# Innovation and Continuous Improvement in Pharmaceutical Manufacturing

**Pharmaceutical CGMPs for the 21^st^ 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 21^st^ 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 21^st^ 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 21^st^ 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 21^st^ 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.  **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 21^st^ Century.

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).

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

+--------------+---------------------+---------------------------------+
| *            |                     | **Characteristics and           |
| *Improvement |                     | Objectives**                    |
| Approaches** |                     |                                 |
+--------------+---------------------+---------------------------------+
| **           | Primary focus area  | Revolutionary, to be a leader   |
| Innovation** | of the PAT Team.    |                                 |
|              |                     | Focused applications - project  |
|              | Manufacturing       | based                           |
|              | Science WG is       |                                 |
|              | contributing to     | Significant capital             |
|              | harmonization of    | expenditure, ROI, Top-down      |
|              | the PAT framework   |                                 |
|              | in ICH              | Strong research component       |
|              |                     |                                 |
|              |                     | Technical experts involved      |
|              |                     |                                 |
|              |                     | New findings and improved       |
|              |                     | knowledge                       |
|              |                     |                                 |
|              |                     | [CGMP Initiative Objective      |
|              |                     | #1]{.underline}                 |
+--------------+---------------------+---------------------------------+
| **Continuous | PAT Framework       | Product is in specification     |
| I            | provides many       |                                 |
| mprovement** | options and         | Acceptance criteria -           |
|              | opportunities       | variable/continuous data        |
|              | including research  |                                 |
|              | data collection in  | Evolutionary, incremental       |
|              | production.         | process optimization,           |
|              | Manufacturing       | continuous, daily activity      |
|              | Science WG creating |                                 |
|              | regulatory          | Carried out by plant and        |
|              | flexibility through | quality staff                   |
|              | ICH Q8.             |                                 |
|              |                     | [CGMP Initiative Objective      |
|              |                     | #1-5]{.underline}               |
+--------------+---------------------+---------------------------------+
| **Corrective | PAT opens the door  | Product is out of specification |
| Actions**    | for new tools for   | (OOS)                           |
|              | root cause          |                                 |
|              | investigations and  | or Procedural deviations        |
|              | data collection in  |                                 |
|              | production.         | \"Crisis\" - immediate action   |
|              |                     | needed                          |
|              | Manufacturing       |                                 |
|              | Science provides    | Required by regulators          |
|              | the foundation for  |                                 |
|              | more effective      | [CGMP Initiative Objectives:    |
|              | approaches.         | #1-5]{.underline}               |
+--------------+---------------------+---------------------------------+

+-----------------------------------------------------------------------+
| *Table 2. Report of the of the FDA\'s CGMP for the 21^st^ 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{ }.*                              |
+-----------------------------------------------------------------------+
| +--------+----------+----------+----------+---------+-----------+     |
| | G      | Ob       |          |          |         |           |     |
| | uiding | jectives |          |          |         |           |     |
| |        |          |          |          |         |           |     |
| | Prin   |          |          |          |         |           |     |
| | ciples |          |          |          |         |           |     |
| +--------+----------+----------+----------+---------+-----------+     |
| |        | *E       | *        | *Ri      | *Fac    | *Enhanced |     |
| |        | ncourage | State-of | sk-based | ilitate | quality   |     |
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| |        |          |          | on       | gement* |           |     |
| |        |          |          | critical |         |           |     |
| |        |          |          | areas*   |         |           |     |
| +--------+----------+----------+----------+---------+-----------+     |
| | *      | Improve  | Improve  | Reduce   | \"Out   | Team      |     |
| | Strong | focus on | focus on | unc      | of the  | approach  |     |
| | Public | process  | \        | ertainty | Cor     | to CMC    |     |
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| |        |          | clinical | d        | to      |           |     |
| |        |          | r        | ecisions | Con     |           |     |
| |        |          | elevance |          | tinuous |           |     |
| |        |          |          |          | Impr    |           |     |
| |        |          |          |          | ovement |           |     |
| +--------+----------+----------+----------+---------+-----------+     |
| | *S     | PAT      | ICH Q8;  | Critical | Science | S         |     |
| | cience | Guidance | \[CPG    | var      | based   | cientific |     |
| | -based |          | 71       | iables - | reg     | f         |     |
| | po     | ASTM     | 32c.08\] | clinical | ulatory | oundation |     |
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| | and    | tandards | \[ICH    | elevance | ibility | FDA\'s    |     |
| | stan   |          | Q9\]     |          | for     | quality   |     |
| | dards* |          |          |          | con     | system    |     |
| |        |          | \[{Compa |          | tinuous |           |     |
| |        |          | rability |          | impr    |           |     |
| |        |          | Pro      |          | ovement |           |     |
| |        |          | tocol}\] |          |         |           |     |
| |        |          |          |          |         |           |     |
| |        |          | {        |          |         |           |     |
| |        |          | Proposed |          |         |           |     |
| |        |          | ICH Q10} |          |         |           |     |
| +--------+----------+----------+----------+---------+-----------+     |
| | *Risk  | Re       | Mec      | Sources  | \"Drive | C         |     |
| | -based | gulatory | hanistic | of       | out     | ontinuous |     |
| | orient | scrutiny | basis    | var      | fear\"  | Im        |     |
| | ation* | based on | for      | iability |         | provement |     |
| |        | the      | under    | and      |         | -Change   |     |
| |        | level of | standing | \"risk   |         | Control & |     |
| |        | sc       | failure  | to       |         | Life      |     |
| |        | ientific | modes    | q        |         | Cycle     |     |
| |        | under    | and      | uality\" |         | M         |     |
| |        | standing | var      |          |         | anagement |     |
| |        |          | iability |          |         |           |     |
| +--------+----------+----------+----------+---------+-----------+     |
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| | grated | Team:    | rengthen | Commun   | of      | of        |     |
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| | s      | certif   | ducation | nowledge | and     | and       |     |
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| | orient | and      | research |          | tinuous | ontinuous |     |
| | ation* | co       | infras   | \[Risk   | L       | Learning  |     |
| |        | ntinuous | tructure | based    | earning |           |     |
| |        | learning |          | site     |         |           |     |
| |        |          | \[       | s        |         |           |     |
| |        | \[Team   | {Product | election |         |           |     |
| |        | Bio\]    | Spec     | for CGMP |         |           |     |
| |        |          | ialist - | Inspe    |         |           |     |
| |        |          | Pharma   | ctions\] |         |           |     |
| |        |          | ceutical |          |         |           |     |
| |        |          | Inspect  |          |         |           |     |
| |        |          | orate}\] |          |         |           |     |
| +--------+----------+----------+----------+---------+-----------+     |
| | *I     | Commun   | ICH      | Emerging | \"Br    | C         |     |
| | nterna | ication, | process, | infras   | eakdown | ontinuous |     |
| | tional | w        | shared   | tructure | organiz | Im        |     |
| | cooper | orkshop, | vision   | for the  | ational | provement |     |
| | ation* | plans    | and      | \        | bar     | -Change   |     |
| |        | for      | \        | "desired | riers\" | Control & |     |
| |        | joint    | "desired | state\"  |         | Life      |     |
| |        | training | state\"  |          |         | Cycle     |     |
| |        |          |          |          |         | M         |     |
| |        |          |          |          |         | anagement |     |
| +--------+----------+----------+----------+---------+-----------+     |
+-----------------------------------------------------------------------+

2.  **The \"Current State\" and the \"Desired State\" of Pharmaceutical
    Manufacturing in the 21^st^ Century**

    1.  **The \"Current State\"**

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 US pharmaceutical manufacturing sector will be
essential in the 21^st^ Century.

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.

    -   This approach requires a high level of control on incoming raw
        material characteristics.

    -   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.

    -   OOS investigations that follow take significant (time) resources
        and have a low rate of success in finding permanent corrective
        and preventive solutions.

    -   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).

    -   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).

    -   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.

    1.  **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.

    -   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.

    -   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.

    -   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.

    -   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).

    -   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).

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-   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).

    -   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.

    -   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.).

    -   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.

    -   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.

    -   Reducing uncertainty is a prerequisite for sound risk-based
        decisions.

#### \"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 21^st^
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 (February 20^th^ 2003):

> *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:*

-   *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*

-   *Continuous \"real time\" assurance of quality*

-   *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*

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)

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-   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.  **Accomplishments: Primary Objectives**

#### 3.1. Encourage new technological advances 

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.

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

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-   Preventing rejects, scrap, and re-processing

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-   Real time release

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-   Increasing automation to improve operator safety and reduce human
    error

-   Improving energy and material use and increasing capacity

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-   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](http://www.astm.org/SNEWS/MAY_2004/NOPARSE#http://www.astm.org/COMMIT/E55.htm)
> 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.

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 (University of Washington, Seattle; National
> Science Foundation (NSF) Center for Process Analytical Chemistry);
> industrial & physical pharmacy (Purdue University; NSF Center for
> Pharmaceutical Process Research), and chemical engineering (University
> of Tennessee; NSF Measurement Control Engineering Center) were
> included in training for the PAT Team.
>
> 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.

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-   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.

    4.  *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 US,
> Europe, and Japan has organized PAT conferences, and some have made
> PAT conferences an annual event (for example, the International
> Society of Pharmaceutical Engineering (ISPE) and the International
> Forum of Process Analytical Chemistry (IFPAC)). The Pharmaceutical
> Technology section of the American Association of Pharmaceutical
> Sciences in collaboration with the Royal Pharmaceutical Society
> organized two consecutive Arden House Conferences in the US and UK on
> the FDA Initiatives in 2003 (PAT Initiative) and the proposed
> \"desired state\" of pharmaceutical manufacturing (2004). These and
> other scientific conferences afforded an opportunity to discuss the
> FDA initiative with industry, academia and regulatory colleagues from
> Canada, Europe and Japan.
>
> 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
> Japan will afford an opportunity to further strengthen the
> collaboration between FDA and MHLW. Health Canada has been invited to
> participate with FDA in the second PAT training program planned for
> the 2004-2005 fiscal year.
>
> 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 US, Europe, Switzerland, and
> Japan have incorporated PAT concepts in their curricula. Some of the
> FDA PAT Team members have been requested to serve as adjunct
> professors to teach and to participate on doctoral dissertation
> committees on PAT research projects.

#### State-of-the-art pharmaceutical science

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.

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.

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-   Product specifications based on mechanistic understanding of how
    formulation and process factors impact product performance.

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-   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).

1.  *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);

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-   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

    1.  *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.

2.  *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 (November 19-21,
> 2003) by the International Pharmaceutical Federation (FIP). This was
> in collaboration with FDA, EMEA, and other European trade and
> professional associations (EFPIA, EUFEPS, APIC/CEFIC and IPEC)
> <http://www.qualityworkshop.nl/html/welkom.html> .

4.  **A Systems Perspective:** \"**Points to Consider\"**

    1.  **Risk-based approaches that focus industry and agency attention
        on critical areas**

        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).

    1.  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.

2.  Emerging support infrastructure for the \"desired state\"

> Several academic institutions in the US, Europe, Switzerland, and
> Japan have incorporated PAT concepts in their curricula and several
> graduate students at these institutions are engaged in PAT research.
> Industry and academic collaborations (e.g., Consortium for Advanced
> Manufacturing of Pharmaceuticals or CAMP) are providing additional
> support.
>
> 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)]{.underline} has continued its discussions on PAT with
    participation of FDA PAT Team members.

> [Forum 5: Multivariate mathematical
> approaches](http://www.rpsgb.org.uk/pdfs/ntf5.pdf)\
> [Forum 6: Rapid methods in
> microbiology](http://www.rpsgb.org.uk/pdfs/ntf6.pdf)

-   [The Product Quality Research Institute]{.underline}

> 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](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)]{.underline}

> <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.

-   [International Society of Pharmaceutical Engineering
    (ISPE)]{.underline} is developing a number of programs to support
    the \"desired state\" of pharmaceutical manufacturing. For example:

    -   Discussions have been initiated to define the role and training
        needs of pharmaceutical engineering professionals.

    -   A process equipment manufacturers' forum is under consideration
        to (a) enable and foster a risk-based approach to manufacturing
        and compliance, (b) accommodate new PAT technologies and
        implementation requirements, (c) speed the delivery of
        manufacturing capacity, and (d) improve quality while reducing
        costs, through a restructuring of current equipment
        qualification practices.

    -   Creation of a peer-reviewed journal for science, engineering and
        Process Analytical Technology. The first issue is anticipated in
        January of 2006.

-   [American Association of Pharmaceutical Scientists
    (AAPS)]{.underline}

> 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>

1.  **Facilitate industry application of modern quality management**

    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.

    1.  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.

2.  \"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.

    -   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.

    -   The example emphasizes that process understanding and quality by
        design principles offer a more attractive means to mitigate
        risks posed in the following example:

![](media/image1.png){width="6.059722222222222in"
height="2.3402777777777777in"}

1.  \"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.

1.  **Enhanced quality systems approaches into the Agency\'s business
    processes**

    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.

2.  Manufacturing Science foundation of the FDA\'s Quality System

> The number of \"quality movement\" or trends in the 20^th^ 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).

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.  \"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.\"

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.  **Collaborations and Recommendations**

    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.

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:

-   *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.*

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.

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.  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.  **Next steps and Considerations for the Critical Path Initiative**

    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 US,
    Europe and Japan

-   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 Canada, MHLW, and EMEA to participate
    in the second training program

-   Share lessons learned and training materials with Health Canada,
    MHLW, and EMEA

-   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*

    1.  **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.

    -   If this is agreed upon in November 2004, ICH Q8 would reach Step
        2 and be available for public comment.

    -   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.

1.  **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
    United States economy. The Federal Government has an important role,
    through the Small Business Innovation Research (SBIR) and the Small
    Business Technology Transfer (STTR) programs, in helping to advance
    innovation, including innovation in manufacturing, through small
    businesses.*\"
    [*http://www.sba.gov/SBIR/execorder.html*](http://www.sba.gov/SBIR/execorder.html)

    -   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.

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-   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.

    -   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.

    -   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.

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-   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.

*Both pure and applied science have gradually pushed further and further
the requirements for accuracy and precision. However, applied science,
particularly in the mass production of interchangeable parts, is even
more exacting than pure science in certain matters of accuracy and
precision. Walter A. Shewhart*

**[The PAT Team Members include:]{.underline}**

**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:]{.underline}

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]{.underline}:

Albinus D'Sa (CDER)

Mike Gavini (CDER)

William Bargo (CVM)

Brenda Uratani (CDER)

[Reviewers:]{.underline}

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]{.underline}:**

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).

**Bibliography and References**

1\. **FDA Science Board Meetings**

-   November 16, 2001: Emerging Science Issues in Pharmaceutical
    Manufacturing

    -   <http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3799t1.htm>

    -   <http://www.fda.gov/ohrms/dockets/ac/01/slides/3799s1.htm>

    -   <http://www.fda.gov/cder/OPS/PAT.htm>

-   April 9, 2002: Emerging Science Issues in Pharmaceutical
    Manufacturing

    -   <http://www.fda.gov/ohrms/dockets/ac/02/transcripts/3853t1.rtf>

    -   <http://www.fda.gov/cder/OPS/PAT.htm>

1.  **Advisory Committee for Pharmaceutical Science Meetings**

-   [July 19, 2001 ACPS Meeting]{.underline}

    -   *Optimal Applications of At-line Process Controls on
        Pharmaceutical Production*

    -   *Orally Inhaled and Nasal Drug Products*

    -   *Risk-Based Chemistry, Manufacturing, and Controls Review*

> <http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3804t2.htm>
>
> <http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3804t2.doc>

-   [November 28 - 29, 2001: ACPS Meeting]{.underline}

    -   *Process Analytical Technology Subcommittee*

    -   *Stability testing and shelf-life*

    -   *Blend uniformity testing*

> <http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3804t1.doc>
>
> <http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3804t2.doc>

-   [October 23, 2002 Process Analytical Technology Subcommittee
    Meeting]{.underline}

    -   *Computer systems validation - Part 11 issues pertinent to PAT*

    -   *Rapid Microbiology Testing*

> <http://www.fda.gov/ohrms/dockets/ac/02/transcripts/3901T1.pdf>

-   [June 12-13, 2002 Process Analytical Technologies Subcommittee
    Meeting]{.underline}

    -   *PAT Training*

    -   *Regulatory \"risk\"*

    -   *Product and Process Development*

    -   *Process and Analytical Validation*

> <http://www.fda.gov/ohrms/dockets/ac/02/transcripts/3869T1.htm>
>
> <http://www.fda.gov/ohrms/dockets/ac/02/transcripts/3869T2.htm>

-   [February 25-26, 2002 Process Analytical Technologies Subcommittee
    Meeting]{.underline}

    -   *Process Analytical Technologies Applications and Benefits*

    -   *Product and Process Development*

    -   *Process and Analytical Validation*

    -   *Chemometrics*

> <http://www.fda.gov/ohrms/dockets/ac/02/transcripts/3841t1.pdf>
>
> <http://www.fda.gov/ohrms/dockets/ac/02/transcripts/3841t2.pdf>

-   [October 21-22, 2003 ACPS Meeting]{.underline}

    -   *Draft PAT Guidance -- Update*

    -   *Parametric Tolerance Interval Test for Dose Content Uniformity*

    -   *Risk-based CMC Review Proposals*

> <http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3996T1.pdf>
>
> <http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3996T2.pdf>

-   [September 17-18, 2003 Manufacturing Subcommittee
    Meeting]{.underline}

    -   *Defining Quality*

    -   *Considerations for \"Quality by Design\"*

    -   *Proposals for Regulatory Assessment of \"Quality by Design\"*

    -   *Quality by Design and Risk Based Regulatory Scrutiny: CMC*
        *Specifications and Post-Approval Changes*

> <http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3980T1.pdf>
>
> <http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3996T2.pdf>

-   [May 21-22, 2003 Manufacturing Subcommittee Meeting]{.underline}

    -   *Transition from Process Analytical Technologies (PAT)
        Subcommittee to Manufacturing Subcommittee*

    -   *Role of PAT in GMP Initiative*

    -   *Perspective on risk analysis for the GMP Initiative*

> <http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3951T1.pdf>
>
> <http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3951T2.pdf>

-   [July 20-21, 2004 Manufacturing Subcommittee Meeting]{.underline}

    -   *Update on ICH Q8, Q9 and Proposed Q10*

    -   *Update on Draft Guidance on Comparability Protocol*

    -   *Moving Towards the \"Desired State\"*

    -   *Manufacturing Science and Quality by Design as a Basis for
        Risk-based CMC Review*

    -   *Risk-based CMC Review Paradigm Under Quality by Design and
        Manufacturing Science Framework \-- Opportunities, Challenges,
        Current Activities, and Next Step*

    -   *Pilot Model for Prioritizing Selection of Manufacturing Sites
        for GMP Inspection*

    -   *Applying Manufacturing Science and Knowledge: Regulatory
        Horizons*

> <http://www.fda.gov/ohrms/dockets/ac/04/transcripts/2004-4052T1.PDF>
>
> <http://www.fda.gov/ohrms/dockets/ac/04/transcripts/2004-4052T2.PDF>

-   [April 13-14, 2004 ACPS Meeting]{.underline}

    -   *Parametric Tolerance Interval Test for Dose Content Uniformity*

    -   *Process Analytical Technologies (PAT) -- Next Steps*

    -   *PAT Applications for products in Office of Biotechnology
        Products (OBP)*

> <http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4034T2.pdf>

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