1 Ispe Pat Cop Dach Awareness Doc Final v1.0

Creating QbD / PAT
Management Awareness
ISPE PAT CoP D/A/CH
Dated September 27, 2007, V1.0

Contents
1 Management Summary .................................................................................................. 4
1.1 Objective ................................................................................................................. 4
1.2 Current situation in pharmaceutical industry ..................................................... 4
1.3 How to build Quality into Processes and Products? ......................................... 4
1.4 Strategic benefit of QbD / PAT-Projects .............................................................. 4
2 Why PAT - Drivers and Benefits ................................................................................... 6
2.1 FDA Drivers............................................................................................................. 6
2.2 FDA Benefits........................................................................................................... 6
2.3 Industry Drivers...................................................................................................... 6
2.4 Industry benefits .................................................................................................... 6
3 Implications of PAT - Organization and Process........................................................ 6
3.1 Organization ........................................................................................................... 6
3.1.1 Personnel........................................................................................................ 6
3.1.2 Management ................................................................................................... 6
3.1.3 QA Approach .................................................................................................. 6
3.2 Process ................................................................................................................... 6
3.2.1 Process Understanding................................................................................. 6
3.2.2 QA/QC ............................................................................................................. 6
3.2.3 Technology ..................................................................................................... 6
3.2.4 IT ...................................................................................................................... 6
4 Project Approach and Case Studies ............................................................................ 6
4.1 Introduction ............................................................................................................ 6
4.2 Questionnaires ....................................................................................................... 6
4.3 Case study results ................................................................................................. 6
4.3.1 Quality ............................................................................................................. 6
4.3.2 Process ........................................................................................................... 6
4.3.3 Risk.................................................................................................................. 6
4.3.4 Cost ................................................................................................................. 6
4.3.5 Personnel........................................................................................................ 6
4.3.6 Tools................................................................................................................ 6
4.3.7 Time................................................................................................................. 6
4.3.8 Validation ........................................................................................................ 6
4.3.9 Organization ................................................................................................... 6
4.3.10 Regulatory .................................................................................................... 6
4.4 Summary ................................................................................................................. 6
5 Appendix: Structured Catalogue of Standardised Questions with
Benchmarking ......................................................................................................... 6
5.1 Quality (category 1)................................................................................................ 6
5.2 Process (category 2).............................................................................................. 6
5.3 Risk (category 3) .................................................................................................... 6
5.4 Costs (category 4).................................................................................................. 6
5.5 Personnel (category 5) .......................................................................................... 6
Creating QbD / PAT , Dated September 27, 2007, V1.0 page 2 of 67

ISPE-PAT-CoP-DACH-Awareness-Doc-Final-V1.0
5.6 Tools (category 6) .................................................................................................. 6
5.7 Time (category 7) ................................................................................................... 6
5.8 Validation (category 8)........................................................................................... 6
5.9 Organization (category 9)...................................................................................... 6
5.10 Regulatory (category 10) ..................................................................................... 6
6 Appendix: Project Approach and Case Studies -- completed questionaires .......... 6
6.1 Case Studies 1 to 2 ................................................................................................ 6
6.2 Case Studies 3 to 6 ................................................................................................ 6
6.3 Case Studies 7 to 8 ................................................................................................ 6
7 Volunteers....................................................................................................................... 6
8 Glossary .......................................................................................................................... 6

1 Management Summary
1.1 Objective
The objective of this document is to create awareness about the FDAs QbD/PAT initiative and its
benefits. It describes
• Drivers and Benefits
• How to benchmark QbD/PAT projects
• Case studies
1.2 Current situation in pharmaceutical industry

Nowadays innovations in the pharmaceutical industry are limited due to regulatory aspects
which inhibit the introduction of new and state of the art technologies in validated processes.
The processes are fixed during clinical trials. Process parameters and quality attributes are part
of the registration file (licence). Most variations require change controls. Changes require a lot of
effort like pre-approval, additional clinical trials and registration activities.
Validated processes are inflexible to process optimisation measures or changes in feedstock by
suppliers. For example, bio-feed-stocks are difficult to handle under GMP conditions due to
regional and seasonal variations. During the product life cycle, process innovations with the
target to improve product quality continuously is related to high cost when changing the
registration file with the authorities.
To reduce this effort in the different areas of the pharmaceutical industry the FDA recommends
to build quality into processes and products. This is a paradigm change with respect to the
earlier way of final product quality testing.
1.3 How to build Quality into Processes and Products?

To build quality into processes and products the authorities recommend to use principles and
tools as QbD/PAT. This is an innovative way of thinking in developing and manufacturing
pharmaceuticals. Pharmaceutical manufacturers should implement innovative and state of the
art technologies to improve the production systems and for a sustainable cost reduction.
QbD/PAT ensures constant and high product quality on the basis of flexible manufacturing
processes. Thorough process understanding in combination with a well defined Design Space
allows much more flexible process control strategies even if input parameters will vary.
Regulatory authorities do not consider variability of the operating conditions within predefined
limits (Design Space) as changes.
1.4 Strategic benefit of QbD / PAT-Projects

Being aware of the regulatory flexibility industry can actively redefine their strategies applying
QbD/PAT principles. Better process understanding leads to higher product quality and process
robustness at lower costs and thus improves competitiveness.

Authority view Commercial Management view
More pharmaceuticals • Time-to-market
• More Innovation
with higher quality • Reduced documentation
• Optimized communication between authorities and
industry
• Guaranteed quality level ("unit-to-unit")
at lower cost • Decreasing cost of production by improved productivity
Further on: Competitive advantage
Image improvement
Existing data and resources can typically be used
Authorities view corresponds to Commercial Management view and the common goals
can be reached by QbD / PAT as an innovative way of thinking in manufacturing
pharmaceuticals.

2 Why PAT - Drivers and Benefits
The goal of the PAT approach is to ensure patient Regulatory
health by the availability of safe, effective and
affordable medicines.
This section summarizes and comments PAT drivers
and benefits from the perspective of the FDA (and
other regulatory authorities) and the pharmaceutical
Drivers QbD/PAT Benefits
industry to help decision makers interpreting and

implementing PAT strategy, processes and tools in
their organizations.
Industry
2.1 FDA Drivers
• Assurance of affordable and safe & effective drugs for citizens

• Ensuring high quality of drugs
• Facilitating innovation for manufacturing processes
Only efficient research of new drugs, optimized processes and dedicated quality control
procedures will provide in future affordable, safe & effective drugs for citizens. The
implementation of PAT principles and tools enables efficient manufacturing while maintaining
today’s quality standards.
Drug quality depends more on best development, production, storage and distribution strategies,
than on expanded quality testing. With PAT there will be a shift from lab based end product
quality testing to in-line, on-line or at-line testing.
Innovation transfer to routine production ensuring “state-of-the-art” manufacturing processes will
be accelerated by regulatory authorities.
2.2 FDA Benefits
• Time-to-approval
• Improved process understanding
• Reduced inspection frequency
Time-to-market means in a first step „time-to-approval“. Regulatory authorities are commited to

reduce time for administration by reduced volumes of CMCs / dossiers for new drugs as well as
for submission changes of approved drugs. The key to reach this goal is appropriate
management of increasing complexity.
Improved process understanding helps both industry and authority running, controlling and
observing processes on a well assessed science and risk based level. Process understanding is

the basis for process control and assured end product quality. Finally, time and frequency for
extended audits or inspections can be reduced.
2.3 Industry Drivers
• Reduced costs of manufacturing

• More flexible manufacturing processes
• Real-time-release
PAT efforts could generate competitive advantages, i.e. better corporate image, increased
quality and efficient management of risks. Cost of manufacturing or QA could be decreased by
increasing productivity and better availability of production equipment. Moreover PAT offers the
opportunity for interdisciplinary communication (e.g. R&D, manufacturing, QA, QC, IT
departments).
Manufacturing processes could become more safe and flexible under PAT. A defined design
space (Quality by design) for production processes offers flexibility for the used raw material,
APIs and even process controls. Process understanding leads to an appropriate management of
variability and improved operational efficiency (e.g.“Lean Manufacturing”, “Right first time”
strategy). Real time release could help reducing time in warehouses of raw materials, final &
intermediate products or bulk (work in progress). PAT projects can start in single unit operations
or could cover the whole production site. Incremental deployment is enabled.
Improved communication between industry and the regulatory authorities is provided by FDA´s
PAT teams („pre-approval“ activities). By implementing PAT tools and principles industry is
prepared in case PAT becomes mandatory. International harmonisation by ICH guidelines Q 8 to
10 defines many PAT elements as today’s GMP standards.
2.4 Industry benefits
• Using of „state-of-the-art“ technologies in manufacturing

• Guaranteed and improved quality level ("unit-to-unit")
• Reduced documentation
• Risk mitigation
• Real time data acquisition and integration
• Knowledge management
Implementation of „state-of-the-art“ and innovative production & control technology is

encouraged by regulatory authorities. Know how transfer from other industries (as IT, food,
automotive, electronic) is reasonable and useful. Reduced transfer time from development to
production by using PAT tools seems to be possible.
Reduced personnel placement, less OOS batches, reduced lead time, cleaning, set-up or
maintenance time lead to increased ROI. At the end a higher quality level of products will be
obtained and yield can be increased.

The use of PAT tools can reduce documentation efforts, e.g. by modified validation approaches.
Risk based manufacturing could abandon frequent audits.
Early and frequent feedback from regulatory authority, e.g. by PAT teams and expanded
communication within pre-approval activities is mandatory for successful PAT projects.
PAT has the potential for drug quality improvement. Increased production safety and process
robustness is created by enhanced process understanding within all departments (QA, QC, R&D
and Manufacturing). Risk mitigation by efficient risk management and the appropriate control of
critical quality & process parameters is the outcome of adequate implementation of PAT tools.
Raised automation of processes helps to assess and control critical process parameters within
the design space. Fewer lab based testing leads to fast and reliable information about product
quality within manufacturing processes. Data should be all time available, auditable and autarkic.
Enhanced process information will be created by structured data management. The process
know how can be documented by process fingerprints, statistical methodology or a total process
approach (e.g. downstream, upstream, tablet production). Knowledge management is the basis
for better process understanding and process transfer from development and manufacturing.
plan
product
QbD
do
act
PAT
process
check

3 Implications of PAT - Organization and Process
QbD/PAT
implications
Process
Organisation
Quality
Understanding
Management
IT
Technology
Personnel
3.1 Organization
3.1.1 Personnel
• Demand on qualification and/or skills of employees may change
PAT may have an impact on qualification profiles in respect to scientific data
analysis, statistics, process control, etc. Similar to implementing Six Sigma,
implementing a PAT program may require dedicated training on methods and
tools, including project management and statistics. (Probably at all levels of the
company comparable with the Six Sigma training structure - master black belts,
black belts, green belts, white belts?).
• Structural change within organization
There may be a need for implementation of a new department or restructuring of
departments to deal with the new demands.
Interaction and collaboration between departments and functions may need to be
increased (e.g. quality, regulatory, development, commercial production, etc.).
Contact to regulatory authorities may need to be intensified.
The implementation of PAT within the organizational structure requires
accountability, roles and responsibilities to be defined (Clearly defined process
owners, project managers, subject matter experts and process analysts).
Depending on the structure of the company, employees working for a PAT project
could stay members of different departments or be integrated in a separate PAT-
team or department.

Depending on the PAT approach (holistic or more specialized) an interdisciplinary
project team maybe useful (QA, R&D, engineering, QC, IT, manufacturing, etc.).
3.1.2 Management
• Commitment of management:
Management has to be committed to PAT to deal with the early phase of PAT,
which could mean more investment.
In later phases, when processes are more flexible due to PAT elements,
companies will be able to maintain quality at lower cost, and will be prepared for
future demands from agencies and be on top of the trend.
• Define PAT and development strategy:
Define general approach.
Define team.
Define which processes or products should be subjected to PAT first.
Define goals and objectives and the expected benefits.
Plan and commit resources (personnel, program money, equipment).
PAT means a paradigm shift from black/grey box to white box processes.
The development strategy may need to be revised – therefore, the specific
requirements concerning PAT need to be analyzed.
• Risk concerning company:
If PAT is ignored, there may be a risk of getting behind the industry (competitive
disadvantage), a risk of image or business loss due to lower operational efficiency
in sustaining reproducible product quality.
• Management objectives:
Regular review of benchmarks helps to stay on top of the project.
• Outsourcing:
Outsourcing partners need to be chosen and reviewed very carefully.
Points to consider are:
- Their ability to perform projects according to PAT.
- Knowledge transfer (content, interfaces, patent, etc.).
- Define accountabilities, roles and responsibilities.
- Communicational structure.
There may be an increased need for secrecacy agreements and/or more detailed
contracts.
• Communication
Communication between all kinds of different partners (e.g. departments Ù
departments, vendor company Ù company, company Ù agencies, etc.) may need
to be intensified.

3.1.3 QA Approach
• There may be an impact on existing QA structure.
• Change in regulatory processes
Communication between regulatory authorities may have to start earlier and may
be more regular (and possibly more informal) with PAT.
• Audits
Regulatory scrutiny will challenge the scientific understanding of quality relevant
factors and how quality relevant risks are mitigated. Developing departments will
get increasingly more attention from regulatory authorities. Continuous
improvement and a clear structure for documenting changes and deviations need
to be demonstrated. Comparison between real design space and documented
design space will be in focus of an audit.
• Validation
Validation will be demonstrated by continuous measurement of critical-to-quality
parameters in real/near time instead of the traditional three batch validation.
• Documentation
Better knowledge of impact of raw material may change specifications.
Specifications for submissions probably need to include design space and control
space.
3.2 Process
The QbD/PAT approach links the four areas of Process Understanding, QA/QC, Technology and
IT together. This is the core of the QbD/PAT paradigm shift, linking these areas together.
The process is controlled and fully understood and the right data for real time release enables
continuous process verification and improvement via knowledge management.
3.2.1 Process Understanding

• Development of process models:
The analysis of the process should define which parts have some flexibility
(Design space) and which are very rigorous.
In order to define system/process boundaries, (re-)structuring of complex
processes may be helpful.
• Situation analysis is the evaluation of historical data (out of specification results, corrective
actions.
• Impact analysis is the identification and evaluation of process steps, sources of variation
and the variables that are critical to quality.
• Identification of critical process parameters are needed to be determined using appropriate
techniques (e.g. FMEA, statistical analysis, risk analysis, root cause analysis, etc.).
• Monitoring/controlling of the process through definition and implementation of relevant
measurements. This is necessary to obtain data which can be reviewed for better
process/product understanding and control.

• Verification of the control cycle is necessary to understand the impact of process
parameters on process/product quality.
3.2.2 QA/QC
• Specifications
Quality control testing will evolve from testing against a discrete specification
(pass/fail) to real-time comparison of process/product signatures against a
reference.
• QC testing
Parametric release and inline control could have an impact on QC headcount and
work.
There may be a necessity for additional verification of parameters and definition of
prerequisites for parametric release.
In order not to miss a slow deviation from expected requirements (e.g. raw
material, wear of material, etc.) additional controls may be needed.
• Continuous improvement
Under PAT, manufacturing processes are monitored and controlled online,
leading to continuous process improvements as opposed to static process
validation. Continuous improvement and control of design space will be
increasingly important.
• Validate equipment including the control cycle
In contrast to the common validation approach, where testing the functionality of
the immediate equipment was sufficient, with PAT the complete control cycle of
the equipment has to be included.
3.2.3 Technology
• Continuous production
New equipment may be needed to enhance data acquisition and process
understanding. Better knowledge of the process could lead to continuous
production and faster release.
Due to design space, production equipment could be used more flexible.
• Availability of suitable sensors/methods
After identification of critical process parameters availability of suitable sensors
and methods has to be verified.
• Interface systems engineering Ù product engineering
Since all parameters of a process have to be well understood system engineers
and product engineers will probably have to work together more closely.

3.2.4 IT
• New software/ tools
New equipment, tools (e.g. SOA, XML) or applications may be needed to
enhance data acquisition and analysis.
Infrastructure, databases and software should enable easy data mining.
• New methods
New methods (e.g. MVDA, DoE, process modeling) including maintanance of
knowledge base must be implemented to enhance data and process analysis.
• Software validation
There will be increasing scrutiny on software validation at regulatory audits.
The requirement for complete validation of software may start even earlier during
research.

4 Project Approach and Case Studies
4.1 Introduction
Identification and evaluation of benchmarking parameters concerning PAT applications is
important for various aspects:
• to raise acceptance in the management
• to proof the maturity of projects
• for monitoring project progress
Following categories have been defined for this assessment already, and may be extended on
the user’s discretion:
• Quality (cat. 1)
• Process (cat. 2)
• Risk (cat. 3)
• Cost (cat. 4)
• Personnel (cat. 5)
• Tools (cat. 6)
• Time (cat. 7)
• Validation (cat. 8)
• Organization (cat. 9)
• Regulatory (cat. 10)
In order to allow a proper benchmarking, quantification is necessary which is independent from

absolute values and instead uses a rating which makes it possible to compare several projects.
Thus the answers should be rated with measures from 1 to 5, whereby 1 corresponds to total
dissatisfaction or not achieved and 5 indicate full satisfaction and success.
It is helpful to comment the decision of a specific rating for future review and audit in the
respective comment field.
4.2 Questionnaires
You will find the blank and completed questionaires in the appendix.

4.3 Case study results
Overall 11 case studies were collected based on the questionnaire in section 4.2. The case
studies origin is taken from manufacturing and development sites of big pharmaceutical
companies. The answers of case studies 5 - 11 were assessed according to the 10 categories in
section 4.1.
Benefits
Case C
Case A
Case B
Degree of QbD/PAT
4.3.1 Quality
Positive effects depend on the degree of the PAT implementation as following
• OOS reduction
• Better quality definition and analysis methods
• Reduction of complaints and recalls
4.3.2 Process
In all investigated case studies the general process understanding has strongly increased, e.g.
by optimized adjustment of known process parameters. In some case studies also new CPPs
were identified and used for advanced process control.
In most cases the process cycle time was reduced significantly and the productivity was
increased.
Introduction and implementation of new technologies for process automation (including sensors,
analytical devices and process control technologies) isn’t a mandatory prerequisite for QbD/PAT.
QbD can also be achieved by existing process and control equipment.
The benefits of implementing QbD/PAT in the process has been estimated very positive.

4.3.3 Risk
Risk assessment is a positive state of the art methodology for risk detection and minimization,
but independent from PAT. Risk assessment will become a key integral methods within PAT.
4.3.4 Cost
Most of the case studies can not answer to the question of ROI, only one case claims a ROI of
less than one year. For all other cases it is too early for any calculation.
As far as there are experiences, less rejected batches, less deviations increased yield higher
OOE, less consumables, less waste and reworks are reported.
4.3.5 Personnel
Up to now there is no reduction in personnel: Production is less lab intensive due to a higher
degree of automation, but the personnel has shifted its tasks to implement and improve PAT.
The mind change encourages communication between different depertments. A better process
understanding is obtained. There are hints to a slight increase in personnel security.
4.3.6 Tools
A clear result of the investigation is that more process data is recorded, analyzed and stored.
The data is additionally used within the batch documentation. In most cases the data is used for
advanced process control and the prediction of process deviations.
Applied analytical methods: e.g. NIR, MIR, Raman, laser diffraction, mass spectroscopy,
accelerated dissolution testing.
Applied statistical methods: e.g. MVDA, DMAIC, DoE.
4.3.7 Time
Summarizing, faster processes are reported:
• Higher utilization of resources.
• Reduced lead time by reduced intermediate off-line testing.
• Faster decisions for on-line quality assessment, faster and earlier decisions on waste
material.
• Due to automated data acquisition, shorter transition time from raw data to meaningful
process information.
• Material variability is detected earlier.
4.3.8 Validation
In total a lower effort for validation is expected but more effort has to be spend for facility,
equipment and software validation during PAT implementation.

4.3.9 Organization
QbD/PAT projects have an impact on the organization of pharmaceutical companies and
increase the interdisciplinary communications between departments.
4.3.10 Regulatory
Regulatory issues have a strong impact on:
• Frequency of contacts and communication (scientific based) with regulatory bodies.
• Earlier and more often contact before and during implementation phase.
• The kind of documentation will be changed (more precise and deeper science based,
earlier documentation during design expected).
• Positive impact on change control is expected.
4.4 Summary
The aspects of quality, risk, validation and regulatory can be summarized as positive experience
when PAT is professionally implemented. Companies with lower implementation expertise have
slightly positive expectations, but needs more experiences.
Process understanding has strongly increased as well as the interdisciplinary communication
between departments.
Generally speaking, a lot more data are stored due to implementation of PAT technologies; and
we notice that a broad variety of sensors is used.
Currently most of the ongoing PAT projects are not mature enough for any sophisticated
calculation of cost benefits. Experiences report about better indirect costs, like less rejected
batches, higher yields etc.
Regarding to costs, benefits are claimed more in terms of higher yield, reduced cycle times and
less rejections/ reworks than in less personnel; there is a shift in tasks for the same staff.

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5 Appendix: Structured Catalogue of Standardised Questions with Benchmarking
5.1 Quality (category 1)
Benchmark parameter Corresponding Description/Refere Comment

question nce
1 Right the first time Has the fraction of Right first time
products that has percentage of the
been produced products at the
right the first time point of
changed? manufacture that
are delivered right
first time with no
defects
Answer:
1 2 3 4 5
Comment:
2 Quality processes Did the quality Quality process e.g. risk

processes change all processes that assessment
in the organization regulate all quality
with PAT related activities in
implementation? an organization
Answer:
1 2 3 4 5
Comment:
3 Quality tests In which kind has Quality control Testing and

the process of all processes and definition of
quality control tests that evaluate specifications,
changed? the status quo Real-time-release
versus
specifications and
requirements
Answer:

question nce
4 Complaints/recalls Did you see a
change in the
amount of
complaints and
recalls of products
with RTR/PR
(Real Time
Release /
Parametric
Release)?
Answer:
1 2 3 4 5
Comment:
5 Product specification Is there an impact

to the product
specification?
Answer:
1 2 3 4 5
Comment:
6 Product specification Is the product

specification more
science based?
Answer:
1 2 3 4 5
Comment:
7 Product specification R&D Is the

development of
product
specification
changed with
PAT?
Answer:
1 2 3 4 5
Comment:

question nce
8 OOS Did you see a
change in the
number of OOS
incidences?
Answer:
1 2 3 4 5
Comment:

5.2 Process (category 2)

question nce
1 Cycle time Has the cycle time Cycle time
changed? this is the total
time from
commencing
manufacture to
delivering products
to the customer
which in many
cases is the
factory warehouse
Answer:
1 2 3 4 5
Comment:
2 Productivity increase Did a better

understanding of
the variability of a
measurement
result in an earlier
transition to the
next unit
operation?
Answer:
1 2 3 4 5
Comment:
3 Process parameters Were new

important process
parameters or
correlations
between process
parameters
identified?
Answer:
1 2 3 4 5
Comment:

question nce
4 Process parameters Were any known Acceptance
process criteria
parameters
adjusted?
Answer:
1 2 3 4 5
Comment:
5 Implementation of new Were new

technologies technologies in
the process
implemented?
Answer:
1 2 3 4 5
Comment:
6 Process understanding Was process i.e. usage of

understanding structured data
increased? management,
statistical
methods
Answer:
1 2 3 4 5
Comment:
7 Process understanding Did better

understanding of
a process help in
other processes?
Answer:
1 2 3 4 5
Comment:
8 Yield Is the yield higher

after PAT than
before?
Answer:
1 2 3 4 5
Comment:

question nce
9 Process control Did you find
additional
possibilities to
control the
process?
Answer:
1 2 3 4 5
Comment:

5.3 Risk (category 3)
Benchmark parameter Corresponding Description/ Comment

question Reference
1 Risk assessment Was the PAT
project a result of
a risk
assessment?
Answer:
1 2 3 4 5
Comment:
2 Risk assessment Did the PAT

project initiate risk
assessments?
Answer:
1 2 3 4 5
Comment:
3 Risk reduction Did the PAT

project reduce
risks?
Answer:
1 2 3 4 5
Comment:

5.4 Costs (category 4)

question Reference
1 Overall equipment Has the OEE Overall equipment Example entry
effectiveness (OEE) changed? effectiveness
This measures
how effectively the
manufacturing
equipment is used.
It is a product of
the product rate
multiplied by the
quality rate
multiplied by the
plant availability. A
figure of 100%
implies that the
plant is running flat
out every hour of
the day making
perfect products
Answer:
1 2 3 4 5
Comment:
2 Cost savings Where did you Personnel,

reduce costs? equipment, QC,
raw material etc.
Answer:
3 Return on Investment What is the period Investment phase

until break even of
the PAT project?
Answer:

5.5 Personnel (category 5)

question Reference
1 Personnel security Did you improve
the operator
or/and product
safety?
Answer:
1 2 3 4 5
Comment:
2 Automation versus human Was number of None

interaction personnel
reduced?
Answer:
1 2 3 4 5
Comment:

5.6 Tools (category 6)

question Reference
1 Information / data management Can the The information of
additional/gained the process can be
information be used on other
used in other levels or in other
areas as well? areas as well
Answer:
1 2 3 4 5
Comment:
2 Information / data management Do you store Data management

more or less of The data you store
information? while processing
the product
Answer:
1 2 3 4 5
Comment:
3 Information / data management Did you change

the
documentation
storage structure?
Answer:
4 Process control Are additional For example

analytical online exploitation
methods used to of data with neural
predict process networks
deviations?
Answer:
1 2 3 4 5
Comment:
5 Methods Which tools and i.e. as result of

methods did you automation,
use in the PAT usage of methods
project?
Answer:

5.7 Time (category 7)

question Reference
1 On time in full delivery Has the on time in On time in full Example entry
full delivery delivery
changed? This is the
percentage of
orders that are
satisfied on time in
full, with zero
defects. Note that
if there is one
defect in an order,
the OTIF is zero
percent
Answer:
1 2 3 4 5
Comment:
2 Time to market Did a better

understanding of
the process
reduce the
number of
iterations in
process
development (e.g.
scaling up)?
Answer:
1 2 3 4 5
Comment:
3 Time to market Is the efficiency in

licensing
processes
(submission
approval) higher
after PAT?
Answer:
1 2 3 4 5
Comment:

5.8 Validation (category 8)

question Reference
1 Process/parameter changes What relief in
validation efforts
did you notice?
Answer:
1 2 3 4 5
Comment:
2 Process/parameter changes Did you change e.g. switch of

the validation responsibilities in
approach? the organization
Answer:
1 2 3 4 5
Comment:
3 (Re)validation effort Did you reduce Effort in

the effort for (Re)validation
(re)validation (Re)validation is a
(how much in regular
percentage)? requirement. The
effort is the
complete work you
must do
(manpower,
paperwork, data
generation etc.) to
reinstate the
validated status
Answer:
1 2 3 4 5
Comment:
4 Validation of software Has PAT changed

your effort in
validating your
computer
systems?
Answer:
1 2 3 4 5
Comment:

5.9 Organization (category 9)

question Reference
1 Advantage to the competition Has the
organization
gained an
advantage to the
competition?
If yes, is this
advantage
measurable?
Answer:
1 2 3 4 5
Comment:
2 Communication between Is there a

departments feedback from the
changes in the
commercial
production to the
development
methodology
applied in R&D?
Answer:
1 2 3 4 5
Comment:
3 Change in IT Department Did the switch to

PAT have an
impact on your IT
department?
Answer:
1 2 3 4 5
Comment:

question Reference
4 Change in mind Has PAT an
impact on the
awareness of
methodologies
used in other
industries?
Answer:
1 2 3 4 5
Comment:

5.10 Regulatory (category 10)

question Reference
1 Regulatory requirements Has PAT an
impact on the
awareness of
regulatory
requirements?
Answer:
1 2 3 4 5
Comment:
2 Regulatory requirements Did PAT have an

impact on change
control processes
with regulatory
bodies?
Answer:
1 2 3 4 5
Comment:
3 Audits Are the

discussions with
regulatory bodies
more scientific?
Answer:
1 2 3 4 5
Comment:
4 Audits Has the frequency

of audits
changed?
Answer:
1 2 3 4 5
Comment:

question Reference
5 Documentation Has PAT an
influence on the
quality of
documentation
generated during
development?
Answer:
1 2 3 4 5
Comment:
6 Documentation Has PAT changed

your way of
applying for
registration?
Answer:
1 2 3 4 5
Comment:
7 Contact with regulatory bodies Did the time of

first contact to
regulatory bodies
change?
Answer:
1 2 3 4 5
Comment:
8 Contact with regulatory bodies Did the regulatory

body respond
earlier than
before?
Answer:
1 2 3 4 5
Comment:

6 Appendix: Project Approach and Case Studies -- completed questionaires
6.1 Case Studies 1 to 2

Case study 1:
• PAT topic "Water Monitoring Freeze Drying"
• Location / company Big Pharma, Switzerland
• Interviewer Dr. Altermatt
Case study 2:
• PAT topic “Blend Monitoring"
• Location / company Big Pharma, Germany
• Interviewer Dr. Christian Schmidt

Cat No Category Benchmark Corresponding Description/ Answer Answer
No Parameter Question References Case study 1 Case study 2
1 1 Quality Right the first time Has the percentage RIGHT FIRST TIME No, not yet No, not yet
of the products that percentage of the
has been produced products at the point of
right the first time manufacture that are
changed? delivered right first time
If yes, how (in with no defects
absolut and
percentage
numbers)?
1 2 Quality Quality processes Has the quality QUALITY PROCESS Yes, PAT data No, not yet
processes changed all processes that has been added
in the organization regulate all quality to the data that
with PAT related activities in an are reviewed prior
implementation? organization to release
1 3 Quality Quality tests In which kind has QUALITY CONTROL See above Not applicable
the process of all processes and tests
quality control that evaluate the status
changed? quo versus
specifications and
requirements
1 4 Quality complaints/ Has changed the No, not yet Not applicable
recalls amount of
complaints and
recalls of products
with RTR/PR (Real
Time
Release/Parametric
Release)?
1 5 Quality Product Is the product No, future impact No, not yet
specification specification more possible
science based? Is (narrower ranges)
there an impact to
the product
specification?

1 6 Quality Product Does the Not applicable Yes, if term
specification R&D developing of the specification is
product meant in a
specification broader
change with PAT? perspective of
intermediate and
end product
specifications
2 1 Process Cycle Time Hour Has the cycle time CYCLE TIME HOURS Elonged time due Not applicable
changed? This is the total time to additional
If yes, how (in from commencing process step
absolut and manufacture to
percentage delivering products to
numbers)? the customer which in
many cases is the
factory warehouse.
2 2 Process Productivity Could a better None Not applicable Theoretically yes,
Increase understanding of but times are in
the variability of a the order of
measurement lead minutes
to earlier transition
to the next unit
operation?
2 3 Process Process Has there be None No No
Parameters identified new
important process
parameters or
correlations
between process
parameters?
2 4 Process Implementation of Has there been Yes, the PAT tool
new technologies implemented new
technologies in the
process?
2 5 Process Process Has there been any Yes
Parameters adjustments to
known process
parameters?
2 6 Process Process Was it possible to Yes
Understanding increase process
understanding?

2 7 Process Process Did better No
Understanding understanding of a
process help in
other processes?
2 8 Process Yield Is the yield higher In terms a single
after PAT than batch: No. In
before? terms of overall
production: in
future potentially
yes
3 1 Risk Risk assessment Was the PAT No
project a result of a
risk assessment?
3 2 Risk Risk assessment Did the PAT project Yes, formal risk
initiate risk assessments
assessments? were introduced
3 3 Risk Risk reduction Did the PAT project Yes (high water
reduce risks? level -->
degradation)
4 1 Costs Overall Equipment Has the OEE OVERALL EQUIPMENT No
Effectiveness changed? EFFECTIVENESS
(OEE) If yes, how (in This measures how
absolut and effectively the
percentage manufacturing
numbers)? equipment is used. It is
a product of the product
rate multiplied by the
quality rate multiplied by
the plant availability. A
figure of 100% implies
that the plant is running
flat out every hour of the
day making perfect
product
4 2 Costs cost savings Where did you No, not yet
reduce costs?
4 3 Costs ROI What is the ROI, in see above
which period?

5 1 Personnel personnel security Could you improve No change
the operator or/and
product safety?
5 2 Personnel Automation versus Could number of None No
human interaction personnel be
reduced?
6 1 Tools Information/ Data Can the additional / The information of the Yes, for other
Management gained information process can be used on freeze drying
be used in other other levels or in other processes
areas as well? areas as well.
6 2 Tools process control Where are For example on-line No
analytical methods exploitation of data with
used to predict neural networks
process deviations?
6 3 Tools Information/ Data Has changed the DATA MANAGEMENT Yes, more data is
Management data management The data you store while currently stored.
with the project? Do processing the product Need for storing
you store more or all data under
less of information? discussion
Did you change the
documentation
storage structure?
6 5 Tools methods Which tools and NIR, MVDA
methods did you
use in the PAT
project?
7 1 Time On Time In Full Has the On Time in ON TIME IN FULL No
delivery Full delivery DELIVERY
changed? This is the percentage
If yes, how (in of orders that are
absolut and satisfied On Time In
percentage Full, with zero defects.
numbers)? Note that if there is one
defect in an order, the
OTIF is zero percent

7 2 Time Time to market Could a better None Yes
understanding of
the process reduce
the number of
iterations in process
development (e.g.
scaling up)?
7 3 Time Time to market Is the efficiency in Not applicable
licencing processes
(submission
approval) higher
after PAT?
8 1 Validation Process / Is a relief in None No
Parameter Changes validation efforts
noticeable?
If yes in which way?
8 2 Validation Process / Did you change the None No, not yet
Parameter Changes validation approach
(switch of
responsibilities in
the organization)? If
yes, how did you
change?
8 3 Validation (Re)validation effort Did you reduce the EFFORT IN No
effort for (RE)VALIDATION
(re)validation (how (Re)validation is a
much in regular requirement.
percentage)? The effort is the
complete work you must
do (manpower,
paperwork, data
generation, etc.)
8 4 Validation Validation of Has PAT changed No
Software your effort in
validating your
computer systems?

9 1 Organization Advantage to the Has the None No
competition organization gained
an advantage to the
competition? If yes,
is this advantage
measurable?
9 2 Organization Communication Is there a feedback Yes, PAT
between from the changes in philosophy
departments the commercial introduced into
production to the R&D
development
methodology
applied in R&D ?
9 3 Organization Change in IT Did changing to No
department PAT have an
impact on your IT
department?
9 4 (not evaluated
in case 1-4)
10 1 Regulatory regulatory Has PAT an impact No
requirements on the awareness
of regulatory
requirements?
10 2 Regulatory regulatory Did PAT have an No
requirements impact on change
control processes
with regulatory
bodies?
10 3 Regulatory audits Is there a more Not applicable
scientific discussion
with regulatory
bodies possible?
10 4 Regulatory audits Has the frequency No
of audits changed?
10 5 Regulatory documentation Has PAT an Not applicable
influence on the
quality of
documentation
during
development?

10 6 Regulatory documentation Has Pat changed No, not yet
your way of
applying for
registration?
1ß 7 (not evaluated
in case 1-4)
10 8 (not evaluated
in case 1-4)

Case study 3:
• PAT topic “PAT in Capsule & Tablet Manufacturing”
• Location / company Big Pharma, Europe
• Interviewer Christian Woelbeling
Case study 4:
• PAT topic PAT in Manufacturing
• Location / company Big Pharma, Europe
• Interviewer Disclosed
Case study 5:
• PAT topic “PAT for secondary operations (formulation filling and freeze drying)”
• Location / company Big Pharma, Belgium
Case study 6:
• PAT topic PAT for Research and Development
• Location / company Big Pharma , Germany

Cat No Category Benchmark Corresponding Description/ Answer Answer Answer Answer
No Parameter Question References Case Study 3 Case Study 4 Case Study 5 Case Study 6
0 1 Type of What is the Prod Final release R&D The project is in R&D
Project environment of the drug product R&D at the
project? moment, but will
go right through
to production.
0 2 Status of the What phase is the Ong Pending start-up Ong At the moment othe Method successful
project project in? inspection the first tests in r established for scale
industrial scale up. No products for
take place scale up at the
(looking for proof moment. No benefit
of concept). for usage of “old”
However there is products during
already routine production.
knowledge gained
out of it.
1 1 Right the first Has the fraction of Right first time 4 Additional testing, - Not yet in 1 At the moment - No relevant products
time the products that percentage of the during commercial there is only at the moment.
has been produced products at the manufacturing, production mode, monitoring of
right the first time point of still end product but this is moisture inside
changed? manufacture that testing, more expected, due to the dryer. The
are delivered right knowledge. implementation of expectation is that
first time with no Improvement: No feedback control. at the beginning
defects surprises during there will be an
end product increase of
testing, only rejects, because
confirmation, Only the process is
1 out of 500 out of more closely
spec batches. watched. Then
through CAPA,
eventually the
process will
become more
robust and “right
the first time” will
increase.

1 2 Quality Did the quality Quality process e.g. risk assessment 4 Still end product - PAT to replace 3 Not yet (still in 2
processes processes change all processes that testing. But more laboratory proof of concept –
in the organization regulate all quality process release test therefore decision
with PAT related activities in knowledge leads will be later), but it
implementation? an organization to less surprises is expected, that
during the final PAT will add a
end product tool for faster
testing. quality decision.
1 3 Quality tests In which kind has Quality control Testing and definition Additional On-In- Real-time release Objective and No change.
the process of all processes and of specifications, Real- At-line testing replacing lab faster quality
quality control tests that evaluate time-release implemented. The assay decision
changed? the status quo existing is still
versus there – No
specifications and regulatory change
requirements and still the same
filing! No change
management
necessary!
1 4 Complaints/re Did you see a 1 No RTR - Not yet 1 Not yet – the - No PTR/PR
calls change in the implemented project has not established.
amount of yet come to this
complaints and stage.
recalls of products
with RTR/PR
(Real Time
Release /
Parametric
Release)?
1 5 Product Is there an impact 1 No, still the same - Release specs 1 No – because 1
specification to the product MBR. consistent, added PAT will impact
specification? Guard band for the process
environmental specification,
variability rather than the
product
specification.

1 6 Product Is the product 1 The new - Yes, the use of 1 The process - No change in
specification specification more analytical tests the PAT release specification is product specification.
science based? are more science test was integral more science
based, but full to discussions based (specific to
science based about appropriate vaccines,
approach is only specifications. because of very
for new products diluted active
under ingredients)
development.
1 7 Product Is the development 5 Change in the - PAT for real-time 1 See above - No product in
specification of product future with the monitoring of development at the
R&D specification new filings under quality moment.
changed with new PAT FDA
PAT? approach!
1 8 OOS Did you see a 5 Dramatic - Not yet 1 No – not far 1
change in the reduction. The enough at the
number of OOS project brought moment.
incidences? OOS nearly to 0!
Process
improvement!
2 1 Cycle time Has the cycle time Cycle time 5 Yes, streamlined - Not anticipated to 3 No feedback at 1
changed? this is the total time the process, change the moment, but
from commencing much shorter significantly, but the aim is yes –
manufacture to cycle times, there will be lower (faster
delivering products proved by some decrease quality decision)
to the customer evaluations! arising from the
which in many elimination of
cases is the factory intermediate off-
warehouse line testing
(particularly
during start-up).
2 2 Productivity Did a better 5 Key point/benefit, - Expected to 3 YES - Not applicable
increase understanding of WIP is no longer provide better
the variability of a in unknown control and
measurement status. provide process
result in an earlier understanding,
transition to the but not increased
next unit productivity
operation?

2 3 Process Were new 2 Yes, but the same - New sources of 5 Yes 3
parameters important process parameters were variability have
parameters or identified. been identified,
correlations but not yet
between process characterized
parameters
identified?
2 4 Process Were any known Acceptance criteria 5 Same parameters - PAT used for 5 YES 1
parameters process much more feedback control
parameters precise, much of filling
adjusted? better process equipment.
understanding
2 5 Implementatio Were new 1 Still the same - First commercial 2 Yes at clinical 1 Not yet.
n of new technologies in the process, new installation of the scale. The
technologies process analytical control robustness of the
implemented? technologies technology process has to be
implemented anywhere in the verified before the
successfully world (NMR on information is
solids) given to the
authorities.
2 6 Process Was process i.e. usage of structured 5 Yes - Yes, including 4 4
understanding understanding data management, insight into
increased? statistical methods previously
undetected
variability.
2 7 Process Did better 5 Cross product - Once new source 2 No because 2
understanding understanding of a effects, shorter of variability is except of NIR, the
process help in process characterized, it technologies are
other processes? optimization for should have too difficult to
other products impact on other transfer.
and shorter time solid filling lines,
to market effect. and the
technology may
help in setting
API specifications
for subsequent
products.

2 8 Yield Is the yield higher - 3 for the process - No. 1 Would not sell Pat 1
after PAT than itself and 5 for no as a project that
before? more lost will increase yield.
batches!! PAT is more a
tool to increase
compliance and
quality, rather
than yield.
2 9 Process Did you find 1 No changes in the - No 4 Yes 4 Part of the process
control additional process control could be controlled
possibilities to by NIR.
control the
process?
3 1 Risk Was the PAT 5 Risk assessment - No. A rigorous 3 There was a good 3
assessment project a result of a made for market FMEA was knowledge of the
risk assessment? supply – developed as process – Risk
Economic Risk part of the PAT Analysis was
assessment! installation. already done
But the
Assessment was
made already 15
years ago.
3 2 Risk Did the PAT 1 No additional in - Yes. 1 No because it 2
assessment project initiate risk this project. Other was already done
assessments? projects with Risk for process
assessment validation
already before the
PAT initiative.
Confirmation of
the chosen
approach.
3 3 Risk reduction Did the PAT 5 Yes, supply is - Anticipated this 4 Yes 5
project reduce with the new will be the case.
risks? more robust and
secured!!

4 1 Overall Has the OEE Overall equipment Example entry 4 Streamlined the - Anticipated that 1 Increase, return 1
equipment changed? effectiveness manufacturing this will be the on investment is
effectiveness This measures case questionable.
(OEE) how effectively the There is a
manufacturing question of what
equipment is used. is more important:
It is a product of quality and
the product rate compliance or
multiplied by the costs.
quality rate
multiplied by the
figure of 100%
implies that the
out every hour of
the day making
perfect products
4 2 Cost savings Where did you Personnel, equipment, Minimized Expected savings Cost could be No reduction in costs
reduce costs? QC, raw material etc. WIP/Work in in recovery of saved due to till now.
Process partial lots and faster decision on
Less rejected elimination (or at good/bad product.
batches least decrease) in
off-line testing.
Early detection of
variability of raw
material.
New detected /
invented critical
parameter
resulted in a new
parameter for the
specification. - >
Hugh saving by
early detection
Minimizing QC
testing by moving
it to the plant

4 3 Return on What is the period Investment phase Less than 1 year Has not been No answer at the
Investment until break even of calculated. Can moment – but is
the PAT project? be performed that really the
once the system purpose of PAT?
is operational.
5 1 Personnel Did you improve 5 Yes - 100% quality 1 No - Not applicable.
security the operator or/and assessment is
product safety? anticipated to
improve product
safety and
efficacy
5 2 Automation Was number of None 1 Same staff - Anticipated 2 What’s the cost of - Not applicable.
versus human personnel outcome, based ownership? PAT
interaction reduced? on PAT being usually means
less labor more technology
intensive at final – so there would
deployment. be more likely a
Some personnel change of skills,
resource will be rather than an
relocated, rather objective
than eliminated, decrease of
but as this is a people.
new process, all
headcount are
projected, rather
than actual.
6 1 Information / Can the The information of 5 The data is - Expected to be 1 No – but not far 5
data additional/gained the process can be gathered in a the case enough at the
management information be used on other special database moment.
used in other areas levels or in other incl. a feedback to
as well? areas as well R&D.
6 2 Information / Do you store more Data management 5 More valuable - Additional data 4 far more - Not applicable.
data or less of The data you store information collected, but
management information? while processing fully automated,
the product whereas
traditional
process was
more labor
intensive

6 3 Information / Did you change PAT data in Batch Incorporated 4 Yes – adapt some Not applicable.
data the documentation Documentation directly into DCS servers
management storage structure? added. PAT data
is in a separate
DB and printed
out.
6 4 Process Are additional For example online 5 Yes new - Much higher data 4 Yes – more long 1
control analytical methods exploitation of data analytical density, but no term quality input
used to predict with neural methods were additional - trend analysis
process networks invented and methods aside
deviations? used for the from PAT
process control.
6 5 Methods Which tools and i.e. as result of Method: NIR – Not clear in the Plasma system, Mass spectrometry
methods did you automation, usage of API content objective of this NIR, two other
use in the PAT methods question. technologies, but
Method:
project? no further
Accelerated
dissolution - film description
quality because of
Intellectual
Method: Laser Property.
defraction -
Particle size
measurement
7 1 On time in full Has the on time in On time in full Example entry 4 - Likely to increase 3 No feedback at - Not applicable.
delivery full delivery delivery due to real-time the moment –
changed? This is the quality target is to
percentage of assessment increase
orders that are
full, with zero
defects. Note that
if there is one
defect in an order,
the OTIF is zero
percent

7 2 Time to Did a better 5 Yes, main project - Will probably 1 PAT will not be a - Not applicable.
market understanding of driver. Also cross actually add big driver to
the process reduce product benefits resources initially reduce time to
the number of realized. to understand market. It will
iterations in and characterize make the process
process sensor response more robust, but
development (e.g. and process this will not have
scaling up)? variability a great impact on
timing.
7 3 Time to Is the efficiency in - Can not be - Yet to be 4 Yes - Not applicable.
market licensing answered yet, determined
processes due to ongoing
(submission submissions
approval) higher under new FDA
after PAT? QbD PAT
approach.
8 1 Process/para What relief in 2 Still traditional - Not yet known 4 - Not applicable.
meter validation efforts validation. There
changes did you notice? is more
confidence in the
Validation
approach, but no
relief in the
validation efforts.
8 2 Process/para Did you change e.g. switch of 1 No change. - Added PAT 1 Not yet – but will - Not yet.
meter the validation responsibilities in the characterization be
changes approach? organization to process
validation
8 3 (Re)validation Did you reduce the Effort in 1 Still the same - Yet to be - Not far enough – 1
effort effort for (Re)validation approach. determined target, but no
(re)validation (how (Re)validation is a feedback.
much in regular
effort is the
complete work you
must do
(manpower,
paperwork, data
generation etc.) to
reinstate the
validated status

8 4 Validation of Has PAT changed 5 More analytical - Imposed 1 No 1

software your effort in devices result in additional CSV
validating your higher validation testing for PAT
computer efforts. system
systems?
9 1 Advantage to Has the 5 Main driver was - Not a high priority 4 1
the organization the shorter Time for this
competition gained an To Market. installation.
advantage to the
competition?
If yes, is this
advantage
measurable?
9 2 Communicatio Is there a feedback 4 Still room for - R&D “owned” 4 5
n between from the changes improvement process control
departments in the commercial strategy and
production to the partnered in PAT
development development.
methodology
applied in R&D?
9 3 Change in IT Did the switch to 5 Yes, additional - Not particularly 1 1
Department PAT have an SW to manage,
impact on your IT higher data
department? volume etc.
9 4 Change in Has PAT an 5 Yes, learning - Installation has 3 It’s coming, but it 4
mind impact on the from others in the raised awareness takes time
awareness of competence and visibility of
methodologies team. PAT, but not
used in other particularly from
industries? other industries.

10 1 Regulatory Has PAT an 5 Following the new - PAT installation 1 No, there is not 3
requirements impact on the FDA Risk based is facilitating much difference
awareness of and PAT oriented discussion with in filing a PAT
regulatory paradigm change. regulatory application,
requirements? agencies because the
regarding description of the
changing process is not so
expectations for big. CMC section
submissions, will be bigger
particularly with
respect to risk
management.
10 2 Regulatory Did PAT have an 5 Submission - Expected to be - Not yet - Not applicable.
requirements impact on change ongoing the case
control processes according to new
with regulatory PAT Guidance.
bodies?
10 3 Audits Are the 5 Yes, lot of - yes 3 It depends on - Not applicable.
discussions with interactive authorities and
regulatory bodies discussions on a inspector.
more scientific? high scientific
level.
10 4 Audits Has the frequency 1 No change - Anticipated to 1 No 1
of audits changed? decrease, but
has not yet
transpired.
10 5 Docu- Has PAT an 5 More precise - Documentation 3 Yes 3
mentation influence on the Documents in quality hasn’t
quality of R&D, justification changed, but
documentation for docs and additional
generated during better process development
development? description, better data was
validation of the required.
CPP ranges,
explanation of
the process and
the process
understanding
increased and is
more extensive

10 6 Docu- Has PAT changed 5 Yes in New - Lilly discussions 3 Especially 1

mentation your way of products! with regulatory validation of
applying for bodies were methods will
registration? more forthcoming increase.
and technical
than traditionally
10 7 Contact with Did the time of first 5 Yes in very early - PAT discussions 1 No 1
regulatory contact to stage, during were held
bodies regulatory bodies filing/submission separately (and
change? phase. earlier) from
traditional
regulatory
conversations to
ensure PAT did
not become
bottleneck to
submission
conversations.
10 8 Contact with Did the regulatory 5 Yes very - Responded in - No feedback yet. 1
regulatory body respond interested, mutually agreed
bodies earlier than educate the EU timeframe.
before? authorities with
the chosen
approach!

Case study 7:
• PAT topic “PAT Case Study from prior company As of April, 2005, PAT Pilot”
• Location / company Big Pharma, Global
• Interviewer David Radspinner
Case study 8:
• PAT topic PAT in R&D Environment
• Location / company Big Pharma , Europe

0 1 Type of What is the Prod Driven by Quality Prod
Project environment of the organization
project?
0 2 Status of the What phase is the Ong As of April, 2005 Ong Study phase
project project in?
1 1 Right the first Has the fraction of Right first time - Not disclosed Not yet
time the products that percentage of the implemented in
has been produced products at the routine production
right the first time point of
changed? manufacture that
are delivered right
first time with no
defects
1 2 Quality Did the quality Quality process e.g. risk assessment 4 Systems remain 1
processes processes change all processes that the same, but
in the organization regulate all quality adapted to reflect
with PAT related activities in a risk-based
implementation? an organization approach

1 3 Quality tests In which kind has Quality control Testing and definition Several end- No change
the process of all processes and of specifications, Real- product,
quality control tests that evaluate time-release laboratory-based
changed? the status quo tests were in a
versus position to be
specifications and replaced with
requirements real-time process
analytics and
predictive models.
1 4 Complaints/re Did you see a - Not disclosed Not yet
calls change in the implemented in
amount of routine production
complaints and
recalls of products
with RTR/PR
(Real Time
Release /
Parametric
Release)?
1 5 Product Is there an impact 3 Specification, as 1
specification to the product defined as an
specification? analytical
property, test and
acceptance
criteria – yes.
The tests were
replaced with on-
line/at-line
analytics and
predictive models.
Possible changes
to the acceptance
criteria were not
disclosed.
1 6 Product Is the product 4 The mechanisms 1
specification specification more by which to
science based? measure and
assess the quality
attributes of
interest were
based upon
sound science.

1 7 Product Is the development - Not disclosed 1
specification of product
R&D specification
changed with
PAT?
1 8 OOS Did you see a - Not disclosed Not yet
change in the implemented in
number of OOS routine production
incidences?
2 1 Cycle time Has the cycle time Cycle time 4 Not disclosed – 5 Not yet – but is
changed? this is the total time only mention was expected
from commencing that analytical
manufacture to testing cycle time
delivering products was reduced.
to the customer
which in many
cases is the factory
warehouse
2 2 Productivity Did a better 1 Not disclosed 5 Not yet – but is
increase understanding of expected
the variability of a
measurement
result in an earlier
transition to the
next unit
operation?
2 3 Process Were new 4 It was disclosed Not yet
parameters important process that material
parameters or attributes and
correlations select process
between process parameters, in
parameters combination,
identified? affected the
dissolution rate of
the product.
Other
relationships were
not disclosed.

2 4 Process Were any known Acceptance criteria - To be expected
parameters process
parameters
adjusted?
2 5 Implementatio Were new 5 New analytical 5
n of new technologies in the technologies
technologies process applied.
implemented?
2 6 Process Was process i.e. usage of structured 5 5
understanding understanding data management,
increased? statistical methods
2 7 Process Did better - Not disclosed 3
understanding understanding of a
process help in
other processes?
2 8 Yield Is the yield higher 5 Disclosed that 5 To be expected
after PAT than drying yield was
before? higher (specific
amount not
disclosed).
2 9 Process Did you find 5 Yes, drying, 5
control additional blending.
possibilities to
control the
process?
3 1 Risk Was the PAT 1 Project started 1
assessment project a result of a prior to PAT
risk assessment? guidance or the
maturation of the
risk-based
approach.
3 2 Risk Did the PAT 5 Significant Risk 5
assessment project initiate risk assessments
assessments? across many
levels were
executed and
utilized.

3 3 Risk reduction Did the PAT 5 This question is Not yet
project reduce too vague. Risks implemented – to
risks? of what? What be expected
has been
presented is that
PAT reduced
risks associated
with poor
sampling, delayed
analytics,
ineffectual
qualification and
validation.
4 1 Overall Has the OEE Overall equipment Example entry - Not disclosed 5 To be expected
equipment changed? effectiveness upon
effectiveness This measures implementation
(OEE) how effectively the
manufacturing
equipment is used.
It is a product of
the product rate
multiplied by the
quality rate
multiplied by the
figure of 100%
implies that the
out every hour of
the day making
perfect products
4 2 Cost savings Where did you Personnel, equipment, Laboratory No cost reduction,
reduce costs? QC, raw material etc. personnel, but better OEE,
consumables, higher yields, …
waste
4 3 Return on What is the period Investment phase Not disclosed Not yet calculated
Investment until break even of
the PAT project?

5 1 Personnel Did you improve 4 API reaction 1
security the operator or/and sampling risk
product safety? reduced. This
was the only area
disclosed.
5 2 Automation Was number of None 5 In the laboratory, 1
versus human personnel yes.
interaction reduced?
6 1 Information / Can the The information of - Not disclosed 5
data additional/gained the process can be
management information be used on other
used in other areas levels or in other
as well? areas as well
6 2 Information / Do you store more Data management - More information. 5
data or less of The data you store Stored for
management information? while processing business reasons.
the product
6 3 Information / Did you change Not disclosed 1
data the documentation
management storage structure?
6 4 Process Are additional For example online 5 Yes 1
control analytical methods exploitation of data
used to predict with neural
process networks
deviations?
6 5 Methods Which tools and i.e. as result of By methods do DMAIC Tools
methods did you automation, usage of you mean (Control charts,
use in the PAT methods measurement process capability
project? systems? NIR analysis, …), NIR
was primarily Measurement
used for process system
analytics.
Multivariate
analysis tools
(e.g. PLS for NIR
model calibration,
other techniques
for dissolution
predictive
models).

7 1 On time in full Has the on time in On time in full Example entry - Not disclosed 5 To be expected
delivery full delivery delivery
changed? This is the
percentage of
orders that are
full, with zero
defects. Note that
if there is one
defect in an order,
the OTIF is zero
percent
7 2 Time to Did a better - Not applicable Not applicable
market understanding of
the process reduce
the number of
iterations in
process
development (e.g.
scaling up)?
7 3 Time to Is the efficiency in - Not disclosed for Submission not
market licensing follow-on yet done
processes products.
(submission Regulatory
approval) higher efficiency for
after PAT? change of this
product improved.
8 1 Process/para What relief in 5 Significant relief 1 No relief
meter validation efforts using a risk-
changes did you notice? based approach
with process
understanding,
monitoring and
control.
8 2 Process/para Did you change e.g. switch of 4 Only to use a risk- 1
meter the validation responsibilities in the based iterative
changes approach? organization and incremental
approach.

8 3 (Re)validation Did you reduce the Effort in - Not disclosed 1
effort effort for (Re)validation
(re)validation (how (Re)validation is a
much in regular
effort is the
complete work you
must do
(manpower,
paperwork, data
generation etc.) to
reinstate the
validated status
8 4 Validation of Has PAT changed 5 Yes, now risk- 1
software your effort in based, iterative
validating your and incremental
computer for many
systems? systems.
9 1 Advantage to Has the - Not disclosed Not yet
the organization
competition gained an
advantage to the
competition?
If yes, is this
advantage
measurable?
9 2 Communicatio Is there a feedback - Not disclosed 3
n between from the changes
departments in the commercial
production to the
development
methodology
applied in R&D?
9 3 Change in IT Did the switch to - Yes, awareness 1
Department PAT have an of criticality of
impact on your IT historians not only
department? for storage, but
for model
predictive control.

9 4 Change in Has PAT an 2 Slow progress. 4
mind impact on the
awareness of
methodologies
used in other
industries?
10 1 Regulatory Has PAT an - 3
requirements impact on the
awareness of
regulatory
requirements?
10 2 Regulatory Did PAT have an 5 Presented that Submission not
requirements impact on change regulatory relief yet done
control processes was granted for
with regulatory changes to
bodies? existing product.
10 3 Audits Are the 5 Absolutely. Not applicable
discussions with (not yet
regulatory bodies implemented)
more scientific?
10 4 Audits Has the frequency - Not disclosed Not applicable
of audits changed? (not yet
implemented)
10 5 Documentatio Has PAT an - Not disclosed 1
n influence on the
quality of
documentation
generated during
development?
10 6 Documentatio Has PAT changed 5 Only disclosed for Submission not
n your way of this project. Yes, yet done
applying for now science and
registration? risk-based.
10 7 Contact with Did the time of first 4 Yes. Engaged Submission not
regulatory contact to earlier than yet done
bodies regulatory bodies typical PAS.
change?
10 8 Contact with Did the regulatory 5 Yes. Submission not
regulatory body respond yet done
bodies earlier than
before?

7 Volunteers
For each chapter a group of volunteers worked on the contents.
Thanks to all the participants spending the effort to make this document happen and to provide
the creative input.
Christian Wölbeling (chairman)
Dr. Schmidt-Bader (coordinator)
Lydia Dolezel (coordinator)
Thomas Peither (coordinator)
Dr. Christian Schmidt (coordinator)
Dr. Rolf Altermatt
Dr. Rolf Bauer
Dr. Reinhard Baumfalk
Josef Braunschädel-Hilger
Dr. Jens Cardinal
Jeannette Ewen
Norbert Franz
Dr. Wolfgang Fischer
Georg Frinke
Dr. Jürgen Haas
Dr. Jörg Häußler
Steffen Himstedt
Dr. Thilo Jahr
Dr. Frauke Jordt
Prof. Dr. Rudolf Kessler
Dr. Wolfgang List
Joachim Mannhardt
Dr. Jochen Mohns
Karin Mühlfriedel
Thomas Peither
Volker Roeder
Dr. Marc Schiller
Dr. Ingo Symietz
Dr. Hans Tups
Michael Voß
Wolfgang Winter

8 Glossary
API Active Pharmaceutical Ingredient
CMC Chemistry, Manufacturing and Control
CoP Community of Practice
CPP Critical Process Parameter
CQA Critical Quality Attributes
CSV Computer System Validation
DB Data Base
DCS Distributed Control System
DMAIC Define Measure Analyze Implement and Control
DoE Design of Experiment
DSC Differential Scanning Calorimetry
EU European Union
FDA Food and Drug Administration
FMEA Failure Mode and Effects Analysis
GMP Good Manufacturing Practice
HPLC High Performance Liquid Chromatography
ICH International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use
IT Information Technology
MIR Mid Infrared (Spectroscopy)
MVDA Multi Variate Data Analysis
NIR Near Infrared (Spectroscopy)
NMR Nuclear Magnetic Resonance (Spectroscopy)
OEE Overall Equipment Effectiveness
OOS Out of Specification
OTIF On Time in Full Delivery
PAS Parental Alienation Syndrome
PAT Process Analytical Technology
PLS Partial Least Squares
PR Parametric Release
QA Quality Assurance

QbD Quality by Design
QC Quality Control
R&D Research and Development
ROI Return on Investment
RTR Real Time Release
SOA Service Oriented Architecture
SW Software
WIP Work in Progress
XML Extensible Markup Language


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Creating QbD / PAT

Dated September 27, 2007, V1.0

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1.2 Current situation in pharmaceutical industry

1.3 How to build Quality into Processes and Products?

1.4 Strategic benefit of QbD / PAT-Projects

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industry to help decision makers interpreting and

2.1 FDA Drivers

• Assurance of affordable and safe & effective drugs for citizens

2.2 FDA Benefits

Time-to-market means in a first step „time-to-approval“. Regulatory authorities are commited to

Creating QbD / PAT , Dated September 27, 2007, V1.0 page 6 of 67

2.3 Industry Drivers

• Reduced costs of manufacturing

2.4 Industry benefits

• Using of „state-of-the-art“ technologies in manufacturing

Implementation of „state-of-the-art“ and innovative production & control technology is

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3.2.1 Process Understanding

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In order to allow a proper benchmarking, quantification is necessary which is independent from

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Creating QbD / PAT , Dated September 27, 2007, V1.0

5.1 Quality (category 1)

Benchmark parameter Corresponding Description/Refere Comment

2 Quality processes Did the quality Quality process e.g. risk

3 Quality tests In which kind has Quality control Testing and

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5 Product specification Is there an impact

6 Product specification Is the product

7 Product specification R&D Is the

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Benchmark parameter Corresponding Description/Refere Comment

2 Productivity increase Did a better

3 Process parameters Were new

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5 Implementation of new Were new

6 Process understanding Was process i.e. usage of

7 Process understanding Did better

8 Yield Is the yield higher

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Creating QbD / PAT , Dated September 27, 2007, V1.0 page 24 of 67

Benchmark parameter Corresponding Description/ Comment

2 Risk assessment Did the PAT

3 Risk reduction Did the PAT

Creating QbD / PAT , Dated September 27, 2007, V1.0 page 25 of 67

Benchmark parameter Corresponding Description/ Comment

2 Cost savings Where did you Personnel,

3 Return on Investment What is the period Investment phase

Creating QbD / PAT , Dated September 27, 2007, V1.0 page 26 of 67

Benchmark parameter Corresponding Description/ Comment