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From Proven Acceptable
Ranges to Design Space
BY TIM FIELDS
❖
INTRODUCTION
International Conference on Harmonization (ICH)
Q8, Pharmaceutical Development1 was finalized in November 2005 and introduced the concept of “Design
Space.” The idea of defining criteria within which one
must control a process to ensure that a quality product is
produced is not a new concept. The late Ken Chapman
proposed the precursor to the design space concept two
decades earlier when he introduced the idea of Proven
Acceptable Ranges or the PAR Approach2 to process validation. The PAR Approach and Design Space are based
on the same principle, that is, quality must be built into
the product, it cannot be tested in. Design Space and the
PAR Approach also emphasize the importance of the
product lifecycle and the process and product knowledge
gained through research and process development.
BACKGROUND
The 1987 FDA, “Guideline on the General Principles
of Process Validation”3 defines process validation as:
“establishing documented evidence which
provides a high degree of assurance that a
specific process will consistently produce a
product meeting its predetermined specifications and quality attributes.”
The PAR Approach focuses on defining the critical
process parameters and the ranges within which they
must be controlled to ensure that the product meets it predetermined quality attributes. The Design Space, on the
other hand, focuses on defining multiple critical elements
of the process, including the critical process parameters,
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which when properly controlled, will ensure that a product meeting its predetermined specifications and quality
attributes is produced.
Chapman proposed the PAR Approach while the FDA
was in the process of drafting the guidelines on process
validation. One concern about the early draft guide was
the use of the terms “worst case” and “edge-of-failure.”
At the time, worst case appeared to be an ambiguous
term, which had multiple interpretations, including:
stress testing, upper and lower PAR limits, upper and
lower operating limits, upper and lower control limits,
and edge-of-failure. The term edge-of-failure appeared to
be a better understood term, meaning that exceeding the
edge-of-failure would result in an adverse event. Although knowing the edge-of-failure for a process parameter may be useful in some cases, its relevance to
process validation is questionable. Establishing the
Proven Acceptable Range or PAR of a process is more
relevant to process validation. The objective of the PAR
Approach is to gather documented evidence (proven acceptable) that supported the upper and lower limits
(range) within which a critical process parameter is to be
controlled to ensure that the product meets its pre-defined
specifications.
The Design Space concept grew out of the ICH Q8
Guideline on Pharmaceutical Development, which focused on using good science and experience to design a
quality product and manufacturing process that would
consistently result in a quality product. The knowledge
gained during process development is used to define the
Design Space for the product. The Design Space can then
be used to establish specifications for materials and to set
process control limits.
While the PAR Approach tends to be two-dimensional
(i.e., critical process parameters and their effect on qual-
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Tim Fields
Figure 1.
The PAR and Design Space Approaches Compared
Raw materials properties
Environmental factors
Processing conditions
High
Low
Design Space
PAR Approach
ity attributes), Design Space, as the name implies, examines multiple aspects of the process (Figure 1). The PAR
Approach examines the effects of altering one parameter
at a time (e.g., adjust tablet hardness and look at the effect on friability or dissolution). Design Space relies on
multi-variant Design of Experiments to look at a number
of variables and their effect on the product. Chapman recognized that there were situations when more than one
variable could affect an attribute or that multiple variables acting together could exacerbate the effect on a
quality attribute. In his 1984 paper on the PAR Approach,
Chapman indicated that notations should be made when
such information was known.
The PAR Approach involves the examination of data
obtained during development, when possible, to support
the critical process parameter ranges. Using lab scale experiments, if possible, or product knowledge, the probable adverse consequences of exceeding the established
ranges are determined. Each critical step is evaluated to
determine the effect that the potential critical process parameters have on the quality attributes. If the proven acceptable ranges are exceeded, one uses knowledge from
the experimental studies to test for the occurrence of
probable adverse consequence. For example, if the development data supported tablet compression settings of 8 to
12, and the probable adverse consequence of exceeding
the range on the low end is poor friability, and exceeding
the range on the upper end is poor dissolution profile,
then when the range is exceeded, the friability or dissolution would be examined, respectively. If the probable adverse event did not occur, the range could be broadened
based on this new Proven Acceptable Range.
Design Space uses the knowledge gained during development and manufacturing experience to provide a
scientific understanding of the interactions of the multiple variables that may be involved in a process including
the process parameters, materials, equipment, and environmental conditions.
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Today, science, technology, and knowledge allow for
a more thorough understanding of the process and the
variables that affect it than were available when Chapman
proposed the PAR Approach. For example, using the
PAR Approach, if one only examined the tablet machine
compression settings to determine the effect on tablet
hardness, then the impact of particle size might be overlooked. Design Space would include consideration of
multiple variables on the process and the product.
To ensure that a process remains in control, a pyramiding approach is often used to set normal operating parameter control limits within the PAR or Design Space
limits. If the difference between the PAR for a process
parameter and the normal operating range is wide, then
the process is robust, because it allows for wide variation
with no effect on the product quality.
The PAR Approach and Design Space concept for
process validation require knowledge to be captured and
retained about the process and the effects that critical
process variables have on the process. Both concepts are
based on a product lifecycle starting with the process development and continuing until the process is retired.
Both concepts advocate the use of small scale lab studies,
when possible, to support the processing parameters and
quality attributes.
RELATIONSHIP WITH OTHER
GUIDELINES
The Design Space concept and The PAR Approach
align well with and rely on compliance with ICH Q9,
Quality Risk Management4, and the FDA Quality System
Guidance Document5.
Using the PAR Approach or the Design Space concepts are only part of process validation. To ensure that a
process is validated also requires that a Quality System
be in place. A good Quality System ensures appropriate
controls over personnel, equipment, facilities, procedures, documentation, deviation investigations and corrections, and change control.
Both the PAR Approach and Design Space also fit
well with a Risk Based Approach to process validation
by providing the documented evidence that supports riskbased decisions regarding the impact of process deviations. In addition to using the knowledge from the PAR
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Approach or Design Space concept to support risk-based
decisions, risk assessment tools and processes can also be
used to identify the critical steps in a process, the critical
process parameters, and the critical quality attributes of
the product.
Chapman recommended that in-process control data
be recorded in addition to the critical operating parameters because such information could be used in making
process-related decisions. In today's regulatory environment, such data can be used to implement Process Analytical Technology (PAT) or continuous process
verification to monitor and control processes. In a similar
manner, Design Space concepts lead to the identification
of key control points (i.e., in-process controls) that can
also be implemented using PAT or continuous process
verification.
The knowledge of the process and the affects of
changes within the PAR and Design Space allow for variation within PAR or the Design Space, and therefore,
should be documented and handled appropriately within
the company without the need for initiating a regulatory
post-approval change.
LIFECYCLE APPROACH
While both the PAR Approach and Design Space are
useful methods for providing documented evidence that
supports the critical process parameter ranges and control
points, it is important to remember that process validation
does not end there. Data must be collected to provide evidence that the process is reproducible and robust. Data
must continually be reviewed for impact on PAR or the
Design Space. As previously mentioned, process variability within the PAR or Design Space should not require regulatory review, however, when exceeding the
PAR or Design Space, evidence of the effects on the validated process must be documented and the PAR or Design Space appropriately revised.
CONCLUSION
The PAR Approach can certainly be viewed as a precursor to Quality by Design and Design Space concepts.
The PAR Approach is two-dimensional, while Design
Space is multi-variant. The PAR Approach is somewhat
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retrospective in that it evaluates data to establish the
Proven Acceptable Ranges, while Design Space is more
prospective in using scientific knowledge to establish
control parameters. There appears to be a greater need for
the application of scientific knowledge involved in the
use of Design Space than needed for the PAR Approach.
Design Space is based on the plan or conception of the
process, while the PAR Approach is based more on
demonstrating the verified, established limits in a given
process.The PAR Approach and Design Space are similar concepts focused on ensuring product quality is designed into the product using good science and product
and process knowledge. Both concepts focus on a lifecycle approach to gain knowledge to improve drug product
quality. The process and product knowledge gained from
these two approaches provide for a better understanding
of the impact of process variability on a product.
With continuing increases in technology and efforts to
find new, better, and cheaper ways of validating
processes, it is likely that Design Space will eventually
lay the foundation for a new approach much as Chapman's PAR Approach laid the foundation for Design
Space. ❏
ABOUT THE AUTHOR
Tim Fields is the President of Drumbeat Dimensions,
Inc. (DBD), a professional compliance management
company located in Mystic, CT, which provides products
and services designed to help firms assess and enhance
their regulatory compliance. Mr. Fields has over 22 years
of experience in the pharmaceutical industry including 13
years with Pfizer where he was responsible for organizing and managing the corporate software quality assurance audit program.
Tim is a member of the Editorial Advisory Board for
the Journal of GXP Compliance as well as a member of
the International Society of Pharmaceutical Engineers
(ISPE), Parenteral Drug Association (PDA), and GAMP
Americas Manufacturing Execution Systems (MES) Special Interest Group. He has published and lectured worldwide on computer-related system validation, electronic
signatures and records, and document management. He
can be reached by telephone at 860-572-7255, or by
email at:Tim_Fields@drumkey.com
REFERENCES
1. International Conference on Harmonization. “ICH Q8,
Pharmaceutical Development,” ICH, November 2005.
2. Chapman, K.G., “The PAR Approach to Process Validation,”
Pharmaceutical Technology, 8 (12), 22-36 (1984).
3. FDA, “Guideline on General Principles of Process Validation,” Final. May 1987.
4. International Conference on Harmonization, “ICH Q9,
Quality Risk Management,” Federal Register 70 (151),
45722-45723 (August 8, 2005).
5. U.S. Food and Drug Administration, “Guidance for Industry;
Quality Systems Approach to Pharmaceutical Current Good
Article Acronym Listing
Manufacturing Practice Regulations,” FDA, September
2006.
6. U.S. Food and Drug Administration, “Pharmaceutical
cGMPs for the 21st Century - A Risk Based Approach,”
FDA, August 2002.
FDA
Food and Drug Administration
ICH
International Conference on Harmonization
PAR
Proven Acceptable Range
PAT
Process Analytical Technology
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