Using Quality by Design (QbD)

in Designing Efficient, FDA Compliant

Pharmaceutical Manufacturing Processes
and Facilities

What is the Impact?

Russ Somma, Ph.D.

SommaTech, LLC

Andy Signore, PE, PMP–DBIA, CPIP

IPS - Integrated Project Services
Quality by Design and Operations
Outline
• What is QbD?

• How do QbD aspects effect pharmaceutical operations?

• Where will QbD principles provide value during facility design and
operation?

• What is the balance between product ,process, and facility using

QbD principles?

• What is the value realized in a QbD based business plan?

Quality by Design and Operations
Objectives

• To highlight aspects of the current industry and regulatory approach

for submitting NDAs using the principles of QbD.

• To extract aspects which directly effect facility and operational

issues.

• To understand how QbD may be used to establish a proactive

business plan for products, processes and the facilities.

• To use examples where facility design and product quality may

interact and suggest strategies for mitigation.
Quality by Design and Operations

We need to be clear about scope.

• The present climate looks upon QbD as an approach or option for

the filing of NDAs.

• Option is the operative word here.

• Many fail to leverage the opportunity to use aspects of QbD to focus

business and development plans.

Our discussion will guide you as thought leaders to better understand this scope.
Quality by Design and Operations

The Desired State: A Mutual Goal of Industry and Regulators, Janet

Woodcock, M.D. ISPE Annual Meeting November 7,2005

“A maximally efficient, agile, flexible pharmaceutical

manufacturing sector that reliably produces high-quality drug
products without extensive regulatory oversight.”
Quality by Design and Operations

Pharmaceutical Manufacturing in the 21st Century – An FDA

Perspective, Moheb Nasr,Ph.D. ISPE Annual Meet November 2006

“The desired state will be realized upon the implementation of QbD

to product & process design/development and establishing robust
QS.”
Quality by Design and Operations
FDA has taken action to realize these goals. The list below identifies
the steps and provides a chronology of the current trend toward
QbD.

• CGMP for the 21st Century

• ICH New Vision and Quality Strategy
• Quality by Design (QbD)
• Pharmaceutical Development (Q8)
• Quality Risk Management (Q9)
• Pharmaceutical Quality Systems
• Pharmaceutical Quality Systems (Q10)
Quality by Design and Operations
Related Regulatory Guidance

Q8 Pharmaceutical Development
• Collecting the knowledge
Facility needed
Operation Q9 Risk Management
QbD Based • Application to our needs
using the knowledge.
Q10 The Enablers
• The maintenance of our
Pharm. Quality Risk Pharm. product, process and
Dev. (Q8) Management Quality facility through the
(Q9) Systems lifecycle of the product.
(Q10)
Quality by Design and Operations
What does FDA see as the benefits of QbD?

• Quality by Design provides increased assurance of product quality

• Design Space captures process understanding for operational
implementation
• Design space is an important part of the product Quality Control
Strategy
• A full presentation of design space includes discussion of CQAs,
input parameters, and linkage between them
• Design Space information should be included in submission
• Quality Risk Management is critical in development of the product
Quality Control Strategy
Quality by Design and Operations
What does this mean for Industry as benefits of QbD?
• Good for business
• Greater supply chain reliability and predictability drives down cost
of goods
• Innovation and improvement encourage the use of new
technologies which accelerate change and enable a proactive
product lifecycle marketing plan.
• Opportunities for doing more for less, this makes us work smarter
• Better defined processes lead to better facilities
• Good for the patient
• Improved product reliability and reproducibility
• Better priced products and enhanced availability
• Newer therapies available sooner
Quality by Design and Operations

What are some of the barriers seen by Industry for using aspects of
QbD?

•Questionable payback
• There will not be much regulatory flexibility given
• Significant amounts of data shared in the filing
• No clear pathway is provided for a filing
•Expensive
• Significant investment early in development
• Products may not make it to market launch
• Seems to be driven as a large company initiative
Quality by Design and Operations

What are the opportunities for industry for using aspects of QbD?

We make our own opportunities. Take an inventory of what we

have in place already to Define Our Quality Analysis and Design
Space?
• Drug substance specifications which include physicochemical
properties.
• Drug product specifications as well as basic knowledge of
excipient interactions and process understanding.
• Raw material characteristics and variability.
• The envisioned facility design, capacity needs through the life
cycle.
• Target product profile, “desired state”.
• Stability of clinical forms / prototype as well as drug substance.
Quality by Design and Operations
Were we working under the delusion of Quality by Accident before?

Components which are needed to address a conventional review

dialogue are fundamentally those needed for a QbD NDA.
• An understanding of the product and process in terms of
fundamental, mechanistic properties as opposed to empirical.
• Utilization of prior knowledge in defining product, process and
facility.
• Facility designed to accommodate the product’s lifecycle.

These are now termed the design space under the QbD approach.

So ask yourself aren’t these data which we leverage routinely?

If we work smarter than we can answer these questions within our
current business model thereby reducing cost and shorten time to
market.
Quality by Design and Operations
Small start ups have used aspects of QbD to work smarter,
move faster and achieve goals.
 Quality by Design and Operations

We have used the precepts of QbD effectively in a range of situations.

These examples vary from biotech to medical devices. They all share a
similar vision speed to market, cost reduction and flexibility.

• Small biotech firm conducting a knowledge inventory / design space

as they approach submission of a novel delivery system for a vaccine.
• Start up molecular design / discovery firm looking to develop a early
stage CMC package with the required “curb appeal” for potential
partners.
• Large scale device manufacturer looking toward seamless reviews
and cost reduction as they enter the combination product market
place.
Quality by Design and Operations
From a facility and operational view we may focus on these
aspects.
•Formulation
• Process
• “Processability”
• Scale-up
•Materials
• Equipment
• Environment
• Technology Transfer
• Assessment of Primary Packaging
• Bulk Holding Times
• Facility impact on Process and Product
 Quality by Design and Operations
What do we know?
“In the normal course of development we create a knowledge
base. We need to understand where it is.”

• Components which are needed to address a review dialogue

are fundamentally those needed for determining facility
requirements.
• In conducting the clinical trails a significant amount of product
and process knowledge is gathered.
• These data must provide an understanding of the product and
process in terms of fundamental, mechanistic properties as
opposed to empirical.
• Utilization of prior knowledge in defining the product, process
and facility.
The key business driver here is our focus on Product Lifecycle.
Quality by Design and Operations
QbD and Facility Costs / Investments / Operation

As we increase: Then we realize:

1. Flexibility 1. Increase investment costs

2. Speed to market 2. Captured opportunities

3. Better defined process 3. Increased risk management

4. Cost of Goods 4. Enhance engineered

systems
Quality by Design and Operations
Knowledge may be categorized into several areas which we need to
manage during development.
• Incremental knowledge is a result of ongoing activities and grows
with each development project.
• Tacit knowledge or “sticky knowledge” can not be communicated
in a formal, systematic or codified language. “Commonly referred
to as a feel for the process”.
• Explicit knowledge may be set down in procedures and easily
codified.

Explicit knowledge is cost effective and transferable.

• It produces a well defined set of core technologies.
• It speeds development and process introduction.
• We deal with explicit knowledge daily. It is the basis of our work
(robust formulations, meaningful specifications, facility design).
 Quality by Design and Operations
So how would we get to the desired state and assure growth of
organizational knowledge?
• Select broad based topics which will drive the collection of
knowledge.
• Begin to form constructs within these topic areas which begin
to answer the big questions of
• What is needed in a submission?
• What will the facility provide in terms of flexibility?
• What is needed to release a product?
• What is needed to manufacture a product?
• What will be our capacity needs over the product lifecycle?
• What is needed to control a product?
• What would be needed to manage post approval
submissions?
 Quality by Design and Operations
Step 1 What knowledge do we have to shape these areas?
• Scientific elements to be considered and explored for potential
product attributes and process parameters.
• Prior knowledge across multi-disciplines and therapeutic areas that
may impact product attributes or process parameters.
• We can begin to define our knowledge area and understand what is
critical to our product.

Step 2 Refine the knowledge so we can make a product.

• We apply risk assessment and experimental design to form a space
within which we know we can make a product.

Step 3 Control the product and process to deliver consistent

results.
• Application of process understanding, engineering, equipment ,
process controls and facility requirements.
Quality by Design and Operations

A graphical representation of these interdependencies:

Knowledge Space

Design Space

Control Strategy
Quality by Design and Operations
What Are The Components of QbD?
Quality by Design
• A systematic approach of building desirable quality by careful
evaluation of all attributes that characterize quality from early
development through the product life cycle.
• Assure identity, purity, quality, and potency as it relates to
efficacy. Patients are our focus here.
Pharmaceutical Development
• Compiled information on studies conducted to establish that
the dosage form, formulation, process and quality attributes
are appropriate.
• It should describe the formulation and process critical
parameters (attributes) as well as supportive requirements
which in our case are facility operation and design.
 Quality by Design and Operations
What Are The Components of QbD?
Knowledge Space
• Scientific elements to be considered and explored for potential
product attributes and process parameters.
• Includes prior knowledge across multi-disciplines and therapeutic
areas that may impact product attributes or process parameters.
• Implications for facility requirements start here.
Design Space
• Region that encompasses combinations of product formulation,
manufacturing process, manufacturing operating parameters and raw
material quality.
• Application to the process environment and facility.
Control Strategy
• Region that encompasses process operating parameters and raw
material quality measurements.
• Engineering controls and monitoring for facility space and process.
Quality by Design and Operations
What is Design Space?
The definition varies based on which reference is used. The two most widely
accepted are:
ICH – Q8 (Product Development)
• Design Space: The established range of process parameters that has been
demonstrated to provide assurance of quality. In some cases design space
can also be applicable to formulation attributes. Working within the design
space is not generally considered a change of the approved ranges for
process parameters and formulation attributes. Movement out of the design
space is considered to be a change and would normally initiate a regulatory
post approval change process.
ASTM
• Design Space: The multi-dimensional region which encompasses the
various combinations of product design, manufacturing process design,
manufacturing process operating parameters and raw material quality which
produce material of suitable (defined) quality.
Quality by Design and Operations
What is Design Space?
• The key difference between these two definitions is that ICH-
Q8,which is the pharmaceutical development aspects also includes
a regulatory dimension.

• In practice, the regulatory aspect may best be addressed in

discussions with individual Health Authorities on a project by project
level.

• Our approach has been to take the design space and overlay the
business needs and using risk management for the product
determine the best strategy which will permit a reasonable degree
of flexibility within the defined area.
 Quality by Design and Operations
The requirement for a “Design Review” is another
connection with the aspects of QbD. This brings into play a
proactive understanding of facility operation.

• Design review will confirm that fundamental requirements are

incorporated in the overall facility plan.
• Design is an essential compliance process element.
• Functional requirements
• Critical systems
• Critical challenges
• Engineering change management
Quality by Design and Operations
What is Critical? Critical is a function of Risk

• Critical: A process step, process condition, test requirement, or

other relevant parameter or item that must be controlled within
predetermined criteria to ensure that the resulting API [or Drug
Product] meets its quality specifications. (ICH Q7A)
• Critical: Any feature or functional attribute, property or characteristic
of a drug substance, component, drug product or device and/or any
process attribute, parameter, condition or factor that has a direct or
indirect impact on:
• Patient Safety
• Therapeutic Efficacy
• In vivo Pharmacokinetic & Pharmacodynamic Performance
• Product Manufacturing
Quality by Design and Operations
What is a Critical? Critical is a function of Risk

• Critical Quality Attribute: A quantifiable property of an intermediate

or final product that is considered critical for establishing the
intended purity, efficacy, and safety of the product. That is, the
property must be within a predetermined range to ensure final
product quality. (PQRI Robustness Paper)
• Critical Process Parameter: A process input that, when varied
beyond a limited range, has a direct and significant influence on a
CQA. (PQRI Robustness Paper)
• The primary assessment and designation of critical should be made
relative to impact to safety and efficacy of the drug product to the
patient.
Quality by Design and Operations
QbD and Essential Facility Design Concepts
Good Engineering Practices and Compliant GMP Designs

Facility Design Essentials:

1.Control Zones
• Levels of protection
2.Critical Flows
• People, materials and utensils
• HVAC / cross contamination
3.Critical Process Elements
• Unit operations
• Parameters
• Components / controls
4.Utility Systems
• Direct Impact
• Indirect Impact / No impact
Quality by Design and Operations
Key Points for Risk Aspects
One aspect which must be made clear is the need defined by ICH-Q9
(Risk Management) concerning risk. Our experience is that a sponsor
must work toward a system which is based on Risk Knowledge or
“What If” Aspects.

This has two components

• Risk Assessment
• Risk Control

The path to achieve this goal must be to leverage product

and process knowledge. This task, knowledge management, may be
seen as an enabler of all the functions and may best be dealt with in a
well defined Quality System.
Quality by Design and Operations
Key Points for Risk Aspects

Risk assessment is fundamental to the delineation of critical in the

evaluation of process dimensions and development of design space.
• Risk should be assessed based on cause and effect and relative to
the following criteria:
• Probability – the likelihood of a consequence.
• Severity – the magnitude of the impact of a consequence.
• Detectability – the level or ability at which a consequence can be
measured.
• Sensitivity – the attenuation of interactions between multivariate
dimensions.
Quality by Design and Operations
Quality by Design and Operations

So ask yourself:

“When we begin to define facility needs and required capacity

did we have all these aspects covered?”
Quality by Design and Operations
Consider these questions we should be asking development. If
answered upfront they have a significant effect on the facility and
position us for success.

• What properties of the drug substance effect product performance?

• What is the formulation intended to do?
• What are the special requirements of the drug substance and drug
product?
• How do we define the critical process steps?
• What are the process parameters for each step and how are they
monitored and controlled?
• What must we design into the facility in order to assure we meet
critical quality attributes of the product?
Quality by Design and Operations

The manner in which we answer these questions and

allocate risk greatly effect our business plan and cost
of the process and / or the facility.

Let’s consider some examples of a few realistic

balancing acts.
Quality by Design and Operations
Quality by Design and Operations
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Quality by Design and Operations

We can see that new technology allows us to place all or part of the
facility requirements within the process itself.

• This must be looked at as a balance between the cost of the

equipment, the development time and multi-use options and
flexibility.
• The use of knowledge and design space allows us to create a
business and development plan to address the entire product
lifecycle.
• Application of control strategy allows us to balance the aspects of
facility against those of the process.
Summary
• The development aspects needed to support a QbD submission are
very similar to those which are key to design of a cost effective
facility and process.
• These are complicated and challenging to implement using internal
resources combined with external expertise make a effective team.
• Systematic data updates provide a means to leverage key CMC
aspects of our submission.
• Answering questions along the way prevents the “fishing expedition”
and delay.
• Clear path to where we see the product in its lifecycle allow
proactive rather than reactive post approval submissions strategies
with regard to facility and process.
• We have the majority of the data available but need to configure it to
defend our product, facility, and process.
Summary
• The systems to achieve this have been effectively applied to
existing business models.
• With product knowledge we are positioned for success and to deal
with QbD NDAs and facility requirements.
• New technologies exist which may move some of the risk from the
facility to the process.
• There are technologies which allow the lab experience to be
transferred directly into manufacture eliminating the scale-up issue
and permitting the lower risk based scale-out scenario.
• Based on the drug substance properties entire trains of unit
operations may be replaced by one highly advanced system.
• Know what you do not know.
References
• O. Gasmann, M. Zedtwitz, R&D Management, 3, 147 (1998)
• W.B. Werther, E. Berman, Organizational Dynamics, 3, 20 (1994)
• R. Kieffer, L. Torbeck, Pharmaceutical Technology, 6, 66 (1998)
• J. Butler, The Pharmaceutical Journal, 1, 31 (1999)
• Guide to Inspection of Solid Dosage Forms Pre/Post Approval Issues
for Development and Validation, Issued January, 1994
• R.Somma, “Using Technology Transfer to Maximize Business
Efficiency” Pharm. Eng. 27,5 (2007)
• P. J. von Dochren, R. St. John Forbes and C. D. Shively, Pharm
Tech, 6, 139 (1982)
• R. Somma, The Research-Production Interface, AAPS Annual
Meeting, 1999
• “Pharmaceutical Process Scale-Up” M. Levin, Marcel Dekker, Inc.,
2002, New York
References (cont’d.)
• “Pharmaceutical Process Validation” R.A. Nash, A.H. Wachter,
Marcel Dekker, Inc., 2003, New York
• R.Somma, “Development Knowledge Can Increase Manufacturing
Capability and Facilitate Quality by Design” J.Pharm. Innov. 2, 87-92
(2007)
• ICH Q8, Pharmaceutical Development, Draft 1, No.3, October 25,
2005.
• QbD Principles to be Implemented in Future FDA Guidance, DIA
Dispatch, Oct. 28, 2005.
• R.Somma, “PQLI Conference Summation” ISPE PQLI Conference,
Arlington,VA, June 7, 2007
• C.Potter, “QbD Now”, ISPE PQLI Conference, Arlington,VA, June 7,
2007
• A.H.Kibbe, Process and Analytical Validation Working Group, June,
2002
References (cont’d.)
• A.S. Hussain, The Subcommittee on Process Analytical
Technologies (PAT): Opening Remarks, June, 2002
• ISPE Good Practice Guide, Technology Transfer,ISPE, Tampa, FL,
2003
• J. Spavins, “Design Space Summation” ISPE PQLI Conference,
Arlington, VA, June 7, 2007
• T. Shultz, “Critical vs. Non-Critical Summation” ISPE PQLI
Conference, Arlington, VA, June 7, 2007
• B.Davis, “Control Strategy Summation” ISPE PQLI Conference,
Arlington, VA, June 7, 2007
• G. Migliaccio, Manufacturing Science, June, 2002
• “Good Design Practices for GMP Pharmaceutical Facilities”, T.
Jacobs, A. Signore and E. Bohn, Taylor and Francis Group, 2005,
New York
 Quality by Design and Operations

Contact Information

Russ Somma, Ph.D. Andy Signore, PE, PMP-DBIA, CPIP

SommaTech, LLC IPS
3 Executive Drive 2001 Joshua Road
Somerset, NJ 08873 Lafayette Hill, PA 19444
732-748-1990 x203
610-828-4090
rsomma@sommatechconsulting.com
asignore@ipsdb.com

The reference list is available by e mail to rsomma@sommatechconsulting.com