decipher the QA requirement
for about 10 years in China and Japan, before
differences for R&D through clinical trials and
moving to industry in the United States. He has
commercial production.
found that this transition, from a drug prescriber
to a drug developer, has been very advantageous As a PDA member, Dr. Wang has benefitted
in using his medical background to bridge medi- from PDA educational and networking events, in-
cal needs with medical product development. troducing him to many industry experts (includ-
ing ourselves) from whom he has been able to
One of the major challenges Dr. Wang fac-
receive professional services. So, the next time
es in his current role is the balance between
you run into Dr. Wang at one of the local South-
in-house expertise and contractor/consultant
ern California events, please feel free to intro-
assistance. As a virtual company, supporting
duce yourself. I’m sure your collaboration with
a large overhead of full time staff (Operations,
him will be mutually beneficial.
QA, Engineering, etc.) is not financially viable
TABLE OF CONTENTS
TABLE OF CONTENTS
Company Spotlight
Prolacta Bioscience, Inc.
BY RUCHIKA RAVAL
P
rolacta Bioscience, Inc. (Prolacta) is the pio- VICE PRESIDENT, PDA SOUTHERN CALIFORNIA CHAPTER
neer in standardized human milk-based nu- PRESIDENT
tritional products for premature infants in GLOBAL BIOPHARM REGULATIONS
the neonatal intensive care unit (NICU). Prolacta
believes that there is no adequate replacement
for human breast milk, particularly for pre-term
infants. As a privately held, for-profit and scien-
tifically driven company, committed to improving
premature infant nutrition, Prolacta is using human
milk to change the standard of care in the NICU.
Mothers who have a surplus of breast milk can help
save the country’s most fragile infants by donating
their extra breast milk through milk donor banks.
Use of Prolacta’s fortified human milk has result-
ed in reduction in sepsis and NEC (necrotizing en-
terocolitis) for neonates. When neonates, who did
not grow well, were given Prolacta’s fortified milk
they had much better outcome. Historically, forti-
fication of human milk was done with powder pre- Pictured: Scott Eaker, Vice President,
pared from Cow’s milk. Prolacta’s milk fortification Quality, Prolacta Bioscience, Inc.
is with human milk itself and does not use animal
products.
59
60
The founders of this company are Dr. Elena

Medo, Dr. David Rachtman and Dr. Martin Lee.
Elena had an idea to focus on breast milk that
could be put into NICU. Early 2001 a friend put
her in touch with Dr. Martin Lee. Martin had
worked with Baxter, where he was comfortable
with making products using fractions of blood.
Few months later, another colleague from Bax-
ter joined which lead to the origin of Prolacta.
It took the better part of 4 years (from 2001 to
2005) to get institutional investors. Until then,
the founders invested both time and money.
First few years the company was run in an in-
formal manner. Biweekly meetings were at the
founder’s kitchen table. There was no manage-
ment structure. It has now grown into a very
mature organization, managing to ride the line
between regulated industry and community do-
nor based organization. Although breast milk
is a food supplement, Martin sees the firm as a
biologic. Martin’s quote “The value I bring is to
help patients survive and have better outcome,
and store breast milk. Prolacta has opted to
and to reduce human suffering”.
cover all incidental costs to donor including
Some of the unique challenges for Prolacta related blood test to screen for communicable
to enter the market, which was largely through disease, sending trained staff to donors’ home
non-profit donor banks like Human Milk Bank- or place of work, video training to show how to
ing Association of North America (HMBANA), collect, store milk, and FedEx it to Prolacta in a
was to collaborate with Dieticians in NIC units gel box. Prolacta is also signing milk banking
and explain fortified human milk and it’s effica- agreements with hospitals.
cy in the pre-natal NIC unit. The next challenge
Unlike over the counter milk, Prolacta’s
was clinical data. The development aspects
product is not cheap. The cost is high. Current-
were addressed in collaboration with neonatal
ly the firm is reimbursed state-by-state through
experts, at premier institutions like Stanford
Medicare reimbursement program. Some states
and Johns Hopkins and Baylor who contribut-
are better than other. Prolacta has achieved
ed with their ideas and suggestions. Last chal-
better success in Texas. Prolacta has also been
lenge being lactating mothers and their aware-
collecting health economic data. For example
ness to donate milk, willingness to fill donor
there is a savings of $8000 dollars per infant
questionnaire, schedule a test and then take
born weighing less than 1250gm as a result
the time out of their busy schedule to collect
of avoidance of medical and surgical NEC. So
61
there is a case to be made for a national reim- etc.,” informs the Vice President of Quality at
bursement. The shift to accountable care in the Prolacta, Mr. Scott Eaker. Scott joined Prolacta 7
current situation is favorable, even though ini- years ago, bringing experience in recombinant
tial cost is higher than standard of care (donor proteins. The most rewarding aspect for Scott
milk, partially cow fortified milk, or mom’s milk). is to help in create an industry that was once
simplistic (moms donating milk to other mom)
Prolacta envisions a tremendous growth
and transition it into a mature sector that re-
for future. The senior executive leadership
sembles biotech. He pointed to Isabell a pa-
has background in plasma fraction as they all
tient Prolacta helped when she was 22 weeks
founded the firm gaining experience at Baxter’s
old. Her mom died of cardio myopathy and so
plasma fractionation plant. Using model similar
Isabella could not receive her mother’s milk.
to Baxter, Prolacta is researching how to devel-
With Prolacta’s fortified milk, she survived and
op a pipeline of co-products that are likely to
is doing well.
be produced with the fortifier. For example a
second product, human milk cream. The specif- Prolacta has become a brand that has set
ic use would be to increase caloric density for a benchmark. Increasingly, breast milk donor
the pre-term infant using the same liter of milk. registries now have a sign “Prolacta qualified
donor” as an icon to recognize breast milk do-
Another area of growth is ex-US markets.
nated by mothers who are part of Prolacta’s do-
Currently the focus is entirely US, but market in
nor registry and therefore screened for several
Canada and Europe is also changing. Human
health hazards.
milk is viewed differently from regulatory per-
spective. In the US, milk is regulated as food. I asked Mr. Eaker, whether Prolacta gets a re-
When regulated as food, one does not think of quest for compassionate use? He informed that
all the implications of a biological raw materi- since alternative therapies are in place such a
al such as breast milk. For example, food raw request is rare. He recalls only one instance
material does not have requirements for do- where a couple from Canada made a request.
nor qualification. Prolacta has been a forward While other nutritional supplements are avail-
thinking firm that has voluntarily embraced bi- able, this couple was adamant to use fully hu-
ologic GMPs where necessary and augmented man milk for their child. Prolacta put together
the food GMPs. Continuous improvement is the a documentation package and in 17 days deliv-
quality concept. For example, when develop- ered product to the infant in Canada. Fulfilling
ing an assay testing method for contaminants, such requests, is a huge burden for a small firm
Prolacta uses the same stringency of validation like Prolacta. Scott Eaker‘s Quote is “Lead the
as the plasma industry. Industry for neonatal safety and well-being. If
we improve outcome of pre-mature infant – it
“Guess what – if you do the right thing,
is good for moms and babies. What is good for
price a little higher product, the market will
them is also good for Prolacta.”
bear the cost. We screen each breast milk do-
nor for many chemicals like tobacco, oxytosin,
and communicable diseases like HIV, Hepatitis TABLE OF CONTENTS
62
TABLE OF CONTENTS
PDA Event Highlight

Southern California Chapter
Q1 Educational Program
BY JOHN HOLMGREN
PRESIDENT, PDA SOUTHERN CALIFORNIA CHAPTER
DIRECTOR QUALITY/VALIDATION
GLOBAL PHARMACEUTICAL SERVICES, IRVINE
ALLERGAN, INC.
al different drug dosage forms including: Unit-

ed States Pharmacopeia (USP) Packaging and
Storage Expert Committee, PQRI Orally Inhaled
and Nasal Drug Product E&L Working Group and
O
PQRI Parenteral and Ophthalmic Drug Product
n February 27th, PDA’s Southern Cali-
E&L Working Group.
fornia chapter held its Q1 2014 Edu-
cational Program. The event featured a Amgen in Thousand Oaks was the host loca-
technical seminar as well as industry exhibitors tion for the speaker and provided the webcast
and networking opportunities with industry to two other host venues: Avid Bioservices in
colleagues. The topic of the technical seminar Tustin and Carefusion in San Diego. Over 120
was “Making Sense of the New Extractables and attendees were able to join the program with-
Leachables Best Practices for Parenteral Prod- in their local area. Given the large geographi-
ucts … A Blueprint for Success!” presented by Dr. cal territory for the Southern California chapter
Michael Ruberto, President of Material Needs and infamous freeway traffic, the combination
Consulting. He has been an active member of of the webcast format and company site hosts
working groups developing best practices for has provided our members with a low cost, con-
characterizing and evaluating the safety of con- venient opportunity to gain knowledge from in-
tainer closure systems and packaging for sever- dustry experts.
63
The chapter extends its gratitude to the event exhibitors for each host venue:
• NSF Health Sciences – Amgen, Avid Bioservices & Carefusion
• Veltek – Amgen
• Azbil Biovigilant – Avid Bioservices
• Eurofins Lancaster Laboratories – Avid Bioservices
• Technical Safety Services – Carefusion
The success of the event can be attributed to the chapter officers, volunteers, the host compa-
nies, the exhibitor representatives and the speaker. The following individuals warrant recognition
for their efforts toward the chapter objectives: Stefany Goldman, Program Director; Randy George,
Membership Chair; Brian Underhill, President-Elect; Bonnie Ward, VP- San Diego; Ruchika Raval,
VP- Orange County/Los Angeles; Stephanie Powers-Kurtz, Treasurer; and Program Volunteers: Vicki
Deason, Erica Schelin, Bruce Davis, Tony Steinberg, Dilip Parikh and Kelly Templeton. We also want
to acknowledge the support from Trevor Swan and Katie Ruiz at PDA National, who continue to
provide outstanding administrative assistance for these events.
Making Sense of the New Extracables &

Leachables Best Practices for Parenteral
Products... A Blueprint For Success
I
would like to thank the Southern California PDA
Chapter for inviting me to present “Making Sense
of the New Extractables and Leachables Best
Practices for Parenteral Products…A Blueprint for
Success” at its February meeting. I was very excit-
ed about the opportunity to discuss some of the Ex-
tractables and Leachables (E&L) trends that we will
BY: MICHAEL RUBERTO, Ph.D. be seeing in 2014 to such a large audience at three
PRESIDENT different sites: Thousand Oaks, Orange County, and
MATERIAL NEEDS CONSULTING, LLC San Diego. The cornerstone of these trends will
center around the new USP general chapters that
recommend a three-stage approach to establish the
64
suitability for use of packaging materials using from these materials, and finally the commer-
a combination of enforceable and informational cially packaged drug products. Your members
general chapters. This approach includes a ma- can view these draft documents on the USP
jor modernization of USP <661> now entitled website at www.usp.org.
“Plastic Packaging Systems and Their Materials
My personal opinion is that the information
of Construction” along with the publication of
and data generated about the materials, sys-
two new chapters, USP <1663> “Assessment
tems, and packaged drug products will allow
of Extractables Associated with Pharmaceuti-
our industry to take a materials based approach
cal Packaging/Delivery Systems” and <1664>
to E&L evaluations of our packaging systems.
“Assessment of Drug Product Leachables Asso-
This can start with a partnership between ven-
ciated with Pharmaceutical Packaging/Delivery
dors of packaging components and pharmaceu-
Systems”. Furthermore, the Product Quality Re-
tical companies to share relevant compositional
search Institute (PQRI) has also published new
information and compendia testing data. Once
“best practices” for performing extractables
the polymers and their ingredients are known,
and leachables assessments on parenteral and
a forecast of potential extractables and leach-
ophthalmic drug products. In my presentation,
ables can be made based on the solvating prop-
I discussed the details of these documents and
erties of the drug and the conditions of use,
emphasized that USP <661.1> will provide
such as the temperature and duration of con-
much needed compositional information on the
tact. Next, a specific extractables testing plan
formulations or ingredients used in the plastic
can be developed that will identify either pos-
materials themselves, before they are extruded
sible or probable leachables depending on the
and molded into the container closure systems.
extraction conditions used in the testing. Tar-
USP <661.2> then provides the testing require-
get compounds are then selected from a review
ments for the plastic containers or systems that
of the extractables testing data and validated
are constructed from these well characterized
methods can be developed for the leachables
polymers and it is in this chapter that the refer-
study. It is important to perform correlations
ences are made to the new E&L general chap-
between the forecasted and actual leachables
ters <1663> and <1664>.
and extractables data to identify any potential
These E&L general chapters are not pre- material / drug compatibility issues or possible
scriptive in nature nor do they establish spec- unexpected leachables.
ification or acceptance criteria. What they do
If any of the Southern California PDA mem-
provide is a framework for the design, justifica-
bers have any questions regarding my recent
tion, and execution of E&L testing that is based
presentation or require any help with material
on some of the best practices previously pub-
selection, design and evaluation of E&L stud-
lished by the PQRI E&L Working Groups. The
ies, or implementing complete E&L programs in
ultimate goal of this three-stage approach is
their companies, I can be contacted at Michael.
a well-characterized container closure system
ruberto@materialneedsconsulting.com
through a separate evaluation of the materi-
als (polymers) themselves, the systems formed
TABLE OF CONTENTS
65
Speaking Opportunities with the

PDA SoCal Student Chapter at KGI
Are you a Subject Matter Expert or a Key Opinion Leader?
Do you have insight or knowledge others would find valuable?
Do you want to help educate and inform future professionals of the
Life Sciences industry?
The PDA Southern California Student Chapter at KGI would like to invite experienced
industry professionals to be special guest speakers at one of our many professional
events for the 2014-2015 academic year. Some of our chapter events include:
• Informational Company Presentations

• Private Industry Roundtable Discussions
• Annual Fall Semester Quality, Regulatory,
and Operations Speaker Series
• Annual Spring Semester Technical
Consulting Event
IF YOU OR SOMEONE YOU KNOW WOULD BE

INTERESTED IN SPEAKING AT KGI, PLEASE
CONTACT WENDY CHEN AT
WCHEN13@STUDENTS.KGI.EDU
66
TABLE OF CONTENTS
Focus Theme
Process Validation Guidance:
Legacy Products
BY STEVE SPEER
ASSOCIATE DIRECTOR, WEST REGION
PROPHARMA GROUP
• Stage 1: process design, the commercial

process is defined based on knowledge
gained through development and scale-up
activities.
• Stage 2: process qualification, the process

design is evaluated and assessed to de-
termine if the process is capable of repro-
ducible commercial manufacturing.
• Stage 3: continued process verification,

ongoing assurance is gained during rou-
tine production that the process remains
in a state of control.
A
s a member of ProPharma Group’s con-
However, it is apparent that many individ-
sulting team, I attend many biotech-
uals and organizations struggle with how to
nology and pharmaceutical industry
apply the guidance for legacy products, es-
affiliated meetings. It is never a difficult
pecially those that were developed without
task to strike up a conversation regarding
the thoroughness and benefits of the Stage
FDA’s 2011 guidance document “Process Val-
1 activities described above. The Critical
idation: Guidance for Industry”.
Process Parameters (CPPs) and Critical Qual-
What I’ve learned is, by now, most ity Attributes (CQAs) of bio-pharmaceuti-
industry professionals understand the cal manufacturing processes are not always
3-stage approach: known or understood for legacy products.
67
It is not difficult to intuit what the pro- lected and analyzed in a cognizant effort to
cess parameters are for most units of a man- develop better understanding of process ca-
ufacturing process. Generally they involve pabilities, CQAs, and CPPs. To compensate
temperature, time, flow rates, pressures, and for missed Stage 1 opportunities, an organi-
numerous other discreet input settings or zation can only rely on past and future data
output readings on the process equipment to effectively achieve process control. For
that are employed in a manufacturing pro- example, an organization may employ the
cess. But what is the criticality of each of following to gather data and build process
those process parameters? Certainly, do not knowledge:
expect a regulatory agency to answer that
• Data collection and trending for each and
question for you. Biopharmaceutical firms every batch; use this data is establish a
that developed their manufacturing process process capability ratio or index.
are expected to have conducted the neces-
• Historical data reviews for older batches
sary experimentation, whether employing a
design of experiments methodology or other • Product reviews – noting variances and
strategy, to document the parameters which capturing data
“To compensate for missed Stage 1 opportunities, an

organization can rely on past and future data to ef-
fectively achieve process control.”
are critical, key or non-key to drive their pro- • Historical and on-going verification regard-
cess. Similarly, the attributes that the active ing the maintenance and calibration of pro-
pharmaceutical ingredient (API), bulk drug cess equipment
substance, or final formulated drug product • Actively seek process improvement oppor-
are purported to possess (in terms of biologi- tunities
cal activity, composition, identity, purity, and
• Perform periodic Management Reviews to
performance) are quality attributes that must
ensure sufficient progress is being made
be firmly understood, tested for, and docu- and that projects are resourced appropri-
mented by the manufacturing firm. These ately.
attributes are not to be simply in-process or
release tests used during routine operations, As knowledge is gained, new informa-
but rather parameters that pose higher risk tion in the form of controlled changes may
and are indicative of process and product be driven into the manufacturing process.
variations. Subsequent batch production will then pro-
duce additional data that can be compared
So, where does an organization begin to to historical process data and also substan-
build this knowledge base for legacy prod- tiate that the changes made lead to greater
ucts? A recommended approach is to start process understanding and control.
with Stage 3, whereby process data is col-
68
Illustration courtesy of Ref: Grace E. McNally FDA (Guide Leader) Sept 15, 2010
The approach is illustrated above. high impact systems and functions within
systems that are critical to product quality
To successfully achieve meaningful “ret- and patient safety
roactive” Stage 1 process design and control
• Have in place a coherent and effective
understanding, an organization must:
Knowledge Management System
• Understand the sources of variation
Gaining this knowledge is the foundation
• Be able to detect the presence and degree of building and implementing a process con-
of variation
trol strategy. By leveraging the use of sta-
• Be able to understand the impact of varia- tistically relevant tools, an organization can
tion on the process and product continue to drive continuous improvement
• Control the variation commensurate with changes into the commercial process while
risk monitoring and verifying the effectiveness
• Understand CQAs; The critical process as- of those changes and their impact on CQAs.
pects should be identified, specified and
An incomplete process understanding
verified as this serves as the basis for sci-
hinders effective and efficient compliance,
ence and risk based decisions and assures
and realization of business productivity
the system is designed and verified to be
fit for intended use. It is best to focus on benefits.
TABLE OF CONTENTS
69
TABLE OF CONTENTS
Focus Theme
Process Validation,
No More Sleepless Nights
BY MICHAEL JARPE, Ph.D.

ADVISORY COUNCIL, KECK GRADUATE INSTITUTE
VICE PRESIDENT, BIOPHARMACEUTICALS
ALLERGAN, INC.
E
arly in my career, “process validation”
always made me nervous. This was the
final test demonstrating that a process
could be approved. I did not want this to be
the one thing that kept our important drug
from getting to the patients that needed it.
Why was I so nervous? The answer was that
in those days we developed mostly by trial
and error. We had a “hunch” of what a good
process would be and started from there. If
a unit operation worked a few times in a row,
we moved on to the next. As the process
came together, we tried it as a whole. Again,
if it worked a few times, we were happy. As
we gained process experience with more
runs and saw how the process ran at scale,
we could see where the weaknesses were
and fixed them as they came up. Our pro-
70
cess experience was mostly with the process All of this allows us to focus all process
parameters run at their set points. This was development efforts throughout develop-
the data set we often used to enter process ment and create a “design space” within
validation. We would run three full batches which we have confidence that the critical
and hope for the best. quality attributes will be met as long as the
key process parameters are within experi-
Fast-forward several years and we now mentally and statistically derived ranges.
recognize that quality by design (QbD) prin-
ciples used during process development im- One point on regulatory expectations: al-
prove confidence in the success of process though agencies have allowed product appli-
validation. In addition to being a science- cations to present the ‘traditional’ method of
and risk-based approach to process develop- process validation, in my opinion, QbD rep-
ment, QbD lends us a framework to conceive, resents good science and a way of prospec-
execute and report our process development tively understanding the critical process tar-
studies, and lends a previously absent rigor gets. This leads to the best possible process
to this vital area. QbD is outlined in several and process understanding, which is always
US and European guidances (i.e. ICH Q8 on the goal.
Pharmaceutical development, and ICH Q11
on Development and manufacture of drug Obviously, time and resource constraints
substances). can limit the amount of work that can be
done at any given stage. The goal is not to
Using QbD principles, we look ahead to be perfect, but to apply as many of these
what the process must be able to deliver principles as possible throughout process
in the commercial phase and create a path development, and I guarantee the result will
to that goal. This starts with a clear quality be fewer sleepless nights during process val-
target product profile, from which we derive idation.
the critical quality attributes that must be
achieved to ensure the product is safe and
“USING QbD PRINCIPLES, WE LOOK AHEAD
efficacious. We can then perform risk as-
sessments against these targets to identify TO WHAT THE PROCESS MUST BE ABLE TO
potential weak spots and allow us to focus DELIVER IN THE COMMERCIAL PHASE AND
on the most critical areas for improvement. CREATE A PATH TO THAT GOAL.”
From there, carefully planned statistical ex-
perimental design, in the form of design of
experiments (DOE), can be used to reduce
the number of experiments needed to make
decisions on process set points and ranges.
TABLE OF CONTENTS
71
TABLE OF CONTENTS
Student Initiative
PDA SoCal Student Chapter

Mentorship Program
BY APRIL YANG
CO-LEADER OF SoCAL PDA STUDENT
CHAPTER MENTORSHIP PROGRAM
T
he PDA Southern California Student
Chapter would like to invite experi-
enced professionals in the biotech in-
dustry to become mentors for Master of Bio-
science (MBS) and Postdoctoral Professional
Masters in Bioscience Management (PPM)
students at the Keck Graduate Institute in
Claremont, California. The PDA Mentorship
Program works to connect enthusiastic and
bright graduate and postdoctoral students
with experienced professionals in the life
sciences and biotech industry. The pro-
gram’s goal is to facilitate relationships that
will help shape the careers of our student
chapter members, and allow professionals to
shape the future of the industry.
72
The SoCal PDA Student Chapter’s Mentorship Team, pictured right to left:
Maria Fillipou (MBS ‘14), Gurvir Sidhu (MBS ‘15), and April Yang (MBS ‘15)
This is a great opportunity to influence gram. The event will take place during the
the next generation of bioscience leaders. fall semester and only the students that have
Mentors are asked to share their experiences been matched, as a part of the program, will
and provide advice or guidance for their men- be invited. Mentors will also have the oppor-
tees. Communication between participants tunity to be featured on the SoCal PDA Stu-
is required twice a year, with the freedom to dent Chapter website and the Nexus Journal.
initiate additional communication as deter-
mined by the mentor and mentee. Mentors Our student PDA members look forward to
will also have the opportunity to network connecting with you.
with industry professionals both within and
outside of their specialty.
For additional information please contact
Both prospective mentors and student April Yang at ayang13@students.kgi.edu.
mentees will be interviewed and profiled
to help align expertise and interests. Stu-
dents will have the opportunity to interact
TABLE OF CONTENTS
with their mentor during an event organized
by the PDA Student Chapter Mentorship Pro-
73
TABLE OF CONTENTS
Student Event Highlight

PDA Student Chapter Professional Events at KGI
Set Foundation for Lasting Relationships between
BioScience Students and Industry Leaders
BY JOANNA D. NAYMARK,
PRESIDENT, SoCAL PDA STUDENT CHAPTER
T
he 2013-2014 academic year was the
second operating year of the Southern
California Student Chapter of the Par-
enteral Drug Association. In our second year,
we were proud to continue and build on some
of the successful events first hosted in our
inaugural year. The goals of the events we
hold on campus are to provide valuable in-
dustry exposure and networking opportuni-
ties to our student PDA members, ultimately
creating experiences that benefit students.
74
THE 2ND ANNUAL QUALITY, REGULATORY maceutical industry is working to prevent

& OPERATIONS SPEAKER SERIES AT KGI mistakes due to quality issues. Ms. Hardiman
illustrated these points using the example of
SPECIAL INDUSTRY GUESTS the meningitis outbreak from last year due to
• Susan Weber, Manager of Technical Ser- compounding pharmacy issues, and shared
vices, Baxter Bioscience information from a lead FDA microbiologist
• Marsha Hardiman, Senior Consultant, on the case regarding the status of the in-
Concordia Valsource vestigation.
• Jim Sesic, Executive Director of Regulatory Jim Sesic wrapped up the event with his
Affairs, CMC, Amgen
lecture on CMC changes to biotechnology
On November 8, 2013, the PDA South- products. Mr. Sesic described some complex-
ern California Student Chapter hosted the ities and challenges of the CMC approval
2nd annual Quality, Regulatory & Operations process, and walked through two case stud-
Speaker Series. The event was held at the ies to elaborate on some of the most inter-
Keck Graduate Institute (KGI) in Claremont, esting and illustrative points.
California, and featured three guest lecturers
The event concluded with a private re-
from the pharmaceutical industry. The speak-
ception, during which PDA student members
ers each held a position representing one
were given the opportunity to meet and net-
of the areas of focus for the event: product
work with both the guest lecturers and the
quality, regulatory affairs, and pharmaceuti-
professional PDA board members.
cal operations. In attendance were members
of the student PDA chapter; students, faculty
and staff from KGI; a group of visiting pro-
spective KGI graduate students; and sever-
al members of the Southern California PDA
board.
The first guest lecturer, Susan Weber

(Manager of Technical Services at Baxter Bio-
science), started off the event by discussing
the steps to create a quality-by-design vision
within a pharmaceutical company, including
considerations of both risks and recent para-
digm shifts in the industry.
Next, Marsha Hardiman (Senior Consul-

tant at Concordia Valsource) presented a
compelling video about the high costs of
poor quality control within a company or
product line, and described how the phar-
Jim Sesic of Amgen presents the challenges of the CMC approval
process to an audience of KGI students, faculty, and guests.
75
PRIVATE ROUND-TABLE DISCUSSION WITH DR. PAUL EISENBERG, SVP OF GLOBAL

REGULATORY AFFAIRS AND SAFETY AT AMGEN
On October 18, 2013, our student chapter hosted a 1-hour private discussion with Dr.
Paul Eisenberg, Senior Vice President of Global Regulatory Affairs and Safety at Amgen. This
private round-table discussion followed Dr. Eisenberg’s address to the Keck Graduate Insti-
tute entitled Integrating Risk Management into Drug Development. This unique opportunity
allowed the student members of our PDA chapter to gain valuable, intimate professional ex-
posure to a senior regulatory executive in the life sciences.
During the round-table discussion, Dr.

Eisenberg engaged with the students on
several topics, including advanced details
of Amgen’s pharmacovigilance system,
toxicity prediction models, the real costs
associated with stages of drug develop-
ment, and important real-world examples
that illustrate some deficiencies in the
current regulatory landscape.
This event allowed student PDA mem-

bers to engage with Dr. Eisenberg on many
relevant issues in regulatory affairs, and
helped foster the relationship between
our student PDA chapter, KGI, and Amgen.
SoCal PDA Student Chapter members discuss risk mitigation

strategies in drug development, with Dr. Eisenberg of Amgen
76
At this event, we were pleased to wel-

come three seasoned veterans of life scienc-
es technical consulting with over 80 years of
combined experience in the field. Our first
speaker was Dr. David DiGiusto, a Director of
the Laboratory for Cellular Medicine at the
Beckman Research Institute at City of Hope,
with extensive independent consulting ex-
perience. Dr. DiGiusto’s work includes both
the clinical and regulatory aspects of the sci-
ence of utilizing cells as therapeutic agents.
This includes the isolation, characterization
and genetic modification of hematopoietic
stem cells and immune cells for clinical ap-
plications. Dr. DiGiusto speech, titled Travel-
Dr. DiGiusto shares his experiences as a cell manufacturing the Yellow-Brick Road of Biotechnology
ing and cGMP technical consulant with a KGI student and Consulting focused on the complex path he
faculty member.
has taken throughout his dual career as an
independent technical consultant, and how
BEYOND MANAGEMENT CONSULTING: this career stemmed from his extensive sci-
TECHNICAL CONSULTING IN LIFE SCIENCES entific work and achievements.
SPECIAL INDUSTRY GUESTS Next, we welcomed a presentation from
• Dr. David DiGiusto, Cellular Medicine Labo- Steve Speer, Associate Director of the West
ratory Director, Beckman Research Institute, Region for ProPharma Group. Mr. Speer has
City of Hope
over 25 years of experience in the medical
• Steve Speer, Associate Director, West Region, devices and biotechnology industries, and
ProPharma Group operates in project management and con-
• Michael Shelly, Western Regional Sales sulting in his current role. He also specializes
Manager, Doe & Ingalls in continuous improvement, Lean Sigma, and
Earlier this month on March 7, the PDA organizational performance management.
Southern California Student Chapter hosted Mr. Speer focused on the stages of scientific
our annual Spring semester event focused process validation, including Process Design,
on technical consulting in the life sciences Process Qualification, and Continued Process
industry. The event was held in the Founders Verification. He also provided interesting
Room at the Keck Graduate Institute, and background information on the profession of
welcomed a diverse audience including technical consulting, and discussed the im-
members of the Southern California portant considerations and career benefits
professional chapter and the extended KGI that graduating students should be aware of
community. when selecting this profession.
77
Wendy Chen, PDA Student Chapter VP (right) talks about

process validation with Steve Speer (left), while Mike Shelly
(middle) discusses technical consulting practices with a
group of eager PDA Student Chapter members.
current knowledge deficiencies in industry.

Many points within this presentation reso-
nated strongly with the student members of
the audience, and helped the students con-
sider how they can create a strong position
for themselves when entering the industry in
the near future.
The event concluded with a panel discus-

sion featuring our three distinguished speak-
ers, with the opportunity for members of the
Finally, we were honored to hear an ad- audience to ask questions and engage with
dress from Mr. Michael Shelly, Western Re- the panel directly. Both students and attend-
gional Sales Manager from Doe & Ingalls. Mr. ing professional PDA members joined in the
Shelly has had a diverse 30-year career in discussion with the guest speakers.
industry, including extensive work for Ther-
mo Fisher Scientific. Mr. Shelly began his talk For more information about events host-
by sharing an amusing and engaging story ed by the PDA Southern California Student
about his first entrepreneurial venture: rais- Chapter, please contact Michael Choy, Di-
ing chickens and selling eggs door-to-door rector of Communications and Media, at
when he was a boy. This tale illustrated sur- mchoy14@students.kgi.edu.
prising similarities to real-world issues and
complications inherent in life sci-
ence technical consulting today, in-
cluding supply chain management,
managing customer satisfaction,
financial planning, and organiza-
tional growth. Mr. Shelly also spoke
about the importance of “being
bold” in one’s career, and managing
one’s own career to help address
Dr. DiGiusto (left), Mr. Speer (middle), and Mr. Shelly

(right) enjoy a few laughs with the PDA Student Chap-
ter members during the panel discussion.
TABLE OF CONTENTS
78
TABLE OF CONTENTS
Academic Partnerships
At the Intersection of Science and
Commerce
BY PAIGE STEIN
MANAGER OF MEDIA RELATIONS
LIFE SCIENCES LEADER

The School of Applied Life Sciences offers
several degrees and certificates: the Master of
Bioscience (MBS), a Postdoctoral Professional
Masters (PPM), a Postbaccalaureate Premedical
Certificate (PPC), a PhD in Applied Life Scienc-
es, and a Certificate in Bioscience Management.
A
member of the Claremont Colleges, The two-year MBS program takes a pio-
Keck Graduate Institute (KGI) is known neering approach to educating industry-ready
for offering a highly innovative and spe- professionals. The curriculum, which mixes ad-
cialized education to graduate students inter- vanced science courses with classes in finance,
ested in pursuing a career in the life sciences. marketing and international business, provides
Founded in 1997, KGI was originally comprised students with a thorough understanding of
of the School of Applied Life Sciences (SALS). how the bioscience industry operates, includ-
Today, KGI also includes a School of Pharma- ing the scientific, intellectual property and reg-
cy (founded in 2013) and the Minerva Schools ulatory issues that dominate the industry. At
at KGI (founded in 2013). A focus on entre- the same time, the program also builds profes-
preneurism, globalism and applied learning is sional skills essential to the industry workplace
common to all three schools. including public speaking, team leadership and
dynamics, and project management. Students
79
What sets KGI’s MBS apart from other PSMs?

The answer is pretty simple: Few other schools
offer students the real-world experience or the
in-depth networking opportunities available at
KGI. These opportunities start in the first year
with course assignments in which teams of stu-
dents prepare reports for outside companies.
They continue during the summer with corpo-
rate internships and culminate in the second
year with the capstone Team Master’s Projects
(TMP). In a TMP, a team of three to six students
in the MBS program can choose from among
works with a leading life science company on
five majors: Bioprocessing, Business of Biosci-
a year-long consulting project to solve a real
ence, Clinical and Regulatory Affairs, Medical
problem.
Devices and Diagnostics and Pharmaceutical
Discovery and Development. HELPING PhDs TRANSITION INTO INDUSTRY
STARTING A MOVEMENT WITH THE FIRST PSM Traditional research and teaching jobs in
academia are becoming harder and harder to
Launched in 2000, KGI’s MBS program was
find. The reality is particularly apparent in the
one of the first Professional Science Master’s
STEM fields where only 10- 20 percent of PhDs
(PSM) degrees. The PSM degree has since been
and postdoctoral fellows can expect to find
adopted by the graduate education community
tenure-track jobs in academia. In response to
nationwide in an effort to produce the kinds of
that reality, KGI created the Postdoctoral Pro-
science and engineering professionals need-
fessional Masters (PPM) program in Bioscience
ed to keep the United States globally com-
Management for postdoctoral students with
petitive. Today, there are more than 300 PSM
backgrounds in science and engineering. This
programs established at 140 PSM-affiliated in-
newly-accredited master’s degree helps PhD
stitutions throughout the U.S. and abroad. KGI
scientists and engineers acquire the business
and the PSM have been featured in The New
and management skills needed to pursue se-
York Times, U.S. News and World Report and
nior management positions within the life sci-
Scientific American, among other leading pub-
ence industry or to embark on entrepreneurial
lications.
“THE VALUE KGI DELIVERED TO ME IN TERMS OF SKILL AND CAPABILITY DEVELOPMENT WAS SUBSTANTIAL.
IT GOES WITHOUT SAYING THE COURSE CONTENT WAS WORLD-CLASS, BUT IT WAS THE INTANGIBLE ASPECTS
OF KGI’S PROGRAM THAT HAVE REALLY POSITIONED ME FOR SUCCESS WITH MY CAREER. WHAT I MEAN BY
INTANGIBLES IS ALL OF THE HYPER-REALISTIC, COMPETITIVE AND APPLIED SITUATIONS KGI PUTS THEIR STU-
DENTS THROUGH. THESE INTANGIBLES, ALONG WITH THE COURSE WORK ITSELF, ARE QUITE UNIQUE AND, IN
MY EYES, SOMETHING YOU CAN’T FIND ELSEWHERE.”
- Jeff Liepman, MBS’07, Senior Vice President, Promidian
80
ventures intended to commercialize technol-

ogies developed in laboratories. The two-se-
mester program includes courses in account-
ing, finance, and organizational behavior that
help scientists and engineers understand how
bioscience companies are managed. Students
interested in launching their own business also
have the opportunity to enroll in specialized
courses in entrepreneurship. Postdoctoral stu-
dents in this program can participate in KGI’s
capstone Team Master’s Projects.
views, group interviews, multi-mini interviews
PREPARING FOR A CAREER IN MEDICINE
(MMI); and clinical and shadowing opportuni-
KGI’s one-year Postbaccalaureate Premed- ties, among others.
ical Certificate Program (PPC) combines the
NEXT-GENERATION PharmDs
best of an “academic enhancer” (AE) program
and a Special Master’s Program (SMP). It’s an The KGI School of Pharmacy (SoP) was
AE because it’s an opportunity for students to founded in 2013, with the inaugural class ma-
demonstrate their ability to succeed in a rigor- triculating in the fall of 2014. It offers majors
ous graduate environment and acquire unique in health operations management, clinical
knowledge and skills about the biomedical trials/regulatory affairs, medication therapy
industry. It’s similar to a SMP in that students outcomes and health information technolo-
have the option to earn a master’s degree with gy. PharmD graduates from the KGI School of
an additional year of study. This additional op- Pharmacy will be prepared for the increasing-
tion is what truly differentiates the PPC pro- ly diverse roles pharmacists play in providing
gram from many other types of post-bac pro- health care. SoP graduates may deliver thera-
grams. Co-curricular learning experiences and pies in a traditional retail or hospital setting.
opportunities include: an on-campus MCAT They may manage operations in community
review course; field trips to local and region- pharmacies, large health care systems or at bio-
al medical schools; simulated individual inter- technology companies. They may use advanced
health information technology to personalize
“I KNEW I WANTED TO GO INTO INDUSTRY, BUT NOT therapies to a patient’s specific genetic code
AS A BENCH SCIENTIST ON THE BUSINESS/MANAGE- and help improve the patient’s ability to take
MENT SIDE. THEN, I READ ABOUT THE PPM PRO- their medications properly. Or, they might help
GRAM. THE FACT THAT IT WAS RELATIVELY SHORT- to develop, test and regulate the next gener-
TERM, INTENSE AND MADE SPECIFICALLY FOR PHD ation of life-saving drugs. In the end, whether
SCIENTISTS INTERESTED IN BUSINESS CAREERS they work at the corner pharmacy or in the cor-
MADE IT SEEM TAILOR-MADE FOR ME.” porate sector, KGI PharmDs will be among the
- Hadi Mirmalek-Sani, PPM ‘13, next-generation of healthcare professionals.
Program Manager, Cell Therapy Catapult
81
“I WAS SURE MY EDUCATION AT KGI WOULD BE RELEVANT TO MY CAREER, BUT I ASSUMED IT WOULDN’T
PLAY MUCH OF A ROLE UNTIL AFTER I GRADUATED FROM MEDICAL SCHOOL. HOWEVER, COURSES I TOOK
IN PHARMACEUTICAL DISCOVERY AT KGI COVERED A LOT OF THE PHARMACODYNAMICS AND PHARMACO-
KINETICS I’M LEARNING HERE. AND, WHEN WE TALK ABOUT THE COSTS OF HEALTH CARE, I AM DRAWING
ON SKILLS AND CONCEPTS I LEARNED IN KGI CLASSES LIKE INTRODUCTION TO BIOSCIENCE INDUSTRIES
AND GLOBAL HEALTH POLICY.”
- Erin White, first-year medical student, Quinnipiac University
RESEARCH CENTERS fessional development workshops and a team-

based project. They also learn how to conduct
KGI students often have the opportunity to
research in industry and how industry thinks
contribute to research that has the potential to
about science. Meanwhile, the Summer Inten-
benefit society through one of the Institute’s
sive Program for Pre Meds (SPP) is a two-week
three research centers: the Amgen Bioprocess-
residential premed program specially designed
ing Center, the Center for Biomarker Research
to introduce students to what it means to be
and the Center for Rare Disease Therapies.
“premed.” The program is geared toward un-
MINERVA SCHOOLS AT KGI dergraduate sophomores and juniors who are
In 2013, KGI formed an educational part- either contemplating a career in medicine
nership with the San Francisco-based Minerva or already committed to applying in the next
Project to establish the Minerva Schools at KGI. medical school admission cycle and seeking
This highly selective undergraduate program supplemental preparation.
will offer students from around the world the
KGI also offers undergraduate anatomy and
opportunity to learn from accomplished facul-
physiology hybrid courses and an online bio-
ty versed in the latest teaching methodologies.
chemistry course. The anatomy course will be
The founding class will matriculate in the fall
taught using online coursework and an innova-
of 2014.
tive cyber-anatomy technology through which
SUMMER OPTIONS students will explore the human body using a
“virtual cadaver” in a simulated 3D space. The
KGI does not slow down in the summer!
courses are open to all undergraduate students
Options for summer study include an inten-
and fulfill required SoP prerequisites in these
sive two-week course for PhD students and
areas. The biochemistry course is also recom-
postdoctoral professionals designed to intro-
mended for students admitted to the MBS and
duce them to the skills and knowledge they
PPC programs.
need to thrive in industry. Offered in collabo-
ration with the American Society for Cell Biol-
ogy (ASCB), “Managing Science in the Biotech For additional information please contact Paige
Industry” exposes participants to the culture Stein at Paige_stein@kgi.edu
and infrastructure of life science companies
through MBA-style case-based teaching, pro-
TABLE OF CONTENTS
82
TABLE OF CONTENTS
Thank You!
Thank you for reading the inaugural
issue of the NEXUS Journal. We hope
it will become a valuable resource for
our readers and that its contents prove
informative and insightful.
We’d like to thank Mohamed Galal

for sharing his time, technical expertise
and experience with us during the
creation of this journal. Also, the Keck
Graduate Institute (KGI) for providing us
with the necessary resources needed
to successfully publish this journal.
A special thank you goes out to Diana Bartlett (Director of Corporate Partnerships, KGI) Marc Salata
(Director of Marketing, KGI), and Paige Stein (Manager of Media Relations, KGI) for their help and support
in generating awareness for the NEXUS. We’d also like to thank KGI President, Dr. Sheldon Schuster for his
enthusiasm for the NEXUS initiative and his generous donation to the NEXUS project.
Until next time,

-The NEXUS Team

Process Validation Lifecycle

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NEXUS

Vol. I, Issue 1 | April 2014

A collaboration between the Southern California PDA chapter

Risk and Statistics Serve as Tools for Application of Risk Management in

Cleaning Validation - Points to Consider Lifecycle Approach to Validation of Water

Recent Technical Advances

Subject Matter Experts

The NEXUS is a non-peer reviewed publication

PDA Event Highlight

62 of the New Extractables & Leachables Best Practices for Parenteral

KGI-PDA SoCal Student Chapter Section

69 Process Validation, No More Sleepless

71 PDA SoCal Student Chapter Mentorship

The NEXUS is a non-peer reviewed publication

Meet the Nexus

MIKE LONG, Ph.D.

Letters from the

Letters from the

If you would like to EITHER contribute an article to the NEXUS, or volunteer on

brian@biospeq.com or (909) 714-3155.

Brian Underhill: brian@biospeq.com or (909) 714-3155

INTERPRETING ciples and Practices, was released. This

The following sections provide some important

At the end of stage 1, it is expected that the

Due to the inherent dependency of stage 2 Successful completion of Stage 2 is required

STAGE 2A - FACILITY, UTILITIES AND EQUIP- STAGE 2 - PROCESS QUALIFICATION

STAGE 2B – PROCESS PERFORMANCE QUALIFICATION

the process and can help identify potential pro-

The starting point for the extent of monitor-

In addition to the manufacturing process, the

BY DR. MIKE LONG, MBB

in assisting to solve variation riddles and

• Understand the product

Have confidence before going into com-

The following steps, embedded

The initial step in the process is

CQA Risk Based PPQ

Figure 2. Line of Sight: CQA Identification to PPQ Sample Size Justification

Table 1. Example of Quality Attribute Criticality Assessment

IDENTIFY RISKS WITH ASSESSMENTS

The Continuum of Criticality assessment is simple from a conceptual standpoint. CQAs

Table 2. Example CQA Contin-

Sources: Technical Report 60: Process

Sources: Technical Report 60: Pro-

STATISTICAL METHODS CONTROL VARIATION

Product Attribute with High

NO Data Normal? YES

Descrete Data Method Continuous Data Method

NO Pool Data? YES NO Pool Data? YES

N=300 N=100 N=30 N=10

Figure 3. Example of Decision Tree for PPQ Sample Size Justification

[Editor’s Note: This article is based upon REFERENCES

ABOUT THE AUTHOR 2. Guidance for Industry Process Validation: General

4. ISO 16269-6 Statistical interpretation of data–Part

reduction of such residues to sufficient lev-

A robust cleaning validation program

“A robust cleaning validation program is necessary to

GMP Cleaning validation requires docu- limited to a robust cleaning development,

“Companies now need to ensure that their EM

in the context of Biopharmaceutical manufac-

Severity of Risk Detectability

Interim Risk Score

Figure 2. Design of Typical Purified Water System