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A Roadmap for PAT Implementation in Pharmaceutical Manufacturing. Robert M. Leasure Principal Scientist Site PAT Champion Pfizer Global Manufacturing 7000 Portage Road, PORT-91-201 Kalamazoo, MI 49001 (269) 833-6198. Presentation Outline. Provide some Definitions about PAT

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a roadmap for pat implementation in pharmaceutical manufacturing

A Roadmap forPAT Implementation in Pharmaceutical Manufacturing

Robert M. Leasure

Principal ScientistSite PAT Champion

Pfizer Global Manufacturing7000 Portage Road, PORT-91-201Kalamazoo, MI 49001(269) 833-6198

presentation outline
Presentation Outline
  • Provide some Definitions about PAT
    • But in the process more Questions will be asked than definitions provided.
    • Asking the right Questions provides the framework for successful implementations.
  • Site perspective of a PAT program
    • Project Selection
    • Resource Allocation – from site and center support
    • Steps for Implementation
  • Examples of PAT Implementations in Kalamazoo Manufacturing Ops
    • Drug ProductParental Sterile Suspension - improved content uniformity
    • Drug ProductDissolution Monitoring of Active during pH adjustment
    • API OperationsSolvent Recovery – improved yield from timely fraction determination.

and Questions

What is PAT?

Process Analytical Technologies

Things that come to mind…..

Questions that come to mind…..

  • Where are you going to stick that probe?
  • How are you going to validate that system?
  • What are you going to do with that data?
  • Probes in TanksAnalyzers in Plant
  • Automation
  • Process Data (lots of it)
what is pat
What is PAT?



Support Groups

Quality andRegulatory Groups

The answer is multivariate and transient.

It depends on who is asking the question,

and who is giving the answer.


IT,Engineering, Maintenance


What is




Bona fideOn-linePAT System

Fiber-Optic Probe

pH Probe


Analog Recorder







fda guidance on pat
FDA Guidance on PAT

FDA Guidance Document on PAT

Released in September 2004.


Ajaz S. Hussain, Ph.D.

Previously Deputy Directory Office of

Pharmaceutical Science, CDER, FDA

Key proponent for the use of PAT inthe pharmaceutical industry.

fda definition of pat
FDA Definition of PAT
  • FDA Guidance – September 2004PAT – A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance
  • Line 158:“For the purposes of this guidance document, PAT is considered to be a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.”
  • Line 158:“For the purposes of this guidance document,PAT isconsidered to bea system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) ofcritical quality and performance attributesof raw and in-process materials and processeswith the goal of ensuring final product quality.”
who benefits from a pat
Who benefits from (a) PAT?

What is (a) PAT?

The Users




IT,Engineering, Maintenance

Support Groups

Quality andRegulatory Groups

1. Manufacturing Operations

2. R&D or Process Scientists

where does pat begin and end
Where does PAT begin (and end)?


R&D or

Process Support

PAT Project Progression


Co-development or

Continuous Improvement Activities

* Proceed with PATs in development?

"Early PAT"

  • Used to determineCritical Process Parameters

"Late PAT"

  • Used to control the process
  • Requires formal validation
  • Low cost / benefit ratio
why do pat
Why do PAT?

Improved quality.

Improved safety.

Cost savings.

Improved quality.

Improved safety.

Cost savings.

Improved quality.

Improved safety.

Cost savings.


Well Controlled Process

Fundamental Goals

Process Control

Process Knowledge

continuous quality verification
Continuous Quality Verification








Quality (Compliance)




Root Cause





What is done on the plant floor.

Process Analytics


Well Controlled Process Model

use of pat to achieve rft benefits
Use of PAT to Achieve RFT Benefits
  • Reduce/eliminate deviations
  • Improve customer service (product availability)
  • Reduce cycle times (operational efficiency)
  • Reduce inventory levels
  • Reduce costs (reworks, resample, retesting, etc)
  • Improve capacity utilization
  • Improve compliance (reduce deviation reports)
  • Improve assurance of quality

Reduced need for end product testing is a potential consequence of RFT performance, but is not the direct goal of Pfizer’s PAT strategy.

six questions
Six Questions


do you want to measure?

Chemical or physical property.

  • How


  • What

Analytical technology.

do you want to measure it?

  • Why


Process Knowledge or Process Control?

do you want to measure it?

  • Where


do you want to measure?

Before, during, or after a process step?

  • When


Sampling frequency.

do you want to measure it?

  • Who



will look at the results?

considerations for project identification
Considerations for Project Identification
  • Is the process “broken”?Are there unknown or unmeasured critical process parameters?
  • How big is the problem?What are the risks of non-conformance?What is the cost of poor throughput?
  • Where should the measurement be made?At-line or On-line? (On-line is usually > 3x more $.)Are there area classification requirements? i.e., Class I Div I
  • How often should a measurement be made?What are the process and instrument limitations?
  • What decisions will be made with the data?Does Quality Operations want to intimately know the process? What are the Regulatory implications?
  • Will implementation affect other processes?What is the impact on Cleaning Validation and probematerial of construction compatibility?
pat system qualification
PAT System Qualification
  • PAT System Qualification and Method Validationshould be based on intended use of data.

Three Levels

1. Development or Proof of Concept

2. Information Only

3. Release Decisions

Quality Impact

No Impact

Indirect Impact

Direct Impact

  • Validation or Commissioning and Qualificationmust conform to applicable:
    • Corporate Quality Standards
    • Site Procedures
quality impact assessments
Quality Impact Assessments
  • Process Knowledge
    • No Impact or Indirect Impact (validation perspective)
    • Short term study used to assess process variability,and potential need for a permanent PAT
  • Process Monitoring
    • Indirect Impact, requiring “Commissioning of Equipment”
    • More permanent implementation.
    • Monitors process to assure RFT, but not used for decision making; i.e., registered or validated assay already exists.
  • Process Control
    • Direct Impact, requiring “Qualification of Equipment”
    • Used for
      • Material Release or Parametric Release
      • GMP Decisions for Critical to Process Parameters (CPP)
      • Advanced Process Control
pat development resources for kalamazoo
PAT Development Resources for Kalamazoo

Two main manufacturing operations:

Active Pharmaceutical Ingredients

Drug Product

  • Fermentation Operations
  • Chemical Operations
  • Sterile Injectables
  • Non-sterile Fluids and Ointments

Site Technology Groups

Kalamazoo ProcessTechnology (KPT)

Product and ProcessTechnology (PPT)

Right First Time (Black, Green, Yellow Belts)

Site PAT Group

Process AnalyticalSupport Group (PASG)

Center Function Support

site implementation plan simp
Site Implementation Plan (SIMP)
  • Updated annually, by PAT Champion.
  • High level plan extending out 3 years.
  • Approvals
    • Site Leadership Team (KLT) and KPT &PPT Management
    • US Area RFT Team Lead
    • PASG Implementation Team Lead
  • Purpose
    • Track existing PAT projects
    • Identify potential new projects
    • Prioritize new and existing projects
    • Implementation Timing
    • Resource Allocation
technology development process
Technology Development Process

Plant POC Report

DevelopmentCPA(if needed)


Site Imple-mentation Plan

Tech Report on Lab POC Studies

PAT Project Charter

Project specific teamorganized

Justificationreview andprojectprioritization

Lab proof ofconcept

Plant proof ofconcept

Decision toproceed

PAT Project Ideas

ProductionQuality OperationsEHSTechnology GroupsAutomationEngineering

PAT Champion

PAT ChampionPASGTech GroupsVendor

PAT ChampionProductionQuality OpsEHSTech GroupsAutomationEngineering

Project TeamPASGVendor

Project TeamSite ManagementPASG

Adapted from an illustration by Seamus O’Neill (PASG, Ireland)

pat implementationteam
PAT ImplementationTeam

Implementation of a PAT requires input from a multi-disciplinary team.












Tech Services(KPT or PPT)





Environmental,Health and Safety



gamp model for instrument qualification
GAMP Model for Instrument Qualification

Good Automated Manufacturing Practice

User Requirements

Performance Qualification

Functional Specifications

Operational Qualification

Design Specifications

Installation Qualification


more q uestions
More Questions

What are you going to do with the data?

  • Is the information used for material release?
  • Do components come into direct contact with product?
  • Is there a GMP Impact?
  • Is there a Regulatory Impact?
  • Does the system affect product quality?
  • What if the system fails?
  • How should the data be archived?
  • Etcetera (ca. 14 questions for a system level impact assessment)

Really asking:Is the PAT for Process Knowledge or Process Control ?

Answer: Quality Impact Assessment document

implementation process
Implementation Process


URSUser RequirementsSpecifications


Performance Qualification


Installation and Operation Qualification



DefinitiveCPACapital ProjectApproval

  • Lifecycle Docs
  • Analytical Methods
  • Operation SOPs
  • Maintenance SOPs
  • Training Docs
  • Change Control
  • Periodic Review
  • Business Continuity Plan


Cost review, justification, vendor selection,and approval

FAT, SAT, installation,qualification




Ready forRoutineOperation?

Cross SiteLearning


Project TeamPASGVendor


Project TeamPASGValidation Services

ProductionQualityPAT Champion

Adapted from an illustration by Seamus O’Neill (PASG, Ireland)

example 1 cu in a sterile suspension
Example #1 – CU in a Sterile Suspension
  • Application: Drug Product Sterile Aqueous Suspension
  • Quality Impact: No Impact, Process Knowledge (product was not for sale)
  • Objective: Improved Content Uniformity during later stages of filling operation.
  • Project: RFT and Continuous Improvement Black Belt project to provide suggested process changes for improved content uniformity.
drug product sterile injectable
Drug Product – Sterile Injectable
  • Parenteral Suspension
  • Solid
    • Drug (20 - 150 mg/mL)
  • Vehicle
    • Water (> 95%)
    • Surfactants
    • Preservative
  • 2 mL vial with 1.2 mL fill
sterile suspension filling operation
Sterile Suspension Filling Operation

On-line Turbidity of Bulk Suspension Recycle Loop

Off-line or At-LineNIR Analysisof Filled Vials

potency vs amount filled
Potency vs. Amount Filled
  • Filling operation is controlled within specifications, but thereis opportunity for improvement near the end of the batch.
at line nir for suspension vial analysis
At-Line NIR for Suspension Vial Analysis
  • Foss NIRSystems Model 6500
    • Dispersive NIR spectrometer
    • fiber-optic probe
  • Spinner - Sample Module
    • fiber-optic probe
    • in-house built accessory
  • Vision® software
  • Analysis time ~ 1 vial/min
  • Non-destructive, Non-invasive
sample spinner schematic
Sample Spinner Schematic

45 °


needle bearing

sleeve holder

rotating gear

(w = 125 rpm)

fiber optic probe



near ir calibration
Near-IR Calibration

Partial Least Squares Model

2 factors, 1st derivative, 1650-1800 nm

optek turbidity sensor
Optek Turbidity Sensor

1. Sensor Body

2. Windows

3. NIR Filter

4. Photo Diode

5. Optics Module

6. Tungsten Lamp

calibration of on line turbidity sensor
Calibration of On-line Turbidity Sensor
  • Incrementally dilute a concentrated suspension with known amounts of vehicle.
  • Correlate calculated suspension potency with turbidity sensor response.
doe study using on line turbidity
DOE Study using On-line Turbidity

Tommy Garner

  • RFT Black Belt Project to improve Content Uniformity by optimizing filling parameters.
  • 6 factor DOE study was conducted varying mixing time, mixing power, recirculation flow-rate, etc.
doe results
DOE Results
  • Bottom mixer has minimal contribution to mixing.
doe results continued
DOE Results continued
  • Mixer power is critical for consistent CU.
improved filling process
Improved Filling Process
  • Proposed process change: leave mixer on longer.
  • Three lots demonstrated no dip and no tail at end of fill.
advantages offered by on line turbidity
Advantages offered by On-Line Turbidity
  • Improved temporal sampling resolution.
  • Cost savings, by reducing or eliminating the need to perform off-line analysis by NIR or HPLC.Note: HPLC analysis by routine labs is ca. $100/analysis.
  • Eliminated error of taking “grab” samples for off-line analysis. This was found to be significant, if the sampling line is not properly configured, due to settling.
  • Time savings - ability to perform several parts of the DOE during the same run, i.e., ability to see when system has become perturbed or equilibrated.
purge data
Purge Data

After startup of filling line following settling of suspension.

nyquist shannon sampling theorem
Nyquist-Shannon Sampling Theorem

The sampling rate must be twice the maximum frequency component of the "signal" being measured, otherwise aliasing will occur.

fsampling= 2 fsignal

Graphical representations see

Aliasing. Bruno A. Olshausen, PCS 129 – Sensory Processes, Oct 10, 2000.


usp compendial cu testing
USP Compendial CU Testing

<905> “Uniformity of Dosage Units” in USP-NF

  • Stage 1 Acceptance CriteriaAssay 10 samples, i.e., n = 10Pass if RSD ≤ 6.0% and no value is outside 85% to 115% claim. Fail if one or more value is outside 75% to 125% claim.
  • Stage 2 Acceptance CriteriaAssay 20 more samples, i.e., n = 30Pass if RSD ≤ 7.8%, no more than one value is outside 85% to 115% claim, and no value is outside 75% to 125% claim.
  • Statistics are based on a small sample population;i.e., analytical testing with low statistical power.
cu testing criteria for large n
CU Testing Criteria for Large N
  • USP <905> is unsuitable for data sets comprised of large sample populations.
  • Proposed Acceptance Criteria outlined in article:Sandell D., Vukovinsky K., Diener M., Hofer J., Pazdan J., and Timmermans J. Development of a Content Uniformity Test Suitable for Large Sample Size. Drug Information Journal, Vol 40, pp. 337-344, 2006.
example 2 dp dissolution monitoring
Example #2 – DP Dissolution Monitoring
  • Objective

Provide a non-qualitative means of assessing completion of API dissolution during compounding prior to aseptic filtration.

  • Quality Impact Assessment

Indirect Impact.Current IPC is by monitoring pH.

  • Key Players

Justine McKenzie Project Management

Bob Witteman Greenbelt, Manufacturing Engineer

Tim Wang Kalamazoo Injectable Manufacturing

Bob Leasure Site PAT Support

solu cortef dissolution monitoring
Solu-Cortef Dissolution Monitoring
  • Solu-Cortef is a sterile lyophilized parenteral product.The hydrocortisone API is converted to the hemisuccinate sodium salt by addition of base, with care not to exceed the specification of pH 7.8.

Excess Base

  • RDWitteman conducted a RFT Greenbelt study,which concluded that slow response of the on-line pH probe can lead to OOS final pH.
  • On-line turbidity provides a more sensitive IPC over pH.
optek forward scatter turbidity probe
Optek Forward Scatter Turbidity Probe

Optek Model AS16-N

Single Channel Photometer

  • Forward scatter Turbidity Probe
  • Operates in NIR from 730 to 970 nm
  • OPL from 1 to 40 mm
  • Aseptic Ingold or Triclover fittings
  • Analog controller, 4-20 mA I/O (no computer)
  • ca. $10K
implementation plans
Implementation Plans
  • Optek Turbidity Probes have been installed in two CIP compounding tanks in Kalamazoo’s new aseptic production facility.
  • C&Q of the analyzers is underway as part of the validation of the new production facilities.
  • Current plans are for the equipment to be used for indirect impact process monitoring.
  • Use of the equipment for direct impact process control will be evaluated after additional process knowledge is gained and with consideration of benefits from RFT and Lean manufacturing.
example 3 api solvent recovery
Example #3 – API Solvent Recovery
  • Application: Cost Savings by Improving Yield for Solvent Recovery in API Operations
  • Quality Impact: Direct Impact (as deemed by QO)
  • Issues: Relatively slow determination of cut for collecting product fraction. Based on In-Plant Lab GC analysis.
  • Project: Install On-line Gas Chromatographic analysis with associated automation.
olgc installation
OLGC Installation
  • One of seven solvent recovery columns at the site.
  • Column #5 is used to recover seven different solvents.
    • DMF
    • Methylene Chloride
    • Ethyl Acetate
    • THF
    • DMAP (THF containing alcohols)
    • Toluene
    • Acetone
  • Photo shows
    • Column
    • Still Pot
    • In-Plant Lab
existing at line gc assay
Existing At-line GC Assay
  • Performed by manufacturing operators in the“In-Plant Lab” (IPL)
  • Analysis is time consuming due to manual steps:
    • Collect sample
    • Transport to IPL
    • Sample preparation and injection
    • Assay runtime,as long as 45 minutes depending on solvent
  • Prompt for manual analysis is based on column temperatures and “wait” times indicated in Master Record
siemens maxum ii on line gc
Siemens Maxum II On-line GC

Dual Oven, Isothermal GC


Sampling Valves

method validation
Method Validation
  • Method parameters assessed during the validation using ablack-box approach, but still addressing the following:

○ Accuracy

○ Detection Limit

○ Range

● Specificity

● Precision – Repeatability

● Linearity

● Quantitation Limit

issue frequent failure of injection rotor
Issue: Frequent Failure of Injection Rotor
  • The variety of solvent polarity and incompatibility of MOC caused “grooving” of the injector rotor
  • Fix involved specifying a different PTFE coated rotor.
projected savings
Projected Savings

The Return on Investment of the implementation was estimated to be one year,based on solvent cost and production volumes at the time of CPA submittal.

lessons learned
Lessons Learned
  • Stick to the PlanDo not deviate from define validation approach established at the beginning of the project;otherwise the project may be delayed.
  • Train Appropriate Personnel AppropriatelyCross-train key users for daily care and troubleshooting of the instrument.User training should be budgeted as part of the project scope.
  • Keep it SimpleDepending on the technology, analysis of multiple streams/products may present challenges and additional overhead.
  • Drug Product Suspension CU
    • Tom Garner - RFT Black Belt and Project Manager
  • Drug Product Dissolution Monitoring
    • Robert Wittemann - RFT Green Belt and Production Engineer
    • Tim Wang - PPT Production Engineering
  • On-line GC for Solvent Recovery
    • Brad Diehl - PASG Implementation Support
    • Frank Sistare - PGM Groton
    • Joe Geiger - Production Engineering Solvent Recovery
    • Jeff Terpstra - Project Management
    • Pete Miilu, Marc Surprenant - IT Automation
    • Donald Zeilenga - KPT and Site PAT Support
    • Scott Wagenaar, Kurt Holton - Production Operations
    • Andrew Meister - Instrumentation Maintenance