Innovation and
Continuous Improvement in Pharmaceutical Manufacturing
Pharmaceutical
CGMPs for the 21st Century
The PAT Team and Manufacturing
Science Working Group Report: A Summary of Learning, Contributions and Proposed
Next Steps for Moving towards the "Desired State" of Pharmaceutical
Manufacturing in the 21st Century
Executive Summary
The health of our citizens depends on the availability of safe, effective and affordable medicines. In the future, pharmaceutical manufacturing will need to employ innovation, cutting edge scientific and engineering knowledge, and the best principles of quality management to respond to the challenges of new discoveries (e.g., complex drug delivery systems and nanotechnology) and ways of doing business such as individualized therapies or genetically tailored treatments.
"Pharmaceutical cGMPs for the 21st Century" was
intended to enhance and modernize the regulation of pharmaceutical
manufacturing and product quality. This report provides an overview of the PAT Team's and
Manufacturing Science Working Group's collaborative efforts, accomplishments,
and points to consider as the initiative moves into its next phase
(implementation and continuous improvement).
The FDA Science Board and
the Advisory Committee for Pharmaceutical Science (ACPS) discussions provided
information on the current state of pharmaceutical manufacturing, challenges
faced, and opportunities for improvement.
These
discussions are the primary basis of this report.
Pharmaceutical manufacturing operations are inefficient and costly. The cost of low efficiency is generally not understood or appreciated (e.g., manufacturing costs far exceed those for research and development operations). Low efficiency is predominantly due to "self-imposed" constraints in the system (e.g., static manufacturing processes, focus on testing as opposed to quality by design, approach to specifications based on discrete or the so called "zero tolerance" criteria, a less than optimal understanding of variability, etc.). These constraints keep the system in a corrective action mode.
Continuous improvement is an essential element in a modern quality system and it aims at improving efficiency by optimizing a process and eliminating wasted efforts in production. In the current system continuous improvement is difficult, if not impossible. Reducing variability provides a "win-win" opportunity from both public health and industry perspectives, therefore continuous improvement needs to be facilitated.
The PAT Team and the
Manufacturing Science Group cooperated internationally to develop a framework
to facilitate innovation, application of cutting edge scientific and
engineering knowledge, and the principles of modern quality management systems
in pharmaceutical manufacturing. A systems approach was adopted to
support the initiative's objectives and conform to its guiding principles. The "desired
state" for pharmaceutical manufacturing in the 21st Century was
articulated and international consensus established. A regulatory framework to support innovation
was developed and described in the PAT
Guidance document. The principles of
this framework are being incorporated into the emerging ICH guidance on Pharmaceutical Development (ICH
Q8).
Quality
by design and process understanding principles were used to develop a flexible
regulatory system to support innovation in the PAT Guidance. A team approach to CMC review and CGMP
inspections, a recognized best practice (e.g., Team Bio), was used to create
the PAT Team to provide appropriate risk coverage. Teambuilding and joint training processes were
successful in reducing organizational and communication barriers that existed
at the beginning of the initiative. Two
assignments, a PAT inspection and pre-operational site visit, have been successfully
completed by this team.
The
pharmaceutical community was asked take on the responsibility for developing
standards to support the introduction of innovative tools and technologies
under the PAT framework. The ASTM
International provided the process to develop these standards using technical
expertise in all relevant disciplines from the pharmaceutical community and
other industrial sectors. A significant
support infrastructure for the desired state is emerging in several academic
and scientific organizations and associations.
A second PAT team is planned and will include
CDER's Office of Biotechnology, Office of Compliance and ORA Team-Bio
representatives. Formation of the second
PAT Team will provide an additional opportunity to develop close collaboration
and cooperation between the PAT team and Team-Bio. Lessons learned from the PAT Team and Team-Bio
should also be utilized to identify best practices
and to develop recommendations for a broader team approach.
ICH Q8 will describe the suggested contents for
the 3.2.P.2 Pharmaceutical Development section of a regulatory submission in
the ICH M4 Common Technical Document (CTD) format. It is not intended to be a "how to"
guidance. It will provide sponsors of
drug applications an opportunity to present knowledge gained during development
of a product and its manufacturing process and relevant prior knowledge. It will indicate areas where the provision of
greater understanding of pharmaceutical and manufacturing sciences can create a
basis for flexible regulatory approaches to support continuous improvement.
The PAT framework and ICH Q8 will provide a
basis for risk mitigation. Risk management principles and tools being developed
under ICH Q9 will be necessary to describe and communicate the level of
risk-mitigation achieved through quality by design and process understanding.
Although
to a large degree consensus has been established on the "desired state,"
it is recognized that there is often a tendency for a consensus on collective
ends to attenuate when specifics are addressed. This is often due to divergent
understanding of the problem being addressed and/or differences in interests
and issues in representation of the problem being addressed.
Under the ACPS Manufacturing Subcommittee a
working group will be formed to identify specific steps needed to move towards
the desired state. The group will also
develop illustrative case studies to support the ICH Q8 document and CPG 7132c.08. ICH Q8 and illustrative examples should then
be a basis to develop the draft comparability guidance to facilitate continuous
improvements.
The combined work products of the CGMP
Initiative are positioned well to provide a comprehensive set of regulatory
tools to facilitate a move towards the desired state. Only companies that achieve a high level of
process understanding will have the opportunity to use their information to
justify a more flexible regulatory path towards continuous improvement. The proposed ICH Q10
should utilize these regulatory polices to provide additional guidance on
quality system for change control under CGMPs to facilitate continuous
improvement.
Significant
challenges lie ahead for the pharmaceutical community and for regulators to
move to the "desired state" for pharmaceutical manufacturing in the
21st century. Nevertheless, critically
important steps have already been taken.
1.
Introduction
Pharmaceuticals will have an increasingly
prominent role in the health care of the future. The health of our citizens depends on the
availability of safe, effective and affordable medicines. In the future, pharmaceutical manufacturing
will need to employ innovation, cutting edge scientific and engineering
knowledge, and the best principles of quality management to respond to the
challenges of new discoveries (e.g., complex drug delivery systems and
nanotechnology) and ways of doing business such as individualized therapies or
genetically tailored treatments.
Regulation of the future will also need to meet
these challenges, by incorporating new scientific information into regulatory
standards and policies. Both industry
and regulatory practices will need to be informed by the best techniques of
risk assessment and management. "Pharmaceutical cGMPs for the 21st
Century" is intended to enhance and modernize the regulation of
pharmaceutical manufacturing and product quality.
Under the CGMP Initiative
the PAT Team and the Manufacturing Science Group cooperated internationally to
develop a framework to facilitate innovation,
application of cutting edge scientific and engineering knowledge, and the
principles of modern quality management systems in pharmaceutical
manufacturing. This report provides an
overview of these collaborative efforts, accomplishments, and points to
consider as the initiative moves into its next phase (implementation and
continuous improvement).
1.1.Pharmaceutical Manufacturing: Challenges and
Opportunities
The FDA Science Board (1) and the Advisory
Committee for Pharmaceutical Science (2) discussions on the current state of
pharmaceutical manufacturing, challenges faced, and opportunities for
improvement are the primary basis of this report. Information gathered at several national and
international scientific workshops provided examples of scientific and
technological opportunities and afforded the opportunity to debate and develop a shared vision for the future. This vision is articulated as the
"desired state" for pharmaceutical manufacturing in the 21st
Century.
1.2.
A Regulatory Framework for Manufacturing Science: A
Systems Perspective
The PAT Initiative and the
PAT Team preceded the CGMP Initiative by about a year; subsequently, the PAT
Initiative became a part of the broader CGMP Initiative. Their efforts were directed towards developing
a regulatory framework to encourage the
early adoption of new technological advances by the pharmaceutical industry.
The Manufacturing Science Working
Group's efforts were directed towards enhancing manufacturing science knowledge
available to the agency to ensure that regulatory review and inspection policies are based on
state-of-the-art pharmaceutical science.
A systems
approach was adopted to ensure appropriate linkage and support for all
objectives of the CGMP Initiative; i.e., (1)
encourage the early adoption of new technological advances by the
pharmaceutical industry, (2) base regulatory review
and inspection policies on
state-of-the-art pharmaceutical science, (3)
facilitate industry application of modern quality management systems, (4) use risk-based approaches that focus both industry and agency
attention on critical areas; and (5)
incorporate enhanced quality system
approaches into the agency's business processes. Inspiration for a systems approach was derived
from the body of work by leaders in modern quality management such as Shewhart,
Deming, Juran,
Box, Taguchi, and others (3-6). This is
reflected in the "desired state" and the regulatory framework
described in the PAT Guidance
document. The principles of this
framework were presented to the ICH and these are being considered in the
emerging guidance on Pharmaceutical
Development (ICH Q8).
Continuous
improvement is an essential element in a modern quality system that aims at
improving efficiency by optimizing a process and eliminating wasted efforts in production. Improvement efforts are carried out in a
structured manner with appropriate pre-defined protocol and oversight. These efforts are primarily directed towards
reducing variability in process and product quality characteristics and are not
for changing the fundamental design of a manufacturing process (5). For continuous improvement products should
already be in compliance with their specifications and process improvement
steps (e.g., adjustment of process parameters, introduction of new equipment of
the same design,and operating principles with advanced
control options) should be within the
original "design space." That
is, such improvement steps are not considered as "changes" because
product quality and performance (e.g., bioavailability, shelf-life) are assured.
Generally
the term continuous
improvement is broadly used for all improvement efforts including corrective actions and the ensuing preventive actions. In the regulatory setting a distinction
between corrective action and continuous improvement is essential. Need for corrective actions occur when product
quality characteristics are in question (e.g., out of specification). Such a situation can require urgent risk
assessment and sound quality decisions to prevent any adverse impact on
patients.
Innovation is different from continuous
improvement since it is not a part of routine production operations and
requires significant investment of resources and may require changes in
production design and operation. Therefore, three types of improvement
approaches-- innovation, continuous improvement, and corrective actions-- are distinguished. These approaches and their roles in a quality
system are shown in Figure 1. The simple
phrases used in Figure 1 to describe a modern quality system were suggested by
the FDA's Quality System Working Group.
Some distinguishing characteristics of the three improvement approaches
and the contributions of the two groups are summarized in Table 1. A need for similar distinction between
improvement approaches was previously suggested in the automotive industry (7).
1.3.Format of this report
The report is organized
into six sections. The following section
(section 2) describes the "current state" and the "desired
state." The primary contributions
of the two groups are described in section 3, followed by "points to
consider" (section 4) and recommendations for other groups of the
initiative (section 5). The final
section (section 6) proposes next steps and identifies broad areas for research
and training under the Critical Path Initiative. Table 2 provides a summary of primary
accomplishments of the two groups within the context of the Initiative's five
guiding principles and objectives (dark shading). Contributions to, or impact on, other
objectives are outlined as "points to consider." Many of these "points to consider"
are based on some of the 14 points for a quality management system articulated
by Deming (3). In Table 2, current
and/or planned collaborations with other groups are based on the lessons
learned [ ]; recommendations for other groups in the initiative are identified
{ }. 
Figure 1: Types of
"improvement"
Table 1: Types of
improvement and their relation to the objectives of the FDA Initiatives
|
Improvement Approaches |
Characteristics and Objectives |
|
|
Innovation |
Primary
focus area of the PAT Team. Manufacturing
Science WG is contributing to harmonization of the PAT framework in ICH |
Revolutionary,
to be a leader Focused
applications - project based Significant
capital expenditure, ROI, Top-down Strong
research component Technical
experts involved New
findings and improved knowledge CGMP
Initiative Objective #1 |
|
Continuous Improvement |
PAT
Framework provides many options and opportunities including research data
collection in production. Manufacturing Science WG creating regulatory
flexibility through ICH Q8. |
Product
is in specification Acceptance
criteria - variable/continuous data Evolutionary,
incremental process optimization, continuous, daily activity Carried
out by plant and quality staff CGMP
Initiative Objective #1-5 |
|
Corrective Actions |
PAT
opens the door for new tools for root cause investigations and data
collection in production. Manufacturing
Science provides the foundation for more effective approaches. |
Product
is out of specification (OOS) or
Procedural deviations "Crisis"
- immediate action needed Required
by regulators CGMP
Initiative Objectives: #1-5 |
Table 2. Report of the of the FDA's CGMP for the 21st
Century Initiative's PAT Team and the Manufacturing Science Working Group Current and/or planned collaborations with other groups, based on
lessons learned are shown in [ ]; recommendations for other groups in the
initiative are identified in{ }. |
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2.
The "
2.1.
The "
Pharmaceutical
manufacturing operations are inefficient and costly. Compared to other industrial sectors, the rate
of introduction of modern engineering process design principles, new
measurement and control technologies, and knowledge management systems is low. Opportunities for improving efficiency and
quality assurance through an improved focus on design and control, from an
engineering perspective, are not generally well recognized. For example, when discussions at the FDA
Science Board and Advisory Committee for Pharmaceutical Science shed light on
the current low efficiency and its cost implications (e.g., costs associated
with manufacturing can far exceed those for research and development operations
in innovator pharmaceutical firms) many at FDA had difficulty understanding
this and common reactions were "how could this be possible?" or "this
can't be true."
Discussion
of the current state by major publications such as The Economist (8), the Wall
Street Journal (9) and the Business Week (10) add to a growing awareness of a
need for improvement. An excellent
analysis of the current state of manufacturing process innovation in
pharmaceutical and biotechnology industry was described in 1996 by Pisano (11).
Over
the last decade a mind-set has evolved among many pharmaceutical business
leaders and others that manufacturing is no longer a necessary "strategic
competency." This view probably
contributes to the general lack of private and public support for fundamental
science and process innovation and to the perception that manufacturing is a
"step-child" in this industry.
Efficient manufacturing process can reduce manufacturing costs, and this
itself can be a significant competitive advantage. Effective and efficient process development
contributes more towards a company's ability to accelerate time to market, ramp
up production rapidly, enhance customer acceptance of new products, and develop
a stronger proprietary position (11).
The
public health objectives and the competitive power of new product development
are well recognized. Development of new
more efficient and effective manufacturing process technology often fails to
generate any excitement among academics, practitioners and the public at large;
since these groups often only come in contact with innovative products and not
with the manufacturing process that delivers these products. A recent estimate of potential world-wide
cost-savings from efficiency improvement is suggested to be as high as US $ 90
billon (12). This would be equivalent to
the current cost of developing 80-90 new drugs every year. A rigorous economic analysis to obtain robust
estimates of cost savings may help to put an end to the lingering question -
"how could this be possible?" - and to fully
engage the pharmaceutical community for developing approaches to realize the
potential "win-win" opportunities.
Quality
and productivity improvement share a common element - reduction in variability
through process understanding. Reducing
variability provides a "win-win" opportunity from both public health
and industry perspectives. And, since
pharmaceutical product manufacturing technologies and practices are generally
similar between both innovator and generic companies, facilitating efficiency
improvements provide opportunities for both sectors of the pharmaceutical
industry. An efficient and secure
2.2.
Low
efficiency: Contributing factors
Often
it is suggested that regulatory policies and practices contribute to the
current low efficiency. Regulators and
many in manufacturing operations express their frustration by suggesting that
manufacturing is a "step-child" in this industry, and that there is
no economic motivation (e.g., cost and price difference) for improvement. Other suggestions include a general lack of
systems perspective, organizational barriers that inhibit exchange of
knowledge, and the attitude that much of pharmaceutical formulation and process
development is an "art." Some
in pharmaceutical development suggest that there are very limited opportunities
("development time crunch") to realize and/or demonstrate the level
of science underlying current formulation and process development efforts (13).
Clearly these are complex and
interrelated issues. Only regulatory and
scientific challenges are discussed in the following sections.
Discussions
at FDA Science Board and Advisory Committee meetings, scientific workshops and
conferences identified the following major contributing factors:
§
Routine pharmaceutical production is conducted by running a plant at
rigidly defined operating conditions described in Standard Operating Procedures
(SOP's). A regulatory submission may
contain limited information (e.g., manufacturing process and parameters used
for bio-batch manufacturing and its executed batch record) and these conditions
then become regulatory commitments. Plant operators are then expected to always
reproduce exactly these same set of conditions.
During routine production adherence to conditions in SOP's and
laboratory evaluation of in-process and final product characteristics provide
assurance that products produced will have the safety and efficacy profile
outlined in the approved product label. This type of operation may be considered a
"static manufacturing operation." Because it is based on limited data, any change
generally requires regulatory notification and in many cases prior approval.
§
Static manufacturing can
create, or is a result of, a mind-set that “the product is approved and
validated - do not change.”
§
Process control is
predominantly based on documented evidence of conformance to SOP's, which
generally include a “fixed process time” and laboratory based testing of
in-process materials.
o This approach requires a high level of control on incoming raw material
characteristics.
o Physical characteristics of pharmaceutical materials (e.g., excipients),
as related to their functionality in process,
are not well understood.
§
Deviations from established
standard operating procedures and out of specification (OOS) observations can
occur frequently.
o OOS investigations that follow take significant (time) resources and
have a low rate of success in finding permanent corrective and preventive
solutions.
o Often batches have to be rejected (internal failure) due to an inability
to document quality assurance.
§
Variability and/or
uncertainty in a measurement system for physical characteristics such as
particle size and dissolution can pose significant challenges when OOS results
are observed.
§
Acceptable quality
characteristics, or specifications, are generally described in terms of
discrete or attribute data (e.g., pass/fail; or no unit outside 75-125%) and
are inappropriately referred to as "zero defect or tolerance" (since
these are for the sample tested).
o The OOS rate can increase with increasing test sample size; investigations
to identify sources of variability (beyond available information in batch
records) and robust estimates of variability are difficult and discouraged
(since increasing sample size increases the risk of OOS).
o It is difficult to differentiate inherent or natural variability (or
common cause variability) from variability due to special causes.
§
Information needed for
process improvement can be in a different organization and often not available
at the right time.
2.3.
Continuous
improvement needs higher level of process understanding
When OOS results are observed there are few, if any, means to re-examine
the fundamental design aspects of a product/process and/or to evaluate the
(clinical) relevance of established specification (quality by design). In production, the focus is predominantly
limited to "quality of conformance." In terms of risk to conformance; quality is inversely proportional to
variability and quality improvement efforts are directed towards reducing
variability (14). Determining corrective and preventive
actions without a sound understanding of sources of variability, and robust
estimates of variability, are difficult. And, in the absence of good information,
attempts to adjust a process can potentially create new problems. Since continuous improvement can only occur
when a product is already in compliance, considering the challenges identified
above (e.g., "zero tolerance," variability and/or uncertainty in
measurement systems, etc.), continuous improvement is difficult (if not impossible)
in the current state.
§
Lack of information and
knowledge creates an uncertain environment that precludes risk-based decisions.
o Static manufacturing processes and reliance on laboratory testing as a
means for control are, in part, a result of insufficient information available
during the CMC review process. In the
absence of an adequate level of process understanding, specifications have to
be established without adequate knowledge of variability in the clinical trial
products and its clinical relevance.
§
Measurement system
variability can be a significant part of total variability.
o Estimates of process variability are based on measurement of variability
in quality characteristics of in-process materials and products. The measurement system (sampling, sample
preparation, analytical method, operator training, etc.) then is the "lens through which we observe a
process" and its variability can contribute to OOS observations and
can be the limit to which we can observe and/or improve a manufacturing
process.
o Over the last three decades tremendous progress has been made in
analytical chemistry and variability in chemical methods has been reduced
dramatically. The situation is quite
different for methods used to measure physical characteristics.
o Currently, significant challenges exist for managing variability in
sampling and sample preparation (e.g., for blend uniformity and particle size
testing), and analytical instruments for physical characteristics such as
dissolution and particle size.
§
Current tests are generally
destructive (i.e., sample is altered or destroyed) and robust estimates of
measurement system variability (all aspects of the procedure including the
operators) are difficult to obtain without using methods such as Gauge R&R
- reproducibility and repeatability (14). Suitability of current methods then is based
on calibration using a calibrator system that has its own built-in variability
and other assumptions (e.g., in physical testing such characteristics as size,
shape, density can alter aerodynamic and/or hydrodynamic behaviour of materials
in a test system and contribute to systems variability).
o In the absence of robust estimates of measurement system variability and
with the inability to verify the inherent assumptions in a measurement system,
attempts at improving a manufacturing process can be difficult and, if
attempted, can potentially create new problems (e.g., in case of common cause
variability, process adjustments can make a system unstable) (3).
§
The term "in-process testing"
is synonymous with "process control." From an engineering perspective tests at the
end of a process do not provide any direct means to keep a process under
"control." It is well
recognized that such tests "simply
accept or reject lots" and depending on the operating characteristic
curve of a test "accepted lots are
no better than the rejected ones" (14).
o A multidisciplinary communication challenge and a general lack of
awareness of scientific developments in different disciplines contribute to a
suspicion about the level of control achieved through product and process
design (the "art" argument). The
pharmaceutical science and engineering knowledge developed over the last two
decades is not optimally relied upon for decision making in regulatory and/or
quality assurance settings.
o
The value and utility of new advances in process
technologies such as on-line process analyzers and controls (e.g., feedforward
and feedback controls) are not widely recognized. A common misperception is that testing is the
only valid approach; when in fact, reliance on testing for quality assurance is
a 19th Century concept and is a lesser form of quality assurance compared to
what can be achieved through design and control. The CGMP regulations and practices have long
recognized this principle. The following
quote from an FDA Warning Letter illustrates this principle: "The practice
of partial releases, no matter how stringent the re-sampling, raises doubt as
to the safety and efficacy
of the product being released. It is not acceptable to substitute testing
over adequate control of a process."
§
Similar and repeating OOS observations (e.g., dissolution failures)
for different products across the industry and the inability to find "root
causes" suggest that some of these observations may be due to
variability from "common
causes" (i.e., inherent variability in raw materials, equipment, measurement system
etc.).
o Furthermore, variable and
unstable external calibrators (e.g., USP Prednisone Tablets RS) raise questions
with regard to the stability of a measurement system. Organizational and functional barriers (e.g.,
analytical and production) add to this challenge through an
information/knowledge gap or disconnect between measurement and manufacturing
process and questions on stability, reproducibility, and repeatability of the measurement
system in the context of variability and OOS may not be addressed adequately.
§
When the source of
variability is from common cause(s) it is essentially a part of the clinical
trial materials and, therefore, included in the clinical assessment of safety
and efficacy and part of the FDA approval decision.
o Adequate characterization of clinical trial materials to describe
variability in quality characteristics and the application of "robust
design" principles (6) can provide opportunities for reducing (regulatory)
uncertainties regarding product failure modes, reliability of controls to
prevent failures and the level of quality assurance achieved by design.
o Reducing uncertainty is a prerequisite for sound risk-based
decisions.
2.4.
"The Desired State" of Pharmaceutical
Manufacturing in the 21st Century
Improving
the foundation of manufacturing science in our current manufacturing practices
should be the primary basis for moving away from the corrective action
"crisis" to continuous improvement. Knowledge of the "variation theory"
is, therefore, an essential element of manufacturing science. It requires an in-depth understanding of a
process or system (15):
"Cease dependence on
inspection [testing]. Depending
on inspection is like treating a symptom while the disease is killing you. The need for inspection results from excessive
variability in the process. The disease
is variability. Ceasing dependence on
inspection means you must understand your processes so well that you can
predict the quality of their outputs from upstream activities and measurements.
To accomplish this you must have a thorough
understanding of the sources of variation in your processes and then work
towards reducing the variation. Ceasing
dependence on inspection forces you to reduce variability."
The
"desired state" for pharmaceutical manufacturing in the 21st
Century therefore emphasizes and aims to improve knowledge on design and
understanding of product and processes. When such information and knowledge is shared
with FDA it can then be a basis to recognize different levels of understanding
achieved by companies and to utilize this information in risk-based decision
criteria. With this as the background,
the "desired state" was articulated in the second progress report of
the CGMP Initiative (
Pharmaceutical manufacturing is evolving from an art form
to one that is now science and engineering based. Effectively using this knowledge in regulatory
decisions in establishing specifications and evaluating manufacturing processes
can substantially improve the efficiency of both manufacturing and regulatory
processes. This initiative is designed
to do just that through an integrated systems approach to product quality
regulation founded on sound science and engineering principles for assessing
and mitigating risks of poor product and process quality in the context of the
intended use of pharmaceutical products. In this regard, the desired future state of
pharmaceutical manufacturing may be characterized as:
o
Product quality
and performance achieved and assured by design of effective and efficient
manufacturing processes
o
Product
specifications based on mechanistic understanding of how formulation and
process factors impact product performance
o
Continuous
"real time" assurance of quality
o
Regulatory
policies and procedures tailored to recognize the level of scientific knowledge
supporting product applications, process validation, and process capability
o
Risk based
regulatory scrutiny that relates to the level of scientific understanding of
how formulation and manufacturing process factors affect product quality and
performance and the capability of process control strategies to prevent or
mitigate risk of producing a poor quality product
This
description reflects a view from the manufacturing side - "beginning with
the end in mind." Therefore, the
goal "Product
quality and performance achieved and assured by design of effective and
efficient manufacturing processes" is
placed before "Product
specifications based on mechanistic understanding of how formulation and
process factors impact product performance."
Mechanistic understanding, as opposed to data derived from
one-factor-at-time type of experiment or simple correlative information,
provides a higher level of knowledge and an ability to generalize within
certain constraints. This provides an
opportunity to develop a flexible regulatory system with appropriate risk
coverage; for example a team approach to CMC reviews and CGMP inspections
(e.g., need for prior approval of post approval changes vs. information to be
held on site and available during inspections).
A manufacturing process is generally considered well
understood when (a) all critical sources of variability are identified and
explained, (b) variability is managed by the process, and (c) product quality
attributes can be accurately and reliably predicted over the design space
established for materials used, process parameters, environmental and other
conditions. The ability to predict
reflects a high degree of process understanding. Companies that achieve a high level of
process understanding should have an opportunity to use their information to
justify a more flexible regulatory path towards continuous improvement.
Risk-based decision criteria would then have to
relate to clinical relevance; different levels of understanding (e.g., correlative,
causal, mechanistic) will need to be recognized within this context. This general approach is utilized in some
current regulatory policies; in the desired state the approach can be extended
to other areas. For example in current
regulatory policies;
§ Establishing in vitro in vivo correlation (IVIVC) for modified release dosage form provides a justification for waiving in vivo bioequivalence evaluation only for certain specified post approval changes. Since a correlation is dependent on the mechanism of drug release, it is not used in situations that could potentially alter its mechanism (16)
§
Waiver of in vivo bioequivalence studies for major
post approval manufacturing changes for the BCS Class I (Biopharmaceutics
Classification System; highly soluble, highly permeable and rapidly dissolving)
solid oral products is NOT recommended for narrow therapeutic index drugs (17).
An objective metric is needed to
gauge the level of manufacturing process understandings and control achieved - process capability can be this
metric. During development studies,
process capability analysis can be performed in terms of probability
distribution (type of distribution, mean and variability) without regard to
specifications (14); such analysis can provide useful supporting information on
variability and may provide additional support for proposed regulatory acceptance
criteria. Inherent variability in
clinical materials can then be a benchmark and a basis for continuous
improvement.
The quality of design (product and its manufacturing process)--
the ability to reliably predict quality and performance, process monitoring and
controls, process capability and appropriate risk-mitigation strategies--
provides an opportunity to achieve "real time" quality assurance (the
ultimate level of efficiency). This also
provides an excellent opportunity to develop efficient and effective quality
assurance systems as an alternative to market or public standards (18).
Assessment of process capability and statistical process control
brings the ability to distinguish between a stable and un-stable process and
provides a means to distinguish between different causes of variability, e.g.,
common cause, special cause, structural (e.g., seasonal), and tampering (e.g.,
deliberate or unintentional). Process
understanding, quality by design and capability analysis can facilitate risk-based
regulatory decisions
for continuous improvements:
·
Regulatory
policies and procedures tailored to recognize the level of scientific knowledge
supporting product applications, process validation, and process capability.
·
Risk based
regulatory scrutiny that relates to the level of scientific understanding of
how formulation and manufacturing process factors affect product quality and
performance and the capability of process control strategies to prevent or
mitigate risk of producing a poor quality product.
It is expected that different companies will develop different
levels of process understanding and the level of understanding for a particular
product can increase over time (life cycle). These differences will need to be accommodated
in regulatory policies through a clear articulation of what is a minimum
regulatory expectation (e.g., current requirements of CMC review information
and process validation) and what is an optional opportunity for companies to
improve efficiency while reducing risk to quality and regulatory concerns.
3.0.
Accomplishments: Primary Objectives
3.1. Encourage new technological
advances
3.1.1 Strong public health protection
The basic tenant of a modern
quality system is that quality cannot be
tested into products; it should be built in by design. An emphasis on building quality into products allows an improved focus on relevant
multi-factorial relationships among material factors, manufacturing process and
environmental variables, and their collective impact on quality. These relationships provide a basis for
identifying and understanding interactions among various critical formulation
and process factors and for developing effective risk mitigation strategies
(e.g., product specifications, process controls, SOP's, training). This can improve identification and evaluation of
product and process variables that are critical to product quality and
performance. A higher level of process understanding should reduce uncertainty
and improve FDA's ability to make scientific risk- based decisions.
The PAT guidance facilitates
introduction of new measurement and control tools in conjunction with well-established
statistical methods such as design of experiments and statistical process
control. It, therefore, can provide more
effective means for product and process design and control, alternate efficient
approaches for quality assurance, and a means for moving away from the
corrective action to a continuous improvement paradigm.
3.1.2 Science-based policies and standards
Guidance for Industry PAT — A Framework for Innovative
Pharmaceutical Development, Manufacturing, and Quality Assurance (19)
This guidance describes a regulatory framework that will encourage the voluntary development and implementation of innovative approaches in pharmaceutical development, manufacturing, and quality assurance. Many new technologies are currently available that provide information on physical, chemical, (micro)biological characteristics of materials to improve process understanding and to measure, control, and/or predict quality and performance. The guidance facilitates introduction of such new technologies to improve efficiency and effectiveness of manufacturing process design and control (e.g., feedforward and feedback controls) and quality assurance. Gains in quality and efficiency will vary depending on a process and a product, and are likely to come from:
·
Reducing production cycle times by using on-,
in-, and/or at-line measurements and controls
·
Preventing rejects, scrap, and re-processing
·
Real time release
·
Increasing automation to improve operator safety
and reduce human error
·
Improving energy and material use and increasing
capacity
·
Facilitating continuous processing to improve
efficiency and manage variability
ASTM International Technical Committee E55: Pharmaceutical
Applications of Process Analytical Technology (20)
Innovation in manufacturing is the responsibility
of private sector and non-regulatory public sector. The PAT Guidance provided the regulatory
framework to facilitate innovation in the interest of the public health. FDA resources are limited and have to be
focused on core regulatory responsibilities. Therefore, the broader pharmaceutical
community should take on the responsibility for developing standards to support
the introduction of innovative tools and technologies. In this regard, ASTM International provides an
excellent process to develop standards in a timely manner using technical
expertise in all relevant disciplines from the pharmaceutical community and
other industrial sectors. Therefore, the
FDA’s PAT team worked with ASTM to establish Technical Committee E55 on
Pharmaceutical Application of Process Analytical Technology.
Focusing
on process monitoring and control, instead of testing, requires process control
standards consistent with guiding principles of the control theory. ASTM provides an opportunity to bring a strong
engineering process control perspective and to learn from other industrial
sectors that have utilized process analyzers and controls for many years. The E55 committee is tasked with developing
standards related to process analytical technology with the primary focus on
process understanding and control. The
PAT Team is represented on E55 committees.
Three subcommittees of E55 include: PAT System Management, PAT System
Implementation and Practice, and PAT Terminology.
The standard E2363-04: Standard Terminology Relating
to Process Analytical Technology in the Pharmaceutical Industry was
recently published.
3.1.3 Risk-based orientation
The PAT
Guidance recognizes that within an established quality system and for a
particular manufacturing process, one would expect an inverse relationship
between the level of process understanding and the risk of producing a poor
quality product. For processes that are
well understood, opportunities exist to develop less restrictive regulatory
approaches to manage change.
Collaboration
with the Risk-Based Site Selection Working Group of the initiative is on-going.
Development of ICH Q9 guidance will
provide additional risk tools and principles and facilitate international
harmonization of these principles.
3.1.4 Integrated quality system orientation
By definition PAT brings a systems perspective on
design and control of manufacturing processes. Therefore, a systems approach is needed for
regulatory assessment of PAT applications. To achieve this objective, the PAT Team for
CMC review and CGMP inspection was created. It includes reviewers, investigators and
compliance officers. A comprehensive
scientific training program was developed with guidance from the Advisory
Committee for Pharmaceutical Science's PAT Subcommittee. The training (didactic and practicum) was
provided by academic and industrial experts. Three scientific disciplines, process
analytical chemistry (
The team members trained together. As a part of their certification process they were asked to work as a team to address comments received on the draft guidance. Two assignments, a PAT inspection and pre-operational site visit, have been successfully completed by this team. Several team members have participated in a number of scientific conferences. The feedback received from their instructors, conference participants and companies has been very positive. The many organizational and communication barriers that existed at the beginning of the initiative are being removed and the team members are functioning as a team committed to a common purpose.
The integrated quality system orientation afforded a flexible regulatory approach for implementation of PAT. For example, regulatory implementation plans can include:
·
PAT can be implemented under the facility's own quality system. CGMP inspections by the PAT Team or PAT
certified investigator can precede, or follow, PAT implementation.
·
A supplement (CBE, CBE-30 or PAS) can be submitted to the Agency prior
to implementation, and, if necessary, an inspection can be performed by a PAT
Team or PAT-Certified Investigator before implementation.
·
A comparability protocol can be submitted to the Agency outlining
PAT research, validation and implementation strategies, and time lines. Following approval of this comparability protocol by the Agency,
one or a combination of the above regulatory pathways can be adopted for
implementation.
3.1.5 International cooperation
Extensive international scientific collaboration
was sought from the very beginning. For
example, before the July 2001 ACPS discussion on PAT, FDA staff participated in
the Royal Pharmaceutical Society's New Technology Forum (a collaborative effort
between the Medicines Control Agency,
now referred to as the Medicines and Healthcare Products
Regulatory Agency, and the British pharmaceutical industry). These discussions were very
valuable and contributed in the development of the FDA's PAT Initiative (21). The list of international scientific
conferences and workshops on PAT in the past three years is too long to
list. Almost every pharmaceutical
scientific association in the
The European Medicines Agency has established an EMEA PAT team and established contact with FDA's PAT team. In the near future FDA plans to share with the EMEA Team PAT training materials and lessons learned.
Following the issuance of the PAT Guidance
workshops are planned in the three ICH regions. The European Workshop will provide an
opportunity for the EMEA and FDA PAT teams to further collaborate on regulatory
implementation of PAT. Similarly the
planned workshop in
The definition of PAT in the FDA guidance and ASTM E55 and other concepts are being incorporated into the ICH Q8 guidance. The ASTM International provides another venue for international cooperation and the current E55 membership reflects broad international interest in these standards.
Several academic institutions in the
3.2.
State-of-the-art pharmaceutical science
3.2.1 Strong public health protection
Information on pharmaceutical development studies in
new drug applications is generally limited and varies from application to
application. This creates an uncertain environment and curtails FDA reviewers' ability to make
risk-based decisions and inhibits their ability to recognize and assess how
quality was built in. Risk communication
between review and inspection staff is also inhibited. Appropriate pharmaceutical development
information can improve public health by improving FDA's risk-based decisions
and by facilitating continuous improvement.
3.2.2 Science-based policies and standards
During the July 2003
ICH meeting in Brussels, agreement was reached on a common vision and approach
for developing an international plan for a harmonized pharmaceutical quality
system that would be applicable across the life cycle of a product. This plan emphasizes an integrated approach to
review (assessment) and inspection based on scientific risk assessment and risk
management. Several actions were
outlined to implement this vision. An
expert-working group (ICH Q8 EWG) was established to develop guidance for
pharmaceutical development.
The "desired
state" description was adopted with slight modification:
· Product quality and
performance achieved and assured by design of effective and efficient
manufacturing processes.
· Product specifications based
on mechanistic understanding of how formulation and process factors impact
product performance.
· An ability to affect continuous
improvement and continuous "real time" assurance of quality.
The ICH Q8 guidance
is currently being developed and is expected to reach the ICH Step 2 in
November 2004. It is intended to provide
guidance on the contents of Section 3.2.P.2 (Pharmaceutical Development) for
drug products as defined in the scope of Module 3 of the Common Technical
Document (ICH topic M4).
3.2.3 Risk-based orientation
Collaboration with
the ICH Q9 is an important element. This
collaboration will provide a means to connect the scientific framework in ICH
Q8 to risk-management principles being developed by ICH Q9.
ICH Q8 creates an
opportunity for an applicant to demonstrate an enhanced knowledge of product
performance over a wider range of material attributes (e.g. particle size
distribution, moisture content, and flow properties), processing options and
process parameters. This knowledge can
be gained in a structured manner by, for example, applications of formal
experimental designs, PAT concepts, or risk management tools (e.g., failure mode
effect analysis or FMEA). Such knowledge
can allow regulatory agencies to develop more flexible regulatory approaches,
for example, to:
·
facilitate risk based
regulatory decisions (reviews and inspections);
· implement manufacturing process improvements, within the boundaries of
the knowledge described in the dossier, without the need for regulatory review;
· implement “real time” quality
control, leading to a reduction of
end-product release testing
3.2.4 Integrated quality system orientation
The ICH
Q8 guidance on Pharmaceutical Development section is intended for use both by
CMC reviewers and CGMP investigators.
Because the aim of pharmaceutical development is to
design a quality product and a manufacturing process to deliver the product in
a reproducible manner, the information and knowledge gained from pharmaceutical
development studies should provide additional scientific understanding to
support establishing more relevant specifications and manufacturing
controls.
Information from
pharmaceutical development studies can be the basis for risk management when
these studies are designed with the aim of demonstrating that quality was built in by design. This document and the manufacturing science
framework provide an area of "common interest" and opportunity for
collaboration between the CMC review and CGMP investigations staff.
3.2.5 International cooperation
The Manufacturing
Science Working Group collaborated with the Product Quality Research Institute
(PQRI) to organize the first workshop (April, 2003) of the CGMP Initiative. This was an international workshop and
provided an opportunity to explain the goals and objectives of the initiative
and to seek stakeholder input (http://www.pqri.org/gmpworkshop/).
A second workshop was
organized in The Netherlands (
4.0.
A Systems Perspective: "Points to Consider"
4.1.
Risk-based approaches that focus industry and agency
attention on critical areas
4.1.1. Reduce uncertainty to enable risk-based decisions; critical variables
and link to clinical relevance; sources of variability and "risk to
quality"
Currently a high
degree of uncertainty with respect to critical variables, sources of
variability and their clinical relevance delays approval of certain complex
drug delivery systems (e.g., inhalation products). With increasing complexity in drugs and drug
delivery systems this challenge is anticipated to increase and is likely to
result in multiple review cycles for new drug applications and/or an inability
to approve generic drug products in a timely manner.
Furthermore, significant
industry and FDA resources are spent debating issues related to acceptable
variability, need for additional in-process testing and how specification
acceptance limits should be established.
Often these debates are focused on acceptance limits or the statistical
aspects. In these debates a
proportionate focus on the underlying manufacturing science is often missing. For example;
·
The protracted (about 10
years) debate on the issue of blend sampling and the relevance of in-process
blend uniformity testing focused mainly on testing and statistics and did not
fully leverage the manufacturing science aspect of the challenge. The PQRI proposal took a few steps in this
direction (2, ACPS November 2001); today the full potential of a manufacturing
science framework remains to be realized.
·
For the last three years FDA
and an industry group (IPAC-RS) have been debating a parametric tolerance
interval test (PTIT) for delivered dose uniformity of inhalation products. The proposed PTIT approach has many desirable
features including an approach to move away from the discrete/attribute
criteria. However, uncertainties in what
is "acceptable" variability have continued the debate for an extended
period of time. Additionally, a focus on
statistics alone has created a situation where the discussions have focused on
"hypothesis testing" in routine production - i.e., testing to
document quality instead of process control principles. The concept of "hypothesis testing"
should essentially end at the process validation stage (2, ACPS October
2003).
4.1.2. Risk communication: Knowledge transfer and management
A major element in
risk management is risk communication. The challenge of risk communication between
industry and FDA and within FDA should not be underestimated. It would be erroneous to assume that
manufacturing science can resolve all important risk to quality issues. Manufacturing science principles combined with
effective risk management tools such as fault trees, failure mode effect
analysis (FMEA) can provide a structure for risk-based decisions. Effective and efficient risk-decisions will
require communication and collaboration between the CMC review and CGMP
inspection functions, common data/knowledge bases, and a continuous learning
and improvement approach.
4.1.3. Emerging support infrastructure for the "desired state"
Several academic institutions in the
In addition to
numerous commercial vendors, several international scientific associations and
societies have developed programs to support the "desired state." A few examples are provided below.
§
The Royal Pharmaceutical Society's New
Technology Forum (NTF) has continued its discussions on PAT with
participation of FDA PAT Team members.
Forum 5: Multivariate mathematical
approaches
Forum 6: Rapid methods in microbiology
§
The Product Quality Research Institute
Several ongoing and planned projects are focused on manufacturing science. The Manufacturing Technical Committee has been established and projects such as “Process Robustness of Oral Solid Dosage” are being developed (http://www.pqri.org). Several other PQRI projects (e.g., on excipients and dissolution testing) are essentially attempting to address common cause variability challenges in the current system.
The ASTM E55 and other efforts such as NTF and PQRI are intended to be complementary in supporting PAT and the manufacturing science framework and to create a path to move efficiently towards the "desired state." The ASTM E55 focus on innovation should provide a "pull" on the "current state" to move it towards the "desired state" while the PQRI efforts provide the "push." The efforts of E55 on developing a standard for process understanding should provide a basis to ensure alignment of efforts and to create a synergistic "pull and push" vector in the direction of the "desired state."
§
International Forum for Process Analytical
Technology Manufacturer’s Association (IFPATMA)
http://www.ifpacma.org/ifpacMA-Benefits.html
IFPATMA is a not-for-profit consortium of manufacturers/suppliers dedicated to the advancement of quality systems for PAT in the pharmaceutical and related industries. The organization has a goal of standardization of practices for process analyzers and reducing the sensor qualification burden on pharmaceutical companies. Its efforts are aligned with ASTM E55 activities and with other organizations having similar goals.
§ American Association of
Pharmaceutical Scientists (AAPS)
AAPS conferences (e.g., the Arden House Conference)
and workshops provided help in defining the "desired state." An AAPS PAT focus group has been established.
http://www.aapspharmaceutica.com/inside/focus_groups/PAT/index.asp
4.2.
Facilitate industry application of modern quality management
4.2.1. "Out of the Corrective Action Crisis": Continuous Improvements
It can be argued that current low efficiency in
pharmaceutical manufacturing is partly due to "self-imposed" constraints
(e.g., approach to specifications based on discrete or the so called "zero
tolerance" criteria, a less than optimal understanding of variability,
etc.). This contributes towards keeping
the current system in a corrective action mode.
This approach also curtails our ability to prepare for future
challenges.
Some would argue that corrective actions provide the
necessary "constancy of purpose for improvement" and are necessary
since manufacturing is a "step-child" of the industry because the
difference between "cost of manufacturing" and the "price of
drugs" is large. Keeping the system
in "corrective action mode" provides the leverage for ensuring
improvements (i.e., to ensure the "current" in the CGMP's).
The argument has some validity, but it is based on
an assumption that current practices (e.g., including measurement systems and
product specifications) provide efficient means for identifying, understanding
and then reducing variability (i.e., improvement). Quality assurance in the 21st Century will
need a sound basis for verifying such assumptions in the current system. To emphasize this point further, the case of
dissolution test is cited again - the manner in which the current dissolution
test is used provides good estimates of the mean dissolution profiles. However, in terms of variability (the dominant
cause of OOS) the current approach to calibration and additional challenges in
verifying certain inherent assumptions (e.g., relevance of hydrodynamic
variability) makes it difficult for a commercial manufacturer to verify
inherent assumptions and to document lower variability than the USP calibrator tablets. Therefore, without the ability to understand
and document variability reduction (improvement) the "corrective action
mode" may not be able to facilitate improvement in many situations. There are other undesirable consequences,
such as:
§ A constant "corrective
action mode" amounts to "crying wolf" on a very frequent basis
thus making the system less responsive to situations when a "real
wolf" appears.
§ This mode produces anxiety,
fear, and disincentives to improvement among the production staff. This can set up an environment of high risk to
quality and safety. Some aspects of this
are further illustrated in section 4.2.3.
4.2.2. Science based regulatory flexibility for continuous improvements
The concept of
continuous improvement has a long history and a well founded structure and
format as exemplified by the Evolutionary Operations or EVOP (5) and the
“Kizen” principles. Kizen (Ky’ zen) is a Japanese word introduced
in the West (~late 70’s) and translated as “Continuous Improvement”—slow,
incremental, but constant.
The basic philosophy of EVOP is that
"it is inefficient to run an industrial process in such a way that only a
product is produced, and that a process should be operated so as to produce not
only a product but also information on how to improve the product." Effective knowledge transfer and communication
between organizations is essential for continuous improvement; equally
important is a system to collect and analyze information throughout a product's life cycle. Such a system can assist in identifying and
addressing sources of variability and sharing this information with all
organizations (e.g., development, regulatory, etc.).
In the current system the "fear" of
finding a ("new") source of variability inhibits information
collection on commercial products beyond the batch records. Although the PAT Guidance provides a
regulatory mechanism to address this issue by clarifying that additional
information is research data, it is limited to PAT applications. The concept of continued learning in the production
setting should be encouraged in the entire regulatory system.
4.2.3. "Drive out fear" that inhibits continuous learning and
improvement, and that which can increase risk
It is important to
appreciate that there are many dimensions to the challenge of "fear."
For those who may engage in amoral or
unethical behaviour, the regulatory "fear" is a desirable
deterrent. Quality by design and process
understanding aspects of manufacturing science provide the regulatory system with
additional means to address many of the "undesirable" and
"desirable" dimensions of "fear."
§
Fear is contradictory to
continuous improvement and a broad regulatory approach is needed to address
this challenge. Timely risk assessment,
communication, information, and collaboration between CMC review and CGMP
inspection functions will be essential components of such a regulatory
approach. In addition, common data bases and information systems
will be necessary.
§
A combination of
"fear" (of failure) and insufficient process understanding can create
situations that can increase risk. The
following example illustrates this point.
o The Warning Letter citation below may be an example of a poorly
understood process since OOS investigations were unable to determine the root
cause(s) of the problem. In order to
conform to in-process blend uniformity test specifications, powder blends were
either enriched with additional drug or diluted with other ingredients. In an essentially closed system (blender) this
is an unacceptable practice (a violation of “Do
what you say") and can pose significant risk to
patients.
o The example emphasizes that process understanding and quality by design
principles offer a more attractive means to mitigate risks posed in the
following example:
4.2.4. "Pride of workmanship" and Continuous Learning
Frequent corrective
actions take away the "pride of workmanship" from production operators
and other staff in industrial operations.
In addition, FDA's penalty system (e.g., Warning Letters) is often
construed to be directed at industrial operations. The ability to distinguish between common
cause and special cause variability can be an important element in the FDA's
penalty system and facilitate a move towards a continuous improvement approach
and help build/improve the "pride of workmanship" dimension.
4.3.
Enhanced quality systems approaches into the Agency's
business processes
4.3.1. PAT Team Approach to CMC Review and CGMP Inspections
The value and
advantages of a team approach to CMC review and CGMP inspections has been
recognized and practiced for many years (e.g., Team Bio). This principle was utilized to develop the PAT
Team. However, to accommodate specific
objectives of the initiative and the need for a systems approach in the PAT
Team, a joint training and certification process with team building was
developed. The entire team of CMC
reviewers, CGMP investigators, and compliance officers trained together on all
aspects of PAT.
To ensure that this
team concept is "institutionalized" and for its continuous
improvement, the PAT Team process will be under the FDA's Quality Systems
Framework. This should also help in
ensuring quality and consistency of reviews, inspections, and other regulatory
activities.
4.3.2. Manufacturing Science foundation of the FDA's Quality System
The number of
"quality movement" or trends in the 20th Century (1950's
-Sampling plans; 1960's Zero-Defect Movement; 1980's - ISO-9000 & Malcolm
Baldrige Award; 1990's - QS-9000, Total Quality Management, Six Sigma, etc) can
create a perception that these trends are "lurching from fad to fad"
or suggest that these trends represent continuous improvement towards an ideal
quality system (22). An element that is essential
to recognize is that of process understanding; without process understanding,
the effectiveness of any quality system will be limited and without a sound
manufacturing science foundation, a pharmaceutical quality system will fail to
realize its full potential. A quality system should
provide a sound framework for the transfer of process knowledge from
development to the commercial manufacturing processes and for post development
changes and optimization (23).
4.3.3. Continuous Improvement - Change Control and Life Cycle Management
A flexible, science
and risk-based approach to post approval changes will be essential to
facilitate continuous improvement. Regulatory
mechanisms for "life cycle management" are necessary. "Change Control" is a well-known CGMP regulatory
concept that focuses on managing change to prevent unintended consequences and
this can be a path towards continuous improvement. In this regard, change towards continuous improvement should be encouraged. This means a manufacturer is empowered to make
changes based on the variability of materials used in manufacturing and
optimization of the process from learning over time (23); therefore, a
company's quality system should consider this opportunity. Regulatory management of a flexible
"change control" process will require
a team approach to CMC review and CGMP inspections, in many ways similar to the
PAT team process.
4.3.4. "Pride of Workmanship" and "Continuous Learning"
Pride of workmanship
of FDA staff should be an essential element of the FDA's Quality System. Manufacturing science and PAT training and
professional development opportunities should provide a means for FDA staff to
be recognized as leaders in a number of scientific and technical areas. Continuing education and training programs
should therefore be supported and be a part of the quality system. The concept of "peer review" should
be considered and mechanisms developed to recognize scientific and regulatory
contributions that help the pharmaceutical community move towards the
"desired state."
4.3.5. Break down organizational barriers
Success of the CGMP
Initiative depends on a team approach to pharmaceutical quality. Lessons learned from the PAT team building
activities suggest that organizational barriers can be removed through open
dialogue and opportunities to engage in activities that relate to areas of
common interests. The manufacturing
science vocabulary and systems thinking it induces can also facilitate
international discussions (e.g., in ICH and PIC/S) and cooperation.
5.0.
Collaborations and Recommendations
5.1.
Team Bio and PAT Team
During the course of
the CGMP Initiative the PAT team was developed and implemented through
collaboration between ORA, CVM and CDER. The Office of Biotechnology moved into CDER
towards the end of the PAT training process.
The final guidance extends the PAT framework to CDER's Office of
Biotechnology (OBP). PAT applications
will be managed through collaborations with the PAT Team. A second PAT team is planned and will include
CDER's Office of Biotechnology, Office of Compliance and ORA Team-Bio
representatives. Formation of the second
PAT Team will provide an additional opportunity to develop close collaboration
and cooperation between the PAT team and Team-Bio. This opportunity should be utilized to
identify best practices and to develop recommendations for a broader team
approach.
5.2.
ICH Q9 & Risk based site
selection model for CGMP inspections
A structured
regulatory format for risk assessment and management will be essential for
moving towards the "desired state." The PAT framework and ICH Q8 will
provide a basis for risk mitigation. Risk management principles and tools will be
necessary to describe and communicate the level of risk-mitigation achieved
through quality by design and process understanding. Therefore, the principles and tools for risk
management and communication currently being developed in ICH Q9 and the
emerging risk based site selection model for CGMP inspections should connect well
with the manufacturing science and the PAT framework to ensure:
o
Regulatory
policies and procedures tailored to recognize the level of scientific knowledge
supporting product applications, process validation, and process capability.
o
Risk based
regulatory scrutiny that relates to the level of scientific understanding of
how formulation and manufacturing process factors affect product quality and
performance and the capability of process control strategies to prevent or
mitigate risk of producing a poor quality product.
5.3.
Changes without prior
review: draft guidance, Comparability Protocol
A flexible, science and risk-based approach to post approval changes will be essential to facilitate continuous
improvement. The new compliance policy
guide CPG 7132c.08 recognizes the role of emerging
advanced engineering principles and control technologies in ensuring batch
quality (24). For drugs produced using
these new principles and technologies, this CPG provides for possible
exceptions to the need for manufacturing multiple conformance batches prior to
initial marketing. This version also
deletes the previous reference to "three" validation (or conformance)
batches at commercial scale as adequate minimum proof of process validity — a
number is no longer suggested. This
is a major step forward in facilitating continuous improvement.
As discussed in section 4.3.3. Change towards continuous
improvement should be encouraged. Quality
by design and process understanding can provide a basis to allow those
manufacturer that have demonstrated adequate level of process understanding to
make changes without prior review within
the "change control" provisions of their quality system under the
CGMP inspectional oversight.
Although progress on ICH Q8
has been significant, additional work is necessary to articulate the
relationship between "adequate level
of process understanding and regulatory flexibility to make changes without
prior review." At the recommendations of the ACPS
Manufacturing Subcommittee (July 2004) a working group will be assembled to
develop illustrative case examples. ICH
Q8 and illustrative examples should then be a basis to further improve the
draft comparability guidance to facilitate continuous improvements.
5.4.
Proposed ICH Q10
Life cycle management
and change control provide a mechanism for continuous improvement. To support continuous improvement through change
control a quality system would need to be based on principles of manufacturing
science and risk-management. The
proposed ICH Q10 guidance is an opportunity to accomplish this task.
5.5.
Product Specialists on
Inspections and Pharmaceutical Inspectorate
The PAT team building and training program identified several challenges, of these the most critical challenge was of that of organizational barrier (review -compliance-inspections). An independent contractor was asked to apply principles of organizational engineering to understand different perspectives and based on this information, team building programs and joint training programs were developed.
Team building exercises and joint training programs were critical for overcoming the organizational barriers and communication challenges. It is recommended that similar team building and training opportunities be created for CMC reviewers, compliance officers and the Pharmaceutical Inspectorate. Lessons learned from the PAT Team and Team-Bio should also be utilized to support the "Product Specialists on Inspection" program.
6.0
Next steps and Considerations for the Critical Path
Initiative
6.1
PAT
The PAT process has
been successful in bringing a systems perspective and a team approach to
facilitate innovation. The PAT team has
approved one application that included a joint team inspection and has recently
completed a pre-operational visit for a major PAT application. Several PAT proposals have been received and
it is expected that many of these will be received as applications in the near
future. The next steps in the PAT
process include:
§
International scientific
workshop on the PAT Guidance in the
§
Incorporation of the PAT
process under the FDA's Quality System
§
Continued participation in ASTM E55 Committee to
support development of standards consistent with the PAT framework
§
CBER and Team-Bio
representative to join PAT Steering Committee
§
Selection of the second PAT
Team (to include Office of Biotechnology, Compliance and ORA Team-Bio CGMP
Inspection staff)
§
Teambuilding, training and
certification of the second team
§
Extend invitations to Health
§
Share lessons learned and
training materials with Health
§
Continuing education for the
current PAT team
§
PAT Team and Team-Bio
collaboration to identify best practices and lessons learned; recommendations
on how to develop a team approach between "Product Specialists" and
Pharmaceutical Inspectorate
§
Critical Path Research and
research collaborations (academia and industry)
§
Strengthen the emerging
support structure in scientific societies and association (e.g., AAPS, ISPE,
IFPATMA, PDA, and others)
§
Following the second PAT
team training, expand the PAT program to include all Product Specialist and Pharmaceutical
Inspectorate
6.2
Manufacturing Science
ICH Q8 will describe
the suggested contents for the 3.2.P.2 Pharmaceutical Development section of a
regulatory submission in the ICH M4 Common Technical Document (CTD) format. It is not intended to be a "how to"
guidance. It will provide sponsors of
drug applications an opportunity to present knowledge gained during development
of a product and its manufacturing process and relevant prior knowledge. It will indicate areas where the provision of
greater understanding of pharmaceutical and manufacturing sciences can create a
basis for flexible regulatory approaches to support continuous improvement.
§
The FDA's goal at the next ICH meeting (November 2004, Japan) is to
articulate and build consensus on a description of how a greater understanding of pharmaceutical and manufacturing sciences can
create a basis for flexible regulatory approaches needed to support continuous
improvement.
o
If this is agreed upon in
November 2004, ICH Q8 would reach Step 2 and be available for public comment.
o
It should be recognized that each section within 3.2.P.2 Pharmaceutical Development section will impact the other P2 sections and
similarly other sections of a submission and the CGMP’s inspection process. By recognizing this as a complex design system
that involves multiple attributes, goals, constraints, multidisciplinary design
teams (subsystems), different degrees of uncertainty, risk tolerance, etc., we
may find opportunities to develop robust designs and design space that provides
a sound basis for risk assessment and mitigation.
§
Although to a large degree consensus has been established on the
"desired state" it should be noted that there is often a tendency for
a consensus on collective ends to attenuate when specifics are addressed. This is often due to divergent understanding
of the problem being addressed and/or differences in interests and/or issues in
representation of the problem being addressed. It is hoped that this report will help in
further consolidating and strengthening
the consensus for moving towards the "desired state"
§
Under the ACPS Manufacturing
Subcommittee a working group will be formed to identify specific steps needed
to move towards the desired state. The
group will also develop illustrative case studies to support the ICH Q8
document and CPG
7132c.08
§ ACPS recommendations on regulatory flexibility for post approval changes
(e.g., reduce the need for prior review) will be considered for improving the
draft Comparability Protocol Guidance (for small molecules only).
§ A combination of the PAT Guidance, CPG 7132c.08, modified draft
Comparability Protocol Guidance (for small molecules only) along with other
work products of the CGMP Initiative are expected to facilitate a move towards
the desired state. The proposed ICH Q10
will need to consider these concepts and policies and provide additional guidance
on quality systems for change control to facilitate continuous improvement.
The effectiveness of the regulatory framework for innovation (PAT
Guidance) and manufacturing science (emerging ICH Q8) when implemented should
be evaluated periodically to guide continuous improvement. Objective metrics will need to be developed
to measure the level of systems thinking achieved in the application of
manufacturing science principles and opportunities realized within the agency,
by the industry, and the larger pharmaceutical community. It is expected that a continuous improvement
plan will be developed for both PAT and ICH Q8 under the FDA's Quality System.
6.3
Critical Path Initiative (25)
In the short duration of the CGMP Initiative
significant progress was made articulating, building consensus on, the
"desired state" for pharmaceutical manufacturing, and developing a regulatory
framework for innovation and continuous improvement. Some have characterized this progress as
"revolutionary" (10). From the
PAT Team and Manufacturing Science Working Group perspective the progress made
to date was because we worked as team to identify and realize opportunities to
improve our ability to meet our public health objectives.
Significant challenges lie ahead for the pharmaceutical
community and for regulators to move to the "desired state" for
pharmaceutical manufacturing in the 21st century. Nevertheless, important steps have already
been taken. In addition, some of these
challenges can be
addressed through the FDA's Critical Path Initiative.
§ The Executive Order 13329
Encouraging Innovation
in Manufacturing (February 2004) recognizes that "Continued technological innovation is critical to a strong
manufacturing sector in the
o
This provides an opportunity for FDA to support innovation by
collaborating with other federal agencies to identify priority for
pharmaceutical manufacturing-related research and development.
§ The team approach and
systems perspective under the CGMP Initiative only addressed a part of the
pharmaceutical system. Quality by design
and process understanding to a large extent is achieved in a research and development
organization; ICH Q8 is the bridge between the CGMP Initiative and the rest of
the regulatory system.
o
Pharmaceutical product development is a complex and creative design
process that involves many factors, many unknowns, many disciplines, many
decision-makers, and has multiple iterations and a long life-cycle. Significant uncertainty is created when a
particular disciplinary design team must try to connect their subsystem to
another disciplinary subsystem (e.g., Clinical-CMC-CGMP). Each subsystem can have its own goals and
constraints that must be satisfied along with the system-level goals and
constraints. It is possible that goals
of one subsystem may not necessarily be satisfactory from the view of another
subsystem and design variables in one subsystem may be controlled by other
disciplinary subsystems.
o
Development of systematic regulatory framework based on complexity and
scientific uncertainty should facilitate all three dimensions of the critical
path. Such a system will also need to
consider the multidisciplinary communication challenges in product
development.
o
The scientific and technical challenges on the critical path towards
the "desired state" are significant. The traditional empirical approaches will need
to be replaced with a much more fundamental scientific understanding (26-27). This will require the talent and know-how of many
scientific and technical disciplines. Without
sufficient and sustained support our Nation's pharmaceutical education and
research system will be unable to meet the needs of the desired state. Significant collaboration and cooperation among
industry, academia, and public agencies (e.g., National Science Foundation and
National Institutes of Health) including FDA will be necessary to find
solutions to this challenge.
Acknowledgments
We
wish to acknowledge the contributions of the FDA Science Board, Advisory
Committee for Pharmaceutical Science and its PAT and Manufacturing
Subcommittees members and participants, scientists who participated in numerous
conferences and workshops, and fellow regulators at FDA and around the world,
and the FDA's PAT Research Team. Without
vigorous discussions and debate our progress would not have been possible.
The PAT Team Members include:
Steering Committee
CDER:
Ajaz S. Hussain (Chairperson), Joe Famulare, Moheb Nasr, Keith Webber, Frank
Holcombe Jr.
ORA: Doug Ellsworth, Patricia Lefler
CVM: Dennis Bensley
Retired:
Yuan-yuan Chiu (CDER), Mike Olson (ORA)
Policy Development and Support:
Chris Watts, Ali Afanan,
Huiquan Wu, Raj Uppoor
Training: John Simmons, Karen Bernard,
See Lam
Review & Inspection Team
Investigators:
Robert Coleman
(DFI/ORA/FDA)
Rebecca Rodriguez (DFA/ORA/FDA)
Erin McCaffery (NJ-DO/NJIB/ORA/FDA)
George Pyramides (PHI-DO/PLB/ORA)
Dennis Guilfoyle (NE-FO/NERL/ORA)
Compliance Officers:
Albinus D’Sa (CDER)
Mike Gavini (CDER)
William Bargo (CVM)
Brenda Uratani (CDER)
Reviewers:
Norman Schmuff (CDER)
Lorenzo Rocca (CDER)
Vibhakar Shah (CDER)
Rosario D’Costa
(CDER)
Raafat
Fahmy (CVM)
Brian Riely (CDER)
The Manufacturing Science Working Group Members include:
Ajaz
Hussain (Chairperson), Raafat Fahmy (CVM);
William Bargo (CVM), Robert Coleman, Robert (ORA); Elise Murphy (ORA), Frank Holcombe Jr (CDER), Chris Watts (CDER),
See Lam (CDER), Jon Clark (CDER), Christopher Joneckis (CBER), John Dietrick (CDER), Diana Kolaitis (ORA), Vilayat Sayeed (CDER), Mai Huynh (CVM), Norman Schmuff (CDER),
Andrew Chang (CBER).
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§
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