1. FOCUS ON... Compliance
Quality By Design and the New
Process Validation Guidance
A Report from IBC’s Biopharmaceutical
Development and Production Week
by Cheryl Scott
W
here were you in 1987, and and the one it replaces, with which
what were you doing? I’m everyone should by now be very
not too embarrassed to say familiar.
that I was beginning my
last year of high school and paying far FDA Session
more attention to guitar lessons and During the Monday morning plenary
writing my first novel than what I session on 14 March (shared with
might eventually do for a career. IBC’s sixth annual “Technology
Meanwhile, the US FDA was Transfer for Biopharmaceuticals” and
publishing a guidance document on seventh annual “Outsourcing
process validation that the Manufacturing of Biopharmaceuticals”
biopharmaceutical industry has relied meetings), three FDA representatives
on ever since. I’m willing to bet that literally phoned in their teleconference
quite a few readers of this issue presentations on the Office of
weren’t yet working in the industry at Biological Products (OBP) pilot
that time either — and one or two program for QbD (Patrick Swann,
could even have been in the New OBP’s deputy director), the concept of
England crowd with me at a Def Analytical laboratories like this one at Roche continuous verification (Grace
Leppard concert that year. are vital to process validation. (www.roche.com) McNally, consumer safety officer at
A lot has happened since then in the Center for Drug Evaluation and
the while, your main source for
the United States: four different Research’s division of manufacturing
answers about the FDA’s expectations
presidential administrations dealing and product quality), and risk-based
regarding process validation has stayed
with wars and major economic boom- approaches to process understanding
the same. It was all about testing,
and-bust cycles, a huge federal budget and control (Mansoor Khan, director
instrument qualification, and process
deficit turned into a surplus and then of CDER’s division of product quality
robustness and repeatability. Now
into an even larger deficit, the growth research). Anyone who attends a west-
finally, as of January 2011, the agency
of the Internet from a niche military/ coast conference has come to expect
has finalized an updated guidance (2)
academic application to a ubiquitous less FDA participation than can be
to bring process validation into the
and vital personal and business tool, had on the east coast, so their long-
modern era of risk management and
and the dawn of a new millennium. distance session was a welcome
quality by design (QbD).
Biopharmaceutical manufacturers saw addition to the program.
It is only fitting, then, that the
the end of the establishment license Pilot Program: The OBP launched
primary focus of IBC’s 15th annual
(ELA) and product license application its QbD pilot program for biotech
“Process and Product Validation”
(PLA) processes, the rise of the products in July 2008 with two
conference (part of “Biopharmaceutical
biologics license application (BLA), streams, one for new molecular
Development and Production Week”)
the birth of the well-characterized entities at the investigational new
in Bellevue, WA, 14–15 March 2011
biologic, dozens of product approvals drug (IND) or BLA stage and the
was the similarities and differences
(1), and the coming of biosimilars. All other for postapproval-stage
between this new guidance document
14 BioProcess International May 2011

2. Other Guidance Documents
The International Conference on Harmonisation of Technical ICH Q10: Pharmaceutical Quality System was adopted by the
Requirements for Registration of Pharmaceuticals for Human European Union in July 2008, by the United States in April 2009,
Use (ICH) brings together regulatory authorities and and by Japan in February 2010 after the tripartite harmonized
pharmaceutical companies from Europe, Japan, and the United ICH guideline had been finalized in June 2008. This document
States to discuss scientific and technical aspects of drug applies to pharmaceutical drug substances and drug products
registration. Since its inception in 1990, ICH has worked through (including biotechnology and biological products) throughout
its global cooperation group to harmonize the increasingly their lifecycles. Companies should apply its elements
global face of drug development. Its mission is to help ensure appropriately and proportionately to each stage. The guideline
that safe, effective, and high-quality medicines are developed can be downloaded online at www.ich.org/fileadmin/Public_
and registered with the most efficient use of resources. The Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4/Q10_
organization focuses on four main subjects: quality, safety, Guideline.pdf.
efficacy, and multidisciplinary guidelines, which include the Other Documents: Real-world experiences of companies and
MedDRA standardized medical terminology guide and the regulators with the Q8, Q9, and Q10 guidelines made ICH aware
common technical document (CTD), a format for submitting of a need for some clarification of key issues. The latest version
information for regulatory review in all participating countries. of its resulting questions-and-answers document was finalized
ICH celebrated its 20th anniversary in 2010 (www.ich.org/ in November 2010 and can be downloaded online at www.ich.
fileadmin/Public_Web_Site/News_room/C_Publications/ org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/
ICH_20_anniversary_Value_Benefits_of_ICH_for_Regulators. Quality/Q8_9_10_QAs/Q-IWG_QAs_Step4/Q8_Q9_Q10_
pdf ). In relation to process validation, four ICH subtopics are Question_and_Answer_R4_step_4_November_2010.pdf.
most relevant: Q8, Q9, Q10, and Q11.
ISPE has published a guidance document that’s free for its
ICH Q8(R2): Pharmaceutical Development was adopted by members and available to nonmembers at a nominal cost: ISPE
the European Union in June 2009, by the United States in Product Quality Lifecycle Implementation Guide: Overview of
November 2009, and by Japan in June 2010, after having been Product Design, Development and Realization — A Science- and
finalized in November 2005. This document is intended to Risk-Based Approach to Implementation. International Society for
provide guidelines for drug products as defined in the scope of Pharmaceutical Engineering: Tampa, FL, October 2010; www.
Module 3 of the common technical document (CTD), which is ispe.org/ispepqliguides/overviewofproductdesign. According to
ICH topic M4. The guideline does not apply to contents of ISPE:, the guide is “the first in a series of product quality lifecycle
submissions for drug products in clinical research, but its implementation good practice guides that will describe
principles are important to consider during that stage. An annex enhanced, QbD approaches to product realization and is an
to the tripartite harmonized ICH text was finalized in November introduction to and an overview of the guides series.” To address
2008 and incorporated into the core document, which was then product and process development, transfer to and
renamed Q8(R1). That annex provided further clarification of establishment of commercial manufacture using science- and
key concepts and described the principles of QbD. It showed risk-based approaches, the series will cover critical quality
how concepts and tools (e.g., design space) outlined in the attributes (CQAs) and critical process parameters (CPPs), design
parent document could be put into practice. When a company space, and control strategy.
applies QbD and quality risk management (ICH Q9, see below)
In addition, ASTM International has published a standard that
as part of a pharmaceutical quality system, opportunities arise
supports ICH Q8 and Q9 titled ASTM E2537-08: Standard Guide
to enhance science- and risk-based regulatory approaches (as
for Application of Continuous Quality Verification to
described in ICH Q10, see below). The Q8 guideline was revised
Pharmaceutical and Biopharmaceutical Manufacturing. According
to (R2) in the summer of 2009 to reflect minor corrections, and
to ASTM, “The accumulated product and process understanding
it can be downloaded online at www.ich.org/fileadmin/Public_
used to identify critical quality attributes (CQAs), together with
Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_
the knowledge that the risk-based monitoring and control
R2_Guideline.pdf.
strategy will enable their control, should provide confidence to
ICH Q9: Quality Risk Management was adopted by the show validation of each batch manufactured — as opposed to a
European Union in January 2006, by the United States in June conventional discrete process validation effort.”
2006, and by Japan in September 2006 after the tripartite
ICH Q11: Development and Manufacture of Drug
harmonized ICH guideline was finalized in November 2005. This
Substances was endorsed as a topic by the ICH Steering
guideline provides principles and examples of tools for quality
Committee in April 2008. This new guidance is proposed for
risk management that can be applied to all aspects of
active pharmaceutical ingredients (APIs) harmonizing the
pharmaceutical quality including development, manufacturing,
scientific and technical principles relating to the description and
distribution, and inspection and submission/review. It can be
justification of the development and manufacturing process
applied throughout the lifecycle of drug substances and
(common technical document sections CTD S2.2–S 2.6) of drug
medicinal products, biologicals, and biotechnological products
substances including both chemical and biotechnological/
and covers the use of raw materials, solvents, excipients,
biological entities. The document is only at stage 1 of the ICH
packaging, and labeling materials. The document can be
process currently, and a concept paper can be found at
downloaded at www.ich.org/fileadmin/Public_Web_Site/ICH_
www.ich.org/fileadmin/Public_Web_Site/ICH_Products/
Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf
Guidelines/Quality/Q11/Concep_Paper/Q11_Concept_Paper.pdf.
16 BioProcess International May 2011

3. molecules. The pilot program has which falls into line with ICH Q8
provided an opportunity for the (see the “Other Guidance” box).
biopharmaceutical industry and the During early product and process
FDA to evaluate and identify best development, process design builds
practices for key QbD elements of criteria for testing, qualification, and
target product profiles, critical quality setting specifications later on. “The
attributes (CQA), risk assessment, commercial manufacturing process is
process characterization for design- defined during this stage based on
space definition, CQA-focused control knowledge gained through
strategies, and expanded change development and scale-up activities” Enhance Cell Productivity
protocols. This builds on the concept (2). Process qualification encompasses Enhance Cell Productivity
Deliver Scalable Results
of well-characterized biologicals (a.k.a. many validation concepts familiar to
Deliver Scalable Reproducible
Make Processes Results
specified biologics), which came about in those who have been working with the
the late 1990s when it was recognized previous guidance document all along: Make Processes Reproducible
that analytical methods had improved Manufacturing equipment, tooling,
to the point at which biologics could and instrumentation, and utilities
be analyzed and described well must be qualified using standard
enough to separate their identities validation protocols along with an Please visit us at:
from their processes, at least associated validation master plan, risk ESACT 2011
Please visit us at:
somewhat (3–5). A few years later, assessment, and requirements ESACT 2011 Vienna
15 – 18 May,
CDER took over responsibility for specifications. “During this stage, the 15 – 18 May,
Booth #216 Vienna
those well-characterizable products process design is evaluated to Booth #216
from the Center for Biologics determine if the process is capable of
Evaluation and Research (CBER). reproducible commercial
The OBP pilot program offers manufacturing.” (2).
individualized examination of QbD Continued process verification, the
initiatives submitted in market final stage, was the focus of Grace
applications for biotech therapies for a McNally’s presentation. “Ongoing
number of original and supplemental assurance is gained during routine
biologic license and new drug production that the process remains in
applications. Manufacturers — such a state of control” (2). McNally
as Genentech, an early program emphasized the “life-cycle approach”
participant — voluntarily provide that makes process validation an
chemistry, manufacturing, and ongoing activity — not something a
controls (CMC) information in an company can do and then move on.
expanded change protocol describing “Criticality” (as of quality attributes) is
their implementation of QbD and risk a continuum, she pointed out, not an
management. Their candidate either–or question. McNally also
products are monitored by trhe OBP pointed to several other sections of the
throughout product development and Code of Federal Regulations that can
testing after early discussions with help those working to implement these
FDA reviewers about R&D issues. concepts into their manufacturing
process development: 21 CFR Part
For the pilot, the Office of
100a, 110a, 110b, 160b3, 165a, 165d,
Compliance (OC) will be part of
180e, 211.42, 211.63, and 211.68.
review communication, so there is a
need to transfer information among
Panel Discussion
OBP, OC, and the field. Ideally, Parallel Bioreactor Systems for Unparalleled Results.
After the FDA presentations, we
product reviewers should be present Parallel
Europe Bioreactor Systems for Unparalleled Results.
followed session chair Victor Vinci
at initial QbD-type inspections. +49 2461
Europe 9800
(director of purification development
The Office of Compliance will play info@dasgip.de
+49 2461 9800
and viral safety in bioproduct R&D,
a key role in understanding the role info@dasgip.de
US East Coast
LRL, at Eli Lilly & Co.) to a smaller
of quality systems in QbD filings +1 800 531 9462
US East Coast
ballroom for process validation biotools@dasgip.com
and their control strategies. (6) +1 800 531 9462
strategies and case studies from biotools@dasgip.com
US West Coast
Continuous Verification: According Acceleron Pharma, Amgen, +1 510 799 6105
US West Coast
to Swann, the new guidance describes Genentech, Hospira, MSD Biologics, tombruggman@dianovainc.com
+1 510 799 6105
three stages of process validation and Pfizer. The next day — along tombruggman@dianovainc.com
during the lifecycle of a drug product, with sessions covering analytical

4. Figure 1: QbD development and product lifecycle (7); no temporal relationship is intended
Prior Clinical Animal In Vitro Input Material Controls
Knowledge Studies Studies Studies
Process Controls
Co nt i nu o u s Pr o ce ss Ve r i fi c at i o n
High-Criticality Attributes
Procedural Controls
Control Strategy Elements
Safety and (1) Quality attributes
Efficacy Data to be considered Process Parameter
and/or controlled by Controls
the manufacturing Process Process
process Targets for Development
Design Testing
Product Criticality and
Quality Space
Quality Assessment (2) Acceptable Characterization In-Process Testing
Attributes
Attributes ranges for
quality attributes
to ensure drug Specifications
safety and efficacy
Characterization and
Attributes that do not Comparability Testing
need to be considered or
controlled by the Process Monitoring
manufacturing process
Low-Criticality Attributes
PR O D U C T U N D E R S TA N D I N G PR O CE SS U N D E R S TA N D I N G
methods validation and transfer and associated with every unit operation in pudding is not in the first three bites,”
drug product validation from the a manufacturing process. Calcott emphasized. “It’s eating the
American Society for Quality, Repetto told us that mature whole thing.”
Amgen, Centocor (Johnson & companies have in recent years done A company must be able to
Johnson), Genentech, Hyde “a pretty thorough job” of integrating adequately explain and defend the
Engineering, Novartis, Pfizer, and risk management and QbD into their choices that it makes. “It’s the data,”
ProBioGen — we were treated to a process validation activities. But not said Repetto, “not the number of lots.”
fascinating panel discussion with every company can employ dozens of For some, three lots may be enough; for
Vinci, Robert Repetto (Pfizer’s statisticians and risk experts so may be others, thee may not be anywhere near
director of external affairs), and less experienced with the new science enough; and for companies with a great
consultants Peter Watler (Hyde and risk based approach. The one- deal of process knowledge and
Engineering and Consulting) and time rule of thumb for running three understanding about its platform
Peter Calcott (Calcott Consulting). verification lots is no longer so process three runs may be more than is
Calcott said that process validation straightforward; it depends on the necessary. “I can foresee a day when
is transitioning “from a check-box level of product and process routine periodic oversight
activity to value-added.” Everyone knowledge the company has acquired demonstrating ongoing process control,
emphasized the interplay between raw from development studies. could become a more valuable tool to
materials, process controls, and final “Is this a new paradigm?” Watler the agencies than coming in to inspect
outcomes (drug products). The new asked. “I hope it is; we really do need everything at one time.
guidance documents what thought- one.” He and others emphasized that An audience member commented
leaders have talked about for a few three lots run early in the lifetime of a that such an approach seems to lend
years now: the team-oriented, life- product cannot be expected to itself well to products that aren’t scaled
cycle approach linking QbD and represent its process a decade later — very large (e.g., personalized medicine
product/process development with risk or beyond. The new guidance and higher-titer production, high-
assessment. Calcott described a “four document is not prescriptive; it is a concentration formulations), for
Ds” approach: design (for standard framework for conversations between example with the commercial scale
requirements), demonstrate (by companies and the FDA, as well as similar to that of clinical trial material
experimenting), document (using among departments and colleagues production. “For this approach to work
good science and good manufacturing within those organizations. Caldwell you need development data that is
practice, GMP), and determine (with warned that such conversations, representative of your full scale process.
ongoing monitoring). The old DQ/ however, can end up pushing product If that can’t be done for a unique
IQ/OQ/PQ approach doesn’t licensing later as the agency asks for production system you will still need to
demonstrate process; equipment more information — unless a demonstrate process control, so your
function is barely half the story. There company begins with the necessary process validation plan would reflect
are raw materials and inputs, process data and understanding to keep that the lower level of process knowledge. ”
controls, and product attributes from happening. “The proof of the said Repetto. As companies move
18 BioProcess International May 2011

5. •
gather with QbD helps you make QbD — can happen without
those decisions,” Watler added. knowledgeable analytical personnel
But Calcott emphasized, “Don’t using dependable equipment to
gather data for data’s sake.” There perform robust and reproducible
“QbD is not only should be a purpose behind annual laboratory methods behind the
the buzzword product reviews, trend charting, and manufacturing scenes.
for 2011, but it other scheduled reviews; companies A presentation from Keith A
shouldn’t continually “tweak” their Davis, a busy senior scientist from
represents a major processes based on every little issue. Pfizer’s bioprocess characterization
step forward in the Only real problems should be and analytical support laboratory in
way FDA regulates addressed with process changes: St. Louis described several
therapeutics. QbD Remember, you’ll have to justify these technological advances that have
things to regulators with good science improved productivity and the quality
will make a huge and common sense. of data his laboratory can gather.
difference in product “As we learn more about these Cross-trained groups of analysts such
safety for years to products and molecules,” Repetto said, as Davis described are increasingly
come.” —Nancy “we’ll know better how to proceed.” tasked with supporting development
And Calcott pointed out that the very of robust manufacturing processes.
Chew, MS, RAC, nature of a CQA as critical makes it Among the vendors and instruments
FRAPS important to investigate every he thanked for stepping up to help
associated failure and issue related to them succeed are
it. Over time, however, “clinical • the Octet platform from ForteBio
experience may lessen the importance “for accurate, rapid MAb titer
forward, they’ll have to be looking at or criticality of some CQAs.” In the determination,” which formerly
the overall process picture through early days of process validation, involved protein A high-performance
trending and base their decisions on Repetto reminded us, a company liquid chromatography (HPLC) or
data. The A-Mab case study published might never know or care whether enzyme-linked immunosorbent assays
by CASSS was identified as a good something shifted within (ELISAs)
example of modeling for predictability specifications. With continued process • ProA PreDictor plates from GE
(7). monitoring, “it may be something you Healthcare for MAb sample
“I think the agency can get past want to look at.” By studying trends preparation using protein A
having things set in stone,” said over time, companies may be able to purification
Calcott, and let companies use data discover real problems earlier than • the Processor Plus automated gel
and science to explain why they they might have otherwise — early staining and blot processing system,
shouldn’t be right away. Experience at enough to prevent process failures, also from GE Healthcare
large scale shows that things may need product losses, and expensive mistakes. • the iBlot dry blotting system
adjusting as time goes on. Those from Invitrogen
working with platform technologies — The Importance • Nanodrop spectrophotometric
e.g., monoclonal antibodies (MAbs) — of Analytical Methods products from Thermo Scientific
get a head start because they have lots After the “Process and Product • Kingfisher-96 systems (also from
of data to begin with. Validation” final sessions focused on Thermo Scientific) for automated
What about continuous analytical methods validation and DNA extraction and qPCR analysis
verification? That’s a major focus of transfer, IBC’s inaugural “Analytical • HPLC systems from Agilent
the new guidance. If a process Technologies for Biopharmaceutical Technologies for amino-acid analysis
changes over time, will its critical Development” meeting packed a small • The BioScale ViBE bioanalyzer
quality attributes (CQAs) do so as hall on 16–18 March, often with some for host-cell protein and protein A
well? For now, there’s no easy answer. attendees standing in the back of the quantitation
“How we choose CQAs will be in room. With the new process • SpotFire data management
flux as we figure out how to interpret validation paradigm, it’s never been software.
these guidances,” said Watler. (ICH more apparent just how vital process Critical quality attributes, as Paul
Q11, “Development and Manufacture analytical technologies (PATs), Motchnik of Genentech described in
of Drug Substances” is only at the statistical design of experiments, his presentation the morning of
first stage of international work, so it bioassays, and data management are to Wednesday 16 March 2011, are
still has a ways to go.) If an the success of a biotherapeutic product identified through analytical testing
opportunity to change a process arises in development. None of the defining, with a solid basis in platform
(e.g., biosimilar competition) a evaluating, trending, and monitoring knowledge and scientific literature.
company will certainly want to revisit described in the new guidance — and Tools such as multidimensional
everything. “All the knowledge you all the other documents relating to chromatography (discussed by Methal
20 BioProcess International May 2011

6. Albarghouthi of MedImmune), As always, the first place you
hydrogen-deuterium exchange with should go is to the guidance document
mass spectrometry detection (described itself. But we hope to offer up some
by Steven Berkowitz of Biogen Idec), expert advice in our pages over the Westfalia Separator® capitalcare
isoelectric focusing (explained by Brian months (and years) to come.
Hosken of Genentech), miniaturized Comprehensive Protection
immunoassays (presented by Mats Acknowledgments for Your Investment
Inganäs of Gyros AB in Sweden), I’m grateful to Peter Calcott, Nancy Chew
(Regulatory Affairs, North America, Inc.),
microchip assays (addressed by Xiaoyu
Robert Repetto, Victor Vinci, and Peter Watler
Chen of Novartis), laboratory for their review of this report.
automation (the focus of presentations
by Martin Vanderlaan of Genentech
Reference
and Susanne Demarco of Pfizer), and 1 Scott C. US-Approved Recombinant
new-era mass spectrometry (reported Cell Culture Products, 1980–2010. BioProcess
on by several speakers to close out the Int. 7(10) 2009: supplemental wallchart.
Analytical Technologies meeting on 2 CDER/CBER/CVM. Guidance for
Friday 18 March 2011) are helping Industry: Process Validation — General Principles
and Practices. US Food and Drug
companies answer the questions
Administration: Rockville, MD, January 2011;
regulators will ask when it comes time www.fda.gov/downloads/Drugs/
for product review. GuidanceComplianceRegulatoryInformation/
A New Way of Thinking: When I Guidances/UCM070336.pdf. You are pursuing a clear objective
worked for BioPharm magazine in the 3 CDER/CBER. Guidance for Industry: with your investments: a high level
late 1990s, I remember numerous Content and Format of Investigational New Drug of performance at minimum cost.
Applications (INDs) for Phase 1 Studies of Drugs,
discussions of the confusion over We have customized our range of
Including Well-Characterized, Therapeutic,
terminology: The word validation only Biotechnology-Derived Products. US Food and
services to take full account of this
applied to processes, whereas throughout the entire life cycle
Drug Administration: Rockville, MD,
of your centrifugal technology.
qualification applied to November 1995; www.fda.gov/downloads/
Westfalia Separator ® capitalcare is
instrumentation, and neither would Drugs/GuidanceComplianceRegulatory
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4 CBER/CDER. Guidance for Industry:
Design qualification (DQ ), installation efficiency and availability of your
Changes to an Approved Application for Specified
qualification (IQ ), operational quali- Biotechnology and Specified Synthetic Biological plant. Our tailor-made service
fication (OQ ), and performance qual- Products. US Food and Drug Administration: products mean you benefit from
ification (PQ ) — none of these appear Rockville, MD, July 1997; www.fda.gov/ the competence and experience of
in the new guidance. Repetition of the downloads/Drugs/GuidanceCompliance the technology leader:
RegulatoryInformation/Guidances/
phrases process qualification and product
UCM124805.pdf. Field service
validation illustrates the fact that in
5 Apffel A, et al. Application of New Original spare parts
many ways, this is a whole new world. Analytical Technology to the Production of a Repairs
Peter Watler told me after the “Well-Characterized Biological.” Dev. Biol. Condition monitoring
meeting that he heard Grace McNally Stand. 96, 1998: 11–25.
Training
make a specific point that the IQ/ 6 Mire-Sluis A, et al. Quality by Design: Service level agreements
OQ/PQ/DQ terms were industry The Next Phase: Potential Regulatory Applied consulting
Implications and Filing of QbD Data.
terminology rather than the FDA’s. “I
BioProcess Int. 7(1) 2009: 34–42.
have certainly heard folks make an
7 CMC Biotech Working Group. A-Mab:
issue out of the terminology,” he said, A Case Study in Bioprocess Development. CASSS,
Your direct route to 24 / 7 service:
“which is really quite silly. The focus an International Separation Science Society:
www.westfalia-separator.com / service
should be on what a study says, not Emeryville, CA; www.casss.org/associations/
pdf. •
about what it is called. And the FDA 9165/files/A-Mab_Case_Study_Version_2-1.
is clear on this. This has caused some
in industry to divert validation efforts
away from a scientific understanding Cheryl Scott is senior technical editor
to strict adherence of terminology and of BioProcess International.
protocol. Fortunately the new
guidance does away with that
nonsense so industry can put resources To order reprints of this article, contact Liquids to Value
into science and understanding rather Rhonda Brown (rhondab@fosterprinting.com)
1-800-382-0808. Download a low-resolution
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