12 BioProcess International 9(10) November 2011
How QbD and the FDA Process
Validation Guidance Affect Product
Development and Operations, Part 1
by Peter H. Calcott
FOCUS ON... COMPLIANCE
E arlier this year, the FDA issued its long-awaited process validation guidance document, which had been several years in
development. It is well written and
effectively articulates what many
progressive companies have been
thinking and doing for years. But
many people in the industry are
asking questions: How will it affect
our process development programs?
How will it affect the submissions and
licensure of our products? And how
will it aid in our commercial
operations? Or will it have no effect?
Consider what the document says.
In the simplest terms, it articulates
four main messages. A strong process
development program is essential —
preferably using quality by design
(QbD) — to eventually obtain
expedited product approval and benefit
from a relaxed regulatory position with
the agency. Process validation (PV) is
linked into that activity in verifying its
conclusions: a set of team-based
activities requiring many disciplines to
work together to be effective. PV is
value added and never stops. It requires
a life-cycle approach with continuous
verification and adjustment. (So
continuous improvement is central to
the activity.) By applying these
principles, you will end up with a more
reliable process that yields consistent
products to meet your customers’
requirements, resulting in more
satisfied customers. The overall take-
home message is that PV is part of the
drug development life cycle, that it
never stops, and that it is a value-
added activity. This can be described
using what I call the “four Ds”:
• Design (build each process to a set
of standards or requirements focusing
on what a customer wants/needs)
• Demonstrate (by conducting
experiments and validation to show
that process and product meet design
requirements)
• Document (the cornerstone of
good work is recording it for posterity)
• Determine (ensure that results
remain valid, or make changes as
knowledge and experience grow — for
continuous improvement).
A LittLe History
To determine what impact the document
will have on all the industry’s questions
and systems will require time. The
answers rest in how companies use the
guidance in process development,
regulatory submissions, and operations.
To fully appreciate its potential, however,
step back and examine the status quo on
PV’s role in product development — as
it began and has evolved until now.
When it was first incorporated in
the mid 1980s, PV was viewed as a new
regulatory requirement to be performed
sometime in phase 3 of the clinical
development cycle. That was when
processes were being locked down and
companies hoped their products would
be proven safe and efficacious. Whether
going for a drug approval or biologics
licensure, a company either submitted
protocols and performed PV later (but
before sale of the first lots) or submitted
the completed PV reports with its
submission. Once that was complete,
you could put your reports on a shelf
and forget about them unless you made
radical changes to your product or
process. This was not a value-added
activity, but rather a check-the-box
process.
Meanwhile, the FDA wanted all
legacy products (those that had been
approved before PV) to have their
processes validated, too. This created a
flurry of activity in the 1990s (and later)
to retroactively validate those products.
But again, the folders were then stored
away and ignored. All that entailed a
great amount of work with very little
return on investment beyond keeping
products on the market and keeping
companies out of regulatory trouble.
That was the old paradigm. Over
time, companies began to use PV
activities to demonstrate ruggedness
of their processes by choosing worse-
case settings for critical parameters in
three PV runs. This method brought
value to the work involved, but it was
Ioana DavIes (www.Istockphoto.com)
14 BioProcess International 9(10) November 2011
impossible to examine all high and low conditions for all
critical parameters in all combinations and permutations in
just three PV exercises or runs. The work was labor
intensive, yielding relatively little return on investment.
However, the paradigm was changing.
Then came QbD, another FDA-driven concept. It was
broadly placed into the “GMP in the 21st Century” initiative
that came about because of several factors. The FDA was
viewed by many detractors as very conservative and not
amenable to change or to encouraging implementation of new
technologies into processes and products — particularly for
those that had already been approved. Further, the agency
was under pressure of increasing workloads with a
noncommensurate increase in resources. It was forced to do
what industry has always done: more with less. Faced with
that, the agency attempted to create new visions whereby
industry investment into creating better interactions with
regulators regarding process and product understanding
might allow the FDA to relax its oversight somewhat. That
would allow it to slacken the strings of control and give
industry more opportunity to control its own destiny.
How QbD works
The principles behind QbD are straightforward. If
companies do a better and more systematic job of process
development, then they will understand their processes and
capabilities better. In turn, that will lead to more rugged
processes that are more successful (and economically more
rewarding). Manufacturers will understand what attributes of
their products are critical to meet customer needs. And they
will learn what factors contribute to process outcomes and
how to control those more effectively. They would also gain
understanding process inputs (raw materials) affect those
outcomes. All of this will link inputs, process controls, and
output (Figure 1).
But that’s not all. Companies must take the results of
validation studies and package them to convince the FDA
that they understand their processes and how to control the
outcomes. If you are successful, you will get regulatory relief.
You might even avoid having a preapproval inspection (PAI)
and be allowed to operate within a very wide “design space”
with confidence regarding the outcome — even outside your
clinical experience — without very extensive regulatory
approval for changes. Of course, change control is required
outside the operating range but within the design space —
but that would be without regulatory oversight (Figure 2).
To date, the best illustrations of QbD success are
Pfizer’s Chantix and Selzentry products. The company had
no PAI in the first case and was allowed to operate within
its design space (using only internal change control) in the
second. To date, I am aware of no equivalent successes in
the biologics arena — yet. But Genentech (a member of the
Roche group) has been very visible in leading the charge.
ICH Q8, Q9, and Q10 (and possibly Q11 when it is
issued) admirably describe the elements of QbD by
incorporating development principles, risk management, and
progressive quality principles reminiscent of how the
International Standards Organization (ISO) works for
devices. A review of these documents will help you
understand the major elements and nuances, but here are
some key principles. In a system or product that has
undergone QbD, the following elements are recognized:
• A product is designed to meet patient needs and
performance requirements defined by its critical quality
attributes (CQAs). In simple terms, if we make a product
that meets its CQAs, then it works each and every time it
is used as prescribed.
• To accomplish that, the production process is designed
to consistently meet and attain a product’s CQAs. They may
include specifications and other requirements not covered by
conventional specifications.
• The impacts of raw materials and process parameters are
well understood, as are their effects on outcomes (CQAs).
Those with little impact are as well understood as those with
major impacts.
• Critical sources of variability are thus identified and
controlled by appropriate strategies. So you know what to
control, and you control it to ensure that your CQAs are
attained.
• The process is continually monitored, evaluated, and
updated to assure consistent quality over time. This
represents a state of continuous improvement.
With all that integrated into a development cycle, a
company moves from operating reactively (obsessed with
simply compliance for compliance’s sake) to proactively
operating under continuous improvement. Experience and
knowledge regarding its manufacturing processes do not
stop in the development phase, but rather grows through
this continuous improvement cycle. Ever-expanding
knowledge and experience increases confidence in both
product and process, thus giving a company the tools to
improve them.
The development cycle defines a design space that does not
stay static but is forever being refined. It is the area within
which a company can operate its process with predictable
outcomes to make acceptable products every time. This space
Figure 1: Relationship of components to outcomes for a process
Process
Input
Output
Controls
Figure 2: comparing design space and standard operating range
Design
Space
Normal
operating
range
Nondesign Space
(failure area; areas with
regulatory submission
required to operate)
Operation
within design
space using internal
change control Alternative operating range
(requires no agency submission)
16 BioProcess International 9(10) November 2011
is greater and broader than the operating ranges for routine
operations. A company that presents this evidence to the FDA
should be allowed to operate without restraint if it stays within
this “space.” ICH Q8 describes in detail the elements for an
effective pharmaceutical development program (1).
Quality Risk Management: Cost-effectively defining a
design space requires introducing a further element: quality
risk management (QRM), which is detailed in ICH Q9 (2).
With multiple process parameters and raw materials inputs, a
company faces thousands of potential experiments or questions
to answer. Apply the principles of risk analysis and directed
efficient experimentation (e.g., using design of experiments,
DoE), then carefully analyze the impact on outcomes of raw
materials and process parameters and controls. So you can
prioritize a complex array of potential experiments and choose
only those that will yield the necessary answers for defining
your design space. Less effort is required to further explore
parameters and inputs demonstrated to have little or no
impact, and limited resources can be focused on those with
significant impact.
To move from a compliance-obsessed reactive state to a
process-knowledgeable proactive state requires a company
to operate quality systems differently. You must still follow
good manufacturing practice (GMP), of course, while
incorporating other elements. ICH Q10 describes these
elements in detail (3). Companies familiar with ISO
processes will immediately recognize these as key tenets in
that philosophy, as well:
• Management must actively ensure that quality systems
are incorporated effectively into operations and champion
continuous improvement for operations, products, and
processes.
• Change control becomes a cornerstone process to help a
company embrace the concept of product (and process) history
files. Each and every change contemplated should move a
product closer to customer requirements. This drives the
manufacturing process into a more predictable outcome, ever
increasing its ability to attain a product’s specific CQAs.
• Nothing remains constant, and everyone actively
pursues continuous improvement, which becomes the driver
for increasing knowledge after a product, process, and
design space are developed.
Although Q11 is not yet complete, it will focus on much
of what is described in Q8 while emphasizing that the
principles of product development apply equally well to
active pharmaceutical ingredients (APIs), bulk drug
substances (BDSs), and drug products. This is well
understood in the biologics industry but perhaps not so well
appreciated in the pharmaceutical world at large.
tHe New PV PArADigm
With QbD, the front end of the PV cycle is clearly
delineated. The new guidance provides a framework for
phases 2 and 3 in this life cycle as well. It describes how PV
activity links into process development and includes the
concept of process monitoring and adjustment (elements of
continuous monitoring and improvement).
With this new paradigm emerging, some people ask, do
we stop validating processes as we have been doing so? Or
must we rethink the mechanics? Inevitably, the answer is
both yes and no. Many principles of PV still stand, but the
reasoning (and hence the execution) may very well change.
Clearly, the execution of classic equipment and facility
qualification and method validations will not go away. But
when you design and execute your qualification program,
think of the end result in your program more than ever
before. Qualification efforts will need to meet the needs of
both product and process:
• Design qualification (DQ ) — what exactly will we
require the equipment or facility to do? What are our
requirements?)
• Installation qualification (IQ ) — is everything there
and connected correctly?
• Operation qualification (OQ ) — when you turn it on,
does it function?
• Performance qualification (PQ ) — does it
reproducibly do what it is supposed to?
With those activities complete, you’re ready to begin the
elements of PV, assuming you have completed the
development phase and defined your design space. Your PV
program should encompass all elements “from vial to vial”
for biological products and further for drug products,
including distribution systems. Roles and responsibilities
must be defined because this is a team activity that requires
the input of several disciplines. Typically, it should include at
least members from production (the process owner), process
development (technical experts), validation (the
administrator and designer of a PV program), QC (sample
Figure 3: how a biologic process could be split into unit operations
T-4
EQ-2 HX-3 T-5
T-6
T-7 T-8 T-9
EQ-3
T-10 Pump-1
Fermentation
Puri�cation
Fill and Finish
Co
lum
n 1
Co
lum
n 2
Co
lum
n 3
Bulk Tank Filling Line
Lyophilizer
Harvest
and
Clari�cation
Pr
od
uc
tio
n
Re
ac
to
r
Expansion Train
Figure 4: Interplay among inputs, controls, and a process with
outputs
PROCESSINPUT OUTPUT
CONTROL Yield, stability, processibility
downstream
(CQA)
Control points and strategy,
acceptance criteria
Raw material
quality, quantity
(output from
previous step)
testers), and QA (for oversight and
approval) groups.
A Master Plan: You may eventually
demonstrate your whole process —
from vial to vial — but it helps to
split the process into distinct unit
operations with their own inputs
(raw materials), control parameters,
acceptance criteria, and output
requirements. Figure 3 suggests how
a biological process might be
divided.
The examples below illustrate how
to set up a validation program for
specific unit operations. This
incorporates familiar elements:
validation master plans, protocols, and
reports. Use what you have developed
and are accustomed to using. Because
biological product processes are highly
complex, a master plan is a critical
element to tie together each unit
operation with its demonstration. As
you develop each protocol for each
unit operation, consider the following
points in planning your activities
(Figure 4): the unit operation itself,
raw material inputs, process controls,
and product attributes.
The unit operation: What is its
purpose? Why is it configured the
way it is? What is the role of each
part? What is not accomplished in
this operation that might affect steps
downstream? All of those are defined
by your QbD program.
Raw material inputs: What are they,
what quality, and how much of each
material is used? Which ones play
significant roles in process outcomes?
Which are otherwise benign?
Process controls: Which parameters
must be controlled for product quality,
and which for business results? What
are acceptable ranges for each
parameter? Do you know how to
control them effectively?
Product attributes: What do you
want as an end product for a given
step? How does it tie into the next
unit operation? One step’s output is a
raw material for the next step. How
does each one fit into a final product?
For example, consider the
fermentor or cell culture production
step for a drug substance and the final
filling step for a drug product. Table 1
lists supporting details.
LookiNg AHeAD
Part 2 will conclude this article with
an upstream and a downstream
example of applying these principles.
It will also go into more detail about
the postapproval phase as well as the
implications of the new paradigm.
refereNces
1 ICH Q8(R2): Pharmaceutical
Development. US Fed. Reg. 71(98) 2009: www.
ich.org/fileadmin/Public_Web_Site/ICH_
Products/Guidelines/Quality/Q8_R1/Step4/
Q8_R2_Guideline.pdf.
2 ICH Q9: Quality Risk Management. US
Fed. Reg. 71(106) 2006: www.ich.org/fileadmin/
Public_Web_Site/ICH_Products/Guidelines/
Quality/Q9/Step4/Q9_Guideline.pdf.
3 ICH 10: Pharmaceutical Quality
System. US Fed. Reg. 74(66) 2009: www.ich.
org/fileadmin/Public_Web_Site/ICH_
Products/Guidelines/Quality/Q10/Step4/Q10_
Guideline.pdf. •
Peter H. Calcott, PhD, is president of
Calcott Consulting, 931 Mendocino Avenue,
Berkeley, CA 94707; 1-510-585-8256;
peterc@calcott-consulting.com;
www.calcott-consulting.com.
BPI November 2011 ibds r1.indd 1 10/26/11 12:41:39 PM
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