pat, one step at a time€¦ · total on/at-line analysis efficient calibration – calibration...

SPCTechnologies, LLC

www.SPCTechLLC.com

PAT, One Step at a Time…

Robert P. Cogdill, Ph.D.Industrial Research Coordinator, DCPT

[email protected]

April 24, 2007Jacob K. Javits Convention Ctr.

New York, NY

mailto:[email protected]

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About Us

DCPT (www.dcpt.duq.edu) Theoretical & applied pharmaceutical science researchPilot-scale solid dosage manufacturing capabilitiesExtensive analytical resources

Process spectrometers, solid-state characterization, NIR & THz imaging spectroscopy

SPCTech, LLC (www.SPCTechLLC.com) Process analytic method design and development specialistsEfficient NIR calibration servicesIndustrial training in PAT, Risk Assessment, and Applied Chemometrics

Technology Partners:

http://www.dcpt.duq.edu/

http://www.spctechllc.com/

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The State of Reality for PAT…

?

1999 2000 2001 2002 2003 2004 2005 2006 2007

ACPS Mtgs. Kickoff21st-Century

cGMPS Initiative …Pre-PATEarly Adopters/Pioneers

CriticalWSJ Article

“3-Story Blender”

PAT Guidance & 21st-Century cGMPS

Final Reports

Risk-BasedInspections

Pilot

Quality SystemsGuidance

ComparabilityProtocols for CMC

Draft Guidance

Revised CPG on Proc. Validation

Sec. 490.100

eCTDGuidance

ICH Q7

ICH Q8

ICH Q9

ICH Q10?

ASTME55

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With the rotation of management at CDER, there is palpable shift in the Agency’s focus with regard to oversight of manufacturing & process analytics:

The (planned) sunset of the PAT Patriot team is nearly completeIssues related to “design space” and Quality by Design (QbD) have grown in relative importance, somewhat at the expense of the wider dialogue on PAT

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Tactical mistakes have been made-In some cases “PAT Projects” have begun and ended with very little to show after relatively large expenditures of time and capital

As the “new-ness” of PAT has begun to wear off, the “movement” has garnered some unfair comparisons to quality-management systems (QMS) fads of prior decadesJust as was the case for many QMS techniques, however, the problem isn’t with the core concepts of PAT, the problems often stem from lack of:

Management commitmentTalent/experienceTimeCapital resourcesFocus

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Even though the climate for PAT has evolved, the regulatory “gifts” which enable opportunities for process improvement related to PAT are solidly in place:

21st Century cGMPsComparability protocols – key for implementing continuous improvementPAT Guidance – Opportunities for real-time release, update or elimination of useless/redundant testsRisk-based inspections – long-term bias favoring adoption of risk-mitigating technologiesEtc…

Now that PAT has lost some of its cachet, managements are likely to be more skeptical of plans for new projects

Increasing burden is being placed on designing projects with quick ROI and high probability of success

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Gains from process analytics?

Implementing PAT should not be a singular objective-PAT should be considered as a collection of tools which support objectives related to improving manufacturing performancei.e.- PAT tools support strategic objectives for quality management and lean operation

Process analytics do not add value to an operationPAT tools enable a greater portion of potential total value added to be preserved

Reduced cost of qualityLeaner operationMore predictable, flexible operationsLower revenue risk factors

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Process Q

uality Analysis

Flow Path Analysis


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Assumptions: Aggregate savings for top 16 publicly-traded branded and generic producersBased on 2005 data from company annual reportsCosts of implementation are not included

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Dispensing Mill/Blend Granulation Mill/Lube Compression

Sensor /Monitor

IT/MES Infrastructure

Process Model

Sensor /Monitor

Sensor /Monitor

Sensor /Monitor

Process Control

The Goal – Beginning with the End in Mind

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Dispensing Mill/Blend Granulation Mill/Lube Compression

Sensor /Monitor

IT/MES Infrastructure

Process Model

Sensor /Monitor

Sensor /Monitor

Sensor /Monitor

Process Control


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Estimated/Instantaneous Cpk

Predicted time (Days) until Batch Release, 95% conf.:

4.2-6.1Predicted probability of right-first-time, 95% conf.:

98.4-99.6

Estimated Quality Parameter

Real-Time DashboardProd. SKU XXX-XXX

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Whole-process projects can be expected to take up to 3-4 years to completeTime for completion will be largely dependent upon:

Refinement of project focus & objectivesResource commitmentAvailability of skills

Train in-house vs. outsourcingCurrent vs. desired level of IT integration

Parallel project implementation may not always be feasible

Design & dev. of subsequent stages may be contingentSufficient management, personnel or capital resources may not be available

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Mistakes or lack of knowledge in early phases leads to cycle of delaysDelays during individual components can easily derail entire projects

Assessment Analysis Control Real-TimeRelease

OptimizationPreparation

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A common approach has been to identify a single product for implementation of a “total” PAT installationWhile implementation of complete systems may be the quickest route to ultimate gains, there are significant risks and limitationsImplementing end-to-end solutions can be a bit like “drinking from a fire hose”

Project management complexityIntensity of capital outlayTime demands for key personnelIncreased risk of not meeting ROI expectationsCan be perceived as threatening an established corporate culture or inter-department functioning


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An Alternative Implementation Path:

Rather than designing end-to-end solutions for individual products, installations can be focused on individual operations and spread across multiple productsTarget selection begins with assessments of opportunities and risks

Most feasible or valuable process improvements are given priorityIndividual installations can be “phased in” according to comparability protocol, and as supported by “passive”evaluation data

Certain skills and infrastructure components can be acquired incrementally

Allows more time to train existing personnel for new responsibilitiesMany specialized functions can be outsourced rather than hired in

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An Alternative Implementation Path:

Working on an individual operation across products (rather than individual products and across the entire process) offers significant tactical advantages:

Significantly less risk of failure, reduced ROI expectationsFacilitates more optimal scaling of ultimate implementationLess capital and personnel resource intensityLess likely to be perceived as risky or threatening operational “comfort zones”

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Project #1 – Dispensary Analytics

Raw material ID/QC adds significant non-value-added time to overall C/TMost current raw materials tests are only sparingly useful for process control, and can typically be replaced by real-time methods:

IDPurityResidual Solvents

Most finished-product quality variation (for solid dosage forms) can be traced to physical aspects of the product or materials; hence, rather than “wet methods” dispensary analytics should focus on solid-state materials characterization:

Particle size distribution (PSD)Tests for profile of morphology and/or crystallinity

Many raw material characterization tools and methods will be applicable across multiple products/lines

Real-time spectroscopy

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Project #1 – Dispensary Analytics

Better understanding of incoming raw materials may ultimately reduce the need for more complicated downstream instrumentation or controls

Information gathered within the dispensary has the greatest potential for feed-forward control and for containing errors before they consume significant tact time

Real-time dispensary analytics can be implemented incrementallyNo need to disrupt ongoing operationsAs comfort and confidence levels increase, PAT operation can be “phased in”Off-line testing capabilities should be maintained as backup- implementation of PAT should never increase risks to C/T

Alternatives for implementation:Candidate analytic platforms might be leased until a decision regarding the value of the metric can be determinedSamples of raw materials can be maintained in storage for later feasibility studies (to identify key technologies)Potential tests can be outsourced to a contract analytical service provider to gain access to new techniques, or to reduce the impact on QC workload

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Project #2 – Unit-Operation ControlsBlend Monitoring

Blend monitoring is nearing the level of a “standard”PAT installation

Robust, relatively inexpensive wireless sensors are available from multiple suppliersSampling systems/optics have been proven across many applicationsOptimization and generalization of endpoint detection schemes and method development techniques

Benefits:Endpoint forecasting – improved asset scheduling flexibilityRisk reduction – prevent errors from upstream operations (dispensing, milling, etc.) from propagating further

Courtesy of:Control Developments, Inc.

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Project #2 – Unit-Operation ControlsBlend Monitoring

Courtesy of:Control Developments, Inc.

Alternatives for implementation:Wireless instrumentation can be quickly swapped among multiple blenders (e.g. tote blenders)In many cases only “local” IT infrastructure is requiredInterchangeable instruments reduce risk of downtime in the event of instrument malfunctionIn the event of sensor failure, options for “traditional”control should always be maintainedEfficient calibration techniques may enable rapid, off-site method development for multiple products with little or no reference testing

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Project #2 – Unit-Operation ControlsRoller Compaction

At-line instrumentation might be used to rapidly verify that equipment setup was performed properly and for feedback control of compact densityProcess analytics may be most useful to accelerate process development and scale-up of roller compactionPassive analysis of equipment diagnostics might be useful for process monitoring or control in addition to, or in lieu of, additional sensors:

Torque/power measurement (μ, σ)Temperature (feed screw, rolls)

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Project #2 – Unit-Operation ControlsHigh-Shear Granulation

Potential sensor technologies:Focused-beam reflectance metrology (FBRM) – real-time characterization of granule morphology distributionNIR Spectroscopy – water/binder uniformity (control rate of addition), surveillance for solid-state changes (formation of hydrates), qualitative characterizationRaman Spectroscopy – surveillance for solid-state changesTorque profilometry – classic indicator of granulation progressAcoustics – qualitative indicator of granulation progress

Objectives for application:Endpoint forecasting, accelerated processingPost-approval adjustment of binder addition/process conditionsIdentification of undesired solid-state changesMulti-batch database might ultimately be correlated to finished-product variation for optimization or control limits, or implementation of real-time release

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Project #2 – Unit-Operation ControlsFluid-Bed Processing

Rapid optimization & scale-up of fluid-bed techniquesBy controlling equipment to achieve uniform quality characteristics, rather than operating parameters, PAT sensors can help to reducedependence on scaleRapid characterization of granule uniformity (e.g. moisture, particle size) during process optimization to reduce variability

Equipment-specific diagnostics may be useful for monitoring and control:

Absolute outlet temperaturedT or difference between inlet and outlet wet-bulb temperaturesStatic bed height vs. airflow vs. charge

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-0.4 -0.2 0 0.2 0.4 0.6 0.8

-2.4

-2.2

-2

-1.8

-1.6

-1.4

PC 1

PC

2

Stage IStage II

Explicit sensor calibration is not always required- in many cases, passive monitoring of instrument signals can reveal important process informationPassively-collected information can be used to build evidence to guide decisions related to further process analytical deployments


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Wildfong, et al., J.Pharm.Sci. 91(3) 2002


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Project #3 – In/On/At-line Quality Analysis

The popularity of non-destructive finished product analysis (i.e. analysis of tablet cores) has enabled many new technologies to simplify implementation

Commercial, off-the-shelf in-line instrumentationAutosamplers and integrated spectroscopic + dimensional + RTS testing for total on/at-line analysisEfficient calibration – calibration using only production-scale samples & relatively few reference tests

Experience has demonstrated that non-destructive tests can be developed for simultaneous multi-component, chemical + physical characterization

Content, content uniformityTablet density (hardness)Coating, coating uniformity

Rapid finished-product quality analysis is the most critical step toward achieving total real-time release (RTR)

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While “traditional methods” of batch release testing may be comfortable, PAT-based methods offer more opportunity than risk:

USP <905> PAT Method

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Increased sampling density is critical to realizing incremental improvements in process performance:

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In some cases, implementation of precise, real-time quality analyses can help build the case to eliminate or replace redundant, uninformative or ineffective testing steps:

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Project #4 – Cleaning/Changeover

Cleaning validation and post-changeover activities are often overlooked by PAT opportunity analyses

Such activities often comprise a large portion of non-value-added tact time (especially for generic, contract facilities)Risk assessment alone can sometimes be used to justify streamlining of cleaning/changeover operations which have “grown” over time

New technologies (e.g. ion-mobility spectroscopy) are enabling rapid, at- or near-line cleaning validation using typical protocols

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Summary

Implementation of PAT should not be a singular objective, and should not be a source of greater riskRecent advances in PAT method development can dramatically reduce the cost and time associated with new implementations of technologyIt may be advantageous in the current business climate to take on smaller projects while working toward a major long-term goal

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Summary

Consider single-operation, multiple product instead of single-product, total-process as a pathway for implementation

Capital and resource allocation intensity can be minimizedNew technologies can be “phased in” parallel to current modes of operation

The FDA should be consulted for advice early in the process to avoid surprises

IT infrastructure development can be targeted to match the scale of PAT implementationsMany PAT-related activities which are peripheral to ongoing operations can be outsourced – calibration, method monitoring/update, project design, risk assessment, etc.

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Acknowledgements

James K. Drennen, III DCPT/SPCTechCarl A. Anderson DCPT/SPCTechPeter L.D. Wildfong DCPTMichael D. Moore DCPTSession sponsors:

Siemens Energy & AutomationTroy Logan, Ingrid Maes

pat, one step at a time€¦ · total on/at-line analysis efficient calibration – calibration...

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