Creating QbD / PAT Management Awareness - ISPE … · Creating QbD / PAT Management Awareness ISPE...

Creating QbD / PAT Management Awareness

ISPE PAT CoP D/A/CH

Dated September 27, 2007, V1.0

Creating QbD / PAT , Dated September 27, 2007, V1.0 page 2 of 67 ISPE-PAT-CoP-DACH-Awareness-Doc-Final-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


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 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 industry to help decision makers interpreting and implementing PAT strategy, processes and tools in their organizations.

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

Drivers BenefitsQbD/PAT

Industry

Regulatory

Drivers BenefitsQbD/PAT

Industry

Regulatory


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.

QbDPAT

plan

check

act do

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QbDPAT

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3 Implications of PAT - Organization and Process

QbD/PATimplications

ProcessOrganisation

Personnel

ManagementUnderstanding

TechnologyIT

Quality

QbD/PATimplications

ProcessOrganisation

Personnel

ManagementUnderstanding

TechnologyIT

Quality

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 departments, vendor company company, company 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 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.

Ben

efits

Degree of QbD/PAT

Case A

Case B

Case C

Ben

efits

Degree of QbD/PAT

Case A

Case B

Case C

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.


"Ranking" of benefits

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5 Appendix: Structured Catalogue of Standardised Questions with Benchmarking

5.1 Quality (category 1)

Benchmark parameter Corresponding question

Description/Reference

Comment

1 Right the first time Has the fraction of products that has been produced right the first time changed?

Right first time percentage of the products at the point of manufacture that are delivered right first time with no defects

Answer: 1 2 3 4 5

Comment:

2 Quality processes Did the quality processes change in the organization with PAT implementation?

Quality process all processes that regulate all quality related activities in an organization

e.g. risk assessment

Answer: 1 2 3 4 5

Comment:

3 Quality tests In which kind has the process of quality control changed?

Quality control all processes and tests that evaluate the status quo versus specifications and requirements

Testing and definition of specifications, Real-time-release

Answer:




Comment

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:




Comment

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)



Comment

1 Cycle time Has the cycle time changed?

Cycle time 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:




Comment

4 Process parameters

Were any known process parameters adjusted?

Acceptance criteria

Answer: 1 2 3 4 5

Comment:

5 Implementation of new technologies

Were new technologies in the process implemented?

Answer: 1 2 3 4 5

Comment:

6 Process understanding Was process understanding increased?

i.e. usage of structured data 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:




Comment

9 Process control Did you find additional possibilities to control the process?

Answer: 1 2 3 4 5

Comment:


5.3 Risk (category 3)


Description/ Reference

Comment

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)



Comment

1 Overall equipment effectiveness (OEE)

Has the OEE changed?

Overall equipment 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

Example entry

Answer: 1 2 3 4 5

Comment:

2 Cost savings Where did you reduce costs?

Personnel, equipment, QC, raw material etc.

Answer:

3 Return on Investment What is the period until break even of the PAT project?

Investment phase

Answer:


5.5 Personnel (category 5)



Comment

1 Personnel security Did you improve the operator or/and product safety?

Answer: 1 2 3 4 5

Comment:

2 Automation versus human interaction

Was number of personnel reduced?

None

Answer: 1 2 3 4 5

Comment:


5.6 Tools (category 6)



Comment

1 Information / data management Can the additional/gained information be used in other areas as well?

The information of the process can be used on other levels or in other areas as well

Answer: 1 2 3 4 5

Comment:

2 Information / data management Do you store more or less of information?

Data management The data you store 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 analytical methods used to predict process deviations?

For example online exploitation of data with neural networks

Answer: 1 2 3 4 5

Comment: 5 Methods Which tools and

methods did you use in the PAT project?

i.e. as result of automation, usage of methods

Answer:


5.7 Time (category 7)



Comment

1 On time in full delivery Has the on time in full delivery changed?

On time in full delivery 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

Example entry

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)



Comment

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 the validation approach?

e.g. switch of responsibilities in the organization

Answer: 1 2 3 4 5

Comment:

3 (Re)validation effort Did you reduce the effort for (re)validation (how much in percentage)?

Effort in (Re)validation (Re)validation is a regular 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)



Comment

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 departments

Is there a 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:




Comment

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)



Comment

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:




Comment

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 of the products that has been produced right the first time changed? If yes, how (in absolut and percentage numbers)?

RIGHT FIRST TIME percentage of the products at the point of manufacture that are delivered right first time with no defects

No, not yet No, not yet

1 2 Quality Quality processes Has the quality processes changed in the organization with PAT implementation?

QUALITY PROCESS all processes that regulate all quality related activities in an organization

Yes, PAT data has been added to the data that are reviewed prior to release

No, not yet

1 3 Quality Quality tests In which kind has the process of quality control changed?

QUALITY CONTROL all processes and tests that evaluate the status quo versus specifications and requirements

See above Not applicable

1 4 Quality complaints/ recalls

Has changed the amount of complaints and recalls of products with RTR/PR (Real Time Release/Parametric Release)?

No, not yet Not applicable

1 5 Quality Product specification

Is the product specification more science based? Is there an impact to the product specification?

No, future impact possible (narrower ranges)

No, not yet



1 6 Quality Product specification R&D

Does the developing of the product specification change with PAT?

Not applicable Yes, if term specification is meant in a broader perspective of intermediate and end product specifications

2 1 Process Cycle Time Hour Has the cycle time changed? If yes, how (in absolut and percentage numbers)?

CYCLE TIME HOURS This is the total time from commencing manufacture to delivering products to the customer which in many cases is the factory warehouse.

Elonged time due to additional process step

Not applicable

2 2 Process Productivity Increase

Could a better understanding of the variability of a measurement lead to earlier transition to the next unit operation?

None Not applicable Theoretically yes, but times are in the order of minutes

2 3 Process Process Parameters

Has there be identified new important process parameters or correlations between process parameters?

None No No

2 4 Process Implementation of new technologies

Has there been implemented new technologies in the process?

Yes, the PAT tool

2 5 Process Process Parameters

Has there been any adjustments to known process parameters?

Yes

2 6 Process Process Understanding

Was it possible to increase process understanding?

Yes



2 7 Process Process Understanding

Did better understanding of a process help in other processes?

No

2 8 Process Yield Is the yield higher after PAT than before?

In terms a single batch: No. In terms of overall production: in future potentially yes

3 1 Risk Risk assessment Was the PAT project a result of a risk assessment?

No

3 2 Risk Risk assessment Did the PAT project initiate risk assessments?

Yes, formal risk assessments were introduced

3 3 Risk Risk reduction Did the PAT project reduce risks?

Yes (high water level --> degradation)

4 1 Costs Overall Equipment Effectiveness (OEE)

Has the OEE changed? If yes, how (in absolut and percentage numbers)?

OVERALL EQUIPMENT 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 product

No

4 2 Costs cost savings Where did you reduce costs?

No, not yet

4 3 Costs ROI What is the ROI, in which period?

see above



5 1 Personnel personnel security Could you improve the operator or/and product safety?

No change

5 2 Personnel Automation versus human interaction

Could number of personnel be reduced?

None No

6 1 Tools Information/ Data Management

Can the additional / gained information be used in other areas as well?

The information of the process can be used on other levels or in other areas as well.

Yes, for other freeze drying processes

6 2 Tools process control Where are analytical methods used to predict process deviations?

For example on-line exploitation of data with neural networks

No

6 3 Tools Information/ Data Management

Has changed the data management with the project? Do you store more or less of information? Did you change the documentation storage structure?

DATA MANAGEMENT The data you store while processing the product

Yes, more data is currently stored. Need for storing all data under discussion

6 5 Tools methods Which tools and methods did you use in the PAT project?

NIR, MVDA

7 1 Time On Time In Full delivery

Has the On Time in Full delivery changed? If yes, how (in absolut and percentage numbers)?

ON TIME IN FULL DELIVERY 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

No



7 2 Time Time to market Could a better understanding of the process reduce the number of iterations in process development (e.g. scaling up)?

None Yes

7 3 Time Time to market Is the efficiency in licencing processes (submission approval) higher after PAT?

Not applicable

8 1 Validation Process / Parameter Changes

Is a relief in validation efforts noticeable? If yes in which way?

None No

8 2 Validation Process / Parameter Changes

Did you change the validation approach (switch of responsibilities in the organization)? If yes, how did you change?

None No, not yet

8 3 Validation (Re)validation effort Did you reduce the effort for (re)validation (how much in percentage)?

EFFORT IN (RE)VALIDATION (Re)validation is a regular requirement. The effort is the complete work you must do (manpower, paperwork, data generation, etc.)

No

8 4 Validation Validation of Software

Has PAT changed your effort in validating your computer systems?

No



9 1 Organization Advantage to the competition

Has the organization gained an advantage to the competition? If yes, is this advantage measurable?

None No

9 2 Organization Communication between departments

Is there a feedback from the changes in the commercial production to the development methodology applied in R&D ?

Yes, PAT philosophy introduced into R&D

9 3 Organization Change in IT department

Did changing to PAT have an impact on your IT department?

No

9 4 (not evaluated in case 1-4)

10 1 Regulatory regulatory requirements

Has PAT an impact on the awareness of regulatory requirements?

No

10 2 Regulatory regulatory requirements

Did PAT have an impact on change control processes with regulatory bodies?

No

10 3 Regulatory audits Is there a more scientific discussion with regulatory bodies possible?

Not applicable

10 4 Regulatory audits Has the frequency of audits changed?

No

10 5 Regulatory documentation Has PAT an influence on the quality of documentation during development?

Not applicable



10 6 Regulatory documentation Has Pat changed your way of applying for registration?

No, not yet

1ß 7 (not evaluated in case 1-4)

10 8 (not evaluated in case 1-4)



• 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 • Interviewer Disclosed

Case study 6: • PAT topic PAT for Research and Development • Location / company Big Pharma , Germany • Interviewer Disclosed


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

Project What is the environment of the project?

Prod Final release drug product

R&D The project is in R&D at the moment, but will go right through to production.

R&D

0 2 Status of the project

What phase is the project in?

Ong Pending start-up inspection

Ong At the moment the first tests in industrial scale take place (looking for proof of concept). However there is already knowledge gained out of it.

other

Method successful established for scale up. No products for scale up at the moment. No benefit for usage of “old” products during routine production.

1 1 Right the first time

Has the fraction of the products that has been produced right the first time changed?


4 Additional testing, during manufacturing, still end product testing, more knowledge. Improvement: No surprises during end product testing, only confirmation, Only 1 out of 500 out of spec batches.

- Not yet in commercial production mode, but this is expected, due to implementation of feedback control.

1 At the moment there is only monitoring of moisture inside the dryer. The expectation is that at the beginning there will be an increase of rejects, because the process is more closely watched. Then through CAPA, eventually the process will become more robust and “right the first time” will increase.

- No relevant products at the moment.



1 2 Quality

processes Did the quality processes change in the organization with PAT implementation?


e.g. risk assessment 4 Still end product testing. But more process knowledge leads to less surprises during the final end product testing.

- PAT to replace laboratory release test

3 Not yet (still in proof of concept – therefore decision will be later), but it is expected, that PAT will add a tool for faster quality decision.

2

1 3 Quality tests In which kind has the process of quality control changed?



Additional On-In-At-line testing implemented. The existing is still there – No regulatory change and still the same filing! No change management necessary!

Real-time release replacing lab assay

Objective and faster quality decision

No change.

1 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)?

1 No RTR implemented

- Not yet 1 Not yet – the project has not yet come to this stage.

- No PTR/PR established.

1 5 Product specification

Is there an impact to the product specification?

1 No, still the same MBR.

- Release specs consistent, added Guard band for environmental variability

1 No – because PAT will impact the process specification, rather than the product specification.

1



1 6 Product

specification Is the product specification more science based?

1 The new analytical tests are more science based, but full science based approach is only for new products under development.

- Yes, the use of the PAT release test was integral to discussions about appropriate specifications.

1 The process specification is more science based (specific to vaccines, because of very diluted active ingredients)

- No change in product specification.

1 7 Product specification R&D

Is the development of product specification changed with PAT?

5 Change in the future with the new filings under new PAT FDA approach!

- PAT for real-time monitoring of quality

1 See above - No product in development at the moment.

1 8 OOS Did you see a change in the number of OOS incidences?

5 Dramatic reduction. The project brought OOS nearly to 0! Process improvement!

- Not yet 1 No – not far enough at the moment.

1

2 1 Cycle time Has the cycle time changed?


5 Yes, streamlined the process, much shorter cycle times, proved by evaluations!

- Not anticipated to change significantly, but there will be some decrease arising from the elimination of intermediate off-line testing (particularly during start-up).

3 No feedback at the moment, but the aim is yes – lower (faster quality decision)

1

2 2 Productivity increase

Did a better understanding of the variability of a measurement result in an earlier transition to the next unit operation?

5 Key point/benefit, WIP is no longer in unknown status.

- Expected to provide better control and provide process understanding, but not increased productivity

3 YES - Not applicable



2 3 Process

parameters Were new important process parameters or correlations between process parameters identified?

2 Yes, but the same parameters were identified.

- New sources of variability have been identified, but not yet characterized

5 Yes 3

2 4 Process parameters


Acceptance criteria 5 Same parameters much more precise, much better process understanding

- PAT used for feedback control of filling equipment.

5 YES 1

2 5 Implementation of new technologies


1 Still the same process, new analytical technologies implemented successfully

- First commercial installation of the control technology anywhere in the world (NMR on solids)

2 Yes at clinical scale. The robustness of the process has to be verified before the information is given to the authorities.

1 Not yet.

2 6 Process understanding

Was process understanding increased?


5 Yes - Yes, including insight into previously undetected variability.

4 4



5 Cross product effects, shorter process optimization for other products and shorter time to market effect.

- Once new source of variability is characterized, it should have impact on other solid filling lines, and the technology may help in setting API specifications for subsequent products.

2 No because except of NIR, the technologies are too difficult to transfer.

2



2 8 Yield Is the yield higher

after PAT than before?

- 3 for the process itself and 5 for no more lost batches!!

- No. 1 Would not sell Pat as a project that will increase yield. PAT is more a tool to increase compliance and quality, rather than yield.

1

2 9 Process control

Did you find additional possibilities to control the process?

1 No changes in the process control

- No 4 Yes 4 Part of the process could be controlled by NIR.

3 1 Risk assessment

Was the PAT project a result of a risk assessment?

5 Risk assessment made for market supply – Economic Risk assessment! But the Assessment was made already 15 years ago.

- No. A rigorous FMEA was developed as part of the PAT installation.

3 There was a good knowledge of the process – Risk Analysis was already done

3

3 2 Risk assessment

Did the PAT project initiate risk assessments?

1 No additional in this project. Other projects with Risk assessment already before the PAT initiative. Confirmation of the chosen approach.

- Yes. 1 No because it was already done for process validation

2

3 3 Risk reduction Did the PAT project reduce risks?

5 Yes, supply is with the new more robust and secured!!

- Anticipated this will be the case.

4 Yes 5



4 1 Overall

equipment effectiveness (OEE)



Example entry 4 Streamlined the manufacturing

- Anticipated that this will be the case

1 Increase, return on investment is questionable. There is a question of what is more important: quality and compliance or costs.

1

4 2 Cost savings Where did you reduce costs?


Minimized WIP/Work in Process Less rejected batches 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

Expected savings in recovery of partial lots and elimination (or at least decrease) in off-line testing.

Cost could be saved due to faster decision on good/bad product.

No reduction in costs till now.



4 3 Return on

Investment What is the period until break even of the PAT project?

Investment phase Less than 1 year Has not been calculated. Can be performed once the system is operational.

No answer at the moment – but is that really the purpose of PAT?

5 1 Personnel security

Did you improve the operator or/and product safety?

5 Yes - 100% quality assessment is anticipated to improve product safety and efficacy

1 No - Not applicable.

5 2 Automation versus human interaction


None 1 Same staff - Anticipated outcome, based on PAT being less labor intensive at final deployment. Some personnel resource will be relocated, rather than eliminated, but as this is a new process, all headcount are projected, rather than actual.

2 What’s the cost of ownership? PAT usually means more technology – so there would be more likely a change of skills, rather than an objective decrease of people.

- Not applicable.

6 1 Information / data management

Can the additional/gained information be used in other areas as well?


5 The data is gathered in a special database incl. a feedback to R&D.

- Expected to be the case

1 No – but not far enough at the moment.

5


Do you store more or less of information?


5 More valuable information

- Additional data collected, but fully automated, whereas traditional process was more labor intensive

4 far more - Not applicable.



6 3 Information /

data management

Did you change the documentation storage structure?

PAT data in Batch Documentation added. PAT data is in a separate DB and printed out.

Incorporated directly into DCS

4 Yes – adapt some servers

Not applicable.

6 4 Process control

Are additional analytical methods used to predict process deviations?


5 Yes new analytical methods were invented and used for the process control.

- Much higher data density, but no additional methods aside from PAT

4 Yes – more long term quality input - trend analysis

1

6 5 Methods Which tools and methods did you use in the PAT project?


Method: NIR – API content Method: Accelerated dissolution - film quality Method: Laser defraction - Particle size measurement

Not clear in the objective of this question.

Plasma system, NIR, two other technologies, but no further description because of Intellectual Property.

Mass spectrometry

7 1 On time in full delivery

Has the on time in full delivery changed?


Example entry 4 - Likely to increase due to real-time quality assessment

3 No feedback at the moment – target is to increase

- Not applicable.



7 2 Time to

market Did a better understanding of the process reduce the number of iterations in process development (e.g. scaling up)?

5 Yes, main project driver. Also cross product benefits realized.

- Will probably actually add resources initially to understand and characterize sensor response and process variability

1 PAT will not be a big driver to reduce time to market. It will make the process more robust, but this will not have a great impact on timing.

- Not applicable.

7 3 Time to market

Is the efficiency in licensing processes (submission approval) higher after PAT?

- Can not be answered yet, due to ongoing submissions under new FDA QbD PAT approach.

- Yet to be determined

4 Yes - Not applicable.

8 1 Process/parameter changes

What relief in validation efforts did you notice?

2 Still traditional validation. There is more confidence in the Validation approach, but no relief in the validation efforts.

- Not yet known 4 - Not applicable.


Did you change the validation approach?


1 No change. - Added PAT characterization to process validation

1 Not yet – but will be

- Not yet.

8 3 (Re)validation effort

Did you reduce the effort for (re)validation (how much in percentage)?


1 Still the same approach.

- Yet to be determined

- Not far enough – target, but no feedback.

1



8 4 Validation of

software Has PAT changed your effort in validating your computer systems?

5 More analytical devices result in higher validation efforts.

- Imposed additional CSV testing for PAT system

1 No 1

9 1 Advantage to the competition


5 Main driver was the shorter Time To Market.

- Not a high priority for this installation.

4 1

9 2 Communication between departments


4 Still room for improvement

- R&D “owned” process control strategy and partnered in PAT development.

4 5

9 3 Change in IT Department

Did the switch to PAT have an impact on your IT department?

5 Yes, additional SW to manage, higher data volume etc.

- Not particularly 1 1

9 4 Change in mind

Has PAT an impact on the awareness of methodologies used in other industries?

5 Yes, learning from others in the competence team.

- Installation has raised awareness and visibility of PAT, but not particularly from other industries.

3 It’s coming, but it takes time

4



10 1 Regulatory

requirements Has PAT an impact on the awareness of regulatory requirements?

5 Following the new FDA Risk based and PAT oriented paradigm change.

- PAT installation is facilitating discussion with regulatory agencies regarding changing expectations for submissions, particularly with respect to risk management.

1 No, there is not much difference in filing a PAT application, because the description of the process is not so big. CMC section will be bigger

3

10 2 Regulatory requirements


5 Submission ongoing according to new PAT Guidance.

- Expected to be the case

- Not yet - Not applicable.

10 3 Audits Are the discussions with regulatory bodies more scientific?

5 Yes, lot of interactive discussions on a high scientific level.

- yes 3 It depends on authorities and inspector.

- Not applicable.

10 4 Audits Has the frequency of audits changed?

1 No change - Anticipated to decrease, but has not yet transpired.

1 No 1

10 5 Docu-mentation

Has PAT an influence on the quality of documentation generated during development?

5 More precise Documents in R&D, justification for docs and better process description, better validation of the CPP ranges, explanation of the process and the process understanding increased and is more extensive

- Documentation quality hasn’t changed, but additional development data was required.

3 Yes 3



10 6 Docu-

mentation Has PAT changed your way of applying for registration?

5 Yes in New products!

- Lilly discussions with regulatory bodies were more forthcoming and technical than traditionally

3 Especially validation of methods will increase.

1

10 7 Contact with regulatory bodies

Did the time of first contact to regulatory bodies change?

5 Yes in very early stage, during filing/submission phase.

- PAT discussions were held separately (and earlier) from traditional regulatory conversations to ensure PAT did not become bottleneck to submission conversations.

1 No 1


Did the regulatory body respond earlier than before?

5 Yes very interested, educate the EU authorities with the chosen approach!

- Responded in mutually agreed timeframe.

- No feedback yet. 1



• 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 • Interviewer Disclosed


0 1 Type of Project

What is the environment of the project?

Prod Driven by Quality organization

Prod

0 2 Status of the project

What phase is the project in?

Ong As of April, 2005 Ong Study phase

1 1 Right the first time

Has the fraction of the products that has been produced right the first time changed?


- Not disclosed Not yet implemented in routine production

1 2 Quality processes

Did the quality processes change in the organization with PAT implementation?


e.g. risk assessment 4 Systems remain the same, but adapted to reflect a risk-based approach

1



1 3 Quality tests In which kind has the process of quality control changed?



Several end-product, laboratory-based tests were in a position to be replaced with real-time process analytics and predictive models.

No change

1 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)?



Is there an impact to the product specification?

3 Specification, as defined as an 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


Is the product specification more science based?

4 The mechanisms by which to measure and assess the quality attributes of interest were based upon sound science.

1



1 7 Product specification R&D

Is the development of product specification changed with PAT?

- Not disclosed 1

1 8 OOS Did you see a change in the number of OOS incidences?


2 1 Cycle time Has the cycle time changed?


4 Not disclosed – only mention was that analytical testing cycle time was reduced.

5 Not yet – but is expected

2 2 Productivity increase

Did a better understanding of the variability of a measurement result in an earlier transition to the next unit operation?

1 Not disclosed 5 Not yet – but is expected


Were new important process parameters or correlations between process parameters identified?

4 It was disclosed that material attributes and select process parameters, in combination, affected the dissolution rate of the product. Other relationships were not disclosed.

Not yet





Acceptance criteria - To be expected

2 5 Implementation of new technologies


5 New analytical technologies applied.

5


Was process understanding increased?


5 5



- Not disclosed 3

2 8 Yield Is the yield higher after PAT than before?

5 Disclosed that drying yield was higher (specific amount not disclosed).

5 To be expected

2 9 Process control

Did you find additional possibilities to control the process?

5 Yes, drying, blending.

5

3 1 Risk assessment

Was the PAT project a result of a risk assessment?

1 Project started prior to PAT guidance or the maturation of the risk-based approach.

1

3 2 Risk assessment

Did the PAT project initiate risk assessments?

5 Significant Risk assessments across many levels were executed and utilized.

5



3 3 Risk reduction Did the PAT project reduce risks?

5 This question is too vague. Risks of what? What has been presented is that PAT reduced risks associated with poor sampling, delayed analytics, ineffectual qualification and validation.

Not yet implemented – to be expected

4 1 Overall equipment effectiveness (OEE)



Example entry - Not disclosed 5 To be expected upon implementation

4 2 Cost savings Where did you reduce costs?


Laboratory personnel, consumables, waste

No cost reduction, but better OEE, higher yields, …

4 3 Return on Investment

What is the period until break even of the PAT project?

Investment phase Not disclosed Not yet calculated



5 1 Personnel security

Did you improve the operator or/and product safety?

4 API reaction sampling risk reduced. This was the only area disclosed.

1

5 2 Automation versus human interaction


None 5 In the laboratory, yes.

1


Can the additional/gained information be used in other areas as well?


- Not disclosed 5


Do you store more or less of information?


- More information. Stored for business reasons.

5


Did you change the documentation storage structure?

Not disclosed 1

6 4 Process control

Are additional analytical methods used to predict process deviations?


5 Yes 1

6 5 Methods Which tools and methods did you use in the PAT project?


By methods do you mean measurement systems? NIR was primarily used for process analytics. Multivariate analysis tools (e.g. PLS for NIR model calibration, other techniques for dissolution predictive models).

DMAIC Tools (Control charts, process capability analysis, …), NIR Measurement system



7 1 On time in full delivery

Has the on time in full delivery changed?


Example entry - Not disclosed 5 To be expected

7 2 Time to market

Did a better understanding of the process reduce the number of iterations in process development (e.g. scaling up)?

- Not applicable Not applicable

7 3 Time to market

Is the efficiency in licensing processes (submission approval) higher after PAT?

- Not disclosed for follow-on products. Regulatory efficiency for change of this product improved.

Submission not yet done


What relief in validation efforts did you notice?

5 Significant relief using a risk-based approach with process understanding, monitoring and control.

1 No relief


Did you change the validation approach?


4 Only to use a risk-based iterative and incremental approach.

1



8 3 (Re)validation effort

Did you reduce the effort for (re)validation (how much in percentage)?


- Not disclosed 1

8 4 Validation of software

Has PAT changed your effort in validating your computer systems?

5 Yes, now risk-based, iterative and incremental for many systems.

1

9 1 Advantage to the competition


- Not disclosed Not yet

9 2 Communication between departments


- Not disclosed 3

9 3 Change in IT Department

Did the switch to PAT have an impact on your IT department?

- Yes, awareness of criticality of historians not only for storage, but for model predictive control.

1



9 4 Change in mind

Has PAT an impact on the awareness of methodologies used in other industries?

2 Slow progress. 4


Has PAT an impact on the awareness of regulatory requirements?

- 3



5 Presented that regulatory relief was granted for changes to existing product.


10 3 Audits Are the discussions with regulatory bodies more scientific?

5 Absolutely. Not applicable (not yet implemented)

10 4 Audits Has the frequency of audits changed?

- Not disclosed Not applicable (not yet implemented)

10 5 Documentation

Has PAT an influence on the quality of documentation generated during development?

- Not disclosed 1

10 6 Documentation

Has PAT changed your way of applying for registration?

5 Only disclosed for this project. Yes, now science and risk-based.



Did the time of first contact to regulatory bodies change?

4 Yes. Engaged earlier than typical PAS.



Did the regulatory body respond earlier than before?

5 Yes. Submission not yet done


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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