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Risk Reduction in Pharmaceutical Manufacturing using Process Analytical Technology

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Title: Risk Reduction in Pharmaceutical Manufacturing using Process Analytical Technology


1
Risk Reduction in Pharmaceutical Manufacturing
using Process Analytical Technology
  • Brian Davies
  • Director Process Analytical Technology
  • Thermo Electron Corporation

2
A Definition of Risk
  • Exposure to
  • Gain
  • or Loss
  • Usually understood as exposure to Loss
  • Its about the potential unknown outcomes of
    events

3
Classically Risk in quantified in terms of
  • Impact
  • What will happen if this exposure occurs?
  • Probability
  • What is the likelihood of the exposure?
  • Detectability
  • Is the exposure easily detected?

4
Classic Risk mitigation strategy
  • Quantify the risks
  • Pareto the risks
  • Establish countermeasures and mitigation routes
    to
  • Minimise
  • Impact
  • Probability
  • Maximise
  • Detectability

5
Pharmaceutical Quality Risk
  • Bad Quality
  • To patient
  • To Good Quality
  • Financial risk
  • Raised expectations

6
Pharmaceutical Financial Risk
  • Scrap
  • COPQ
  • Disposal costs
  • Environmental Impact
  • Wasted resources
  • Inventory tied up
  • Raw Materials
  • WIP
  • Finished goods
  • Capacity lost
  • Cycle time up
  • Recalls
  • Brand

7
Pharmaceutical Regulatory Risk
  • More scrutiny from the regulators
  • Todays products
  • New products undergoing licensing
  • Tomorrows products

8
Risk and the Pharma manufacturing value chain
  • Most Pharma manufacturing processes
  • Take relatively low value raw materials from
    suppliers
  • Add value during formulation
  • Add value during finishing
  • Add value during packaging
  • Add value during distribution
  • Each stage has its own associated risks
  • Each stage has its own mitigation strategies
  • Classical approach
  • Measure quality of raw materials
  • Measure quality of finished goods

9
How will PAT reduce risk?
10
Definition of PAT
  • PAT is 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

11
PAT reducing variances
12
Off line testing of product quality Policing
function
On-line monitoring/control of critical process
parameters - Control function
Assess conformance
Control as appropriate
13
One Role of PAT
  • Obtaining improved process knowledge in order to
    identify and remove sources of variability and
    hence achieve RFT performance

14
Benefits of Right First Time
  • Assures product QUALITY
  • Enhances SUPPLY reliability
  • Improves COST
  • Reduces INVENTORY
  • Reduces CYCLE TIME
  • Improves CAPACITY UTILIZATION
  • Increases JOB SATISFACTION
  • transforms the organization from a REACTIVE
    through PROACTIVE to being PREDICTIVE

Enhances Strategic Effectiveness of Manufacturing
15
Sources of Variability
  • Inputs to the process
  • control variability
  • of the output

People
I N P U T S (x)
y f(x)
Equipment
y
Measurement
Process
Output
Materials
Variability - source of the big risks to the
product
Environment
16
Use of PAT to Reduce Variation
  • Monitor variation throughout process
  • Raw materials
  • In-process parameters
  • Finished product parameters
  • Determine what is Critical to Quality (CTQ)
  • Correlation to performance (statistics)
  • Designed experiments
  • Use PAT to remove/control unwanted variation in
    CTQ parameters
  • Mitigate the risk of the process to product
    quality

17
Off line testing of product quality Policing
function
On-line monitoring/control of critical process
parameters - Control function
Assess conformance
Control as appropriate
18
PAT controlling processes
19
Todays Validated Process
20
Tomorrows Controlled and Monitored Process
21
PAT and Process Monitoring and Control
22
PAT Example in the Tablet Value Chain
23
Basic Tablet Manufacturing Process
24
Risk Raw Materials
  • Correct Material?
  • Correct Specification?
  • Purity
  • Water content
  • Etc.
  • Manufacturability?
  • Chemical
  • Physical properties

25
Qualitative Analysis Application - Raw Material
ID
  • Pharmaceutical users want to apply NIR to inspect
    incoming raw materials quickly at the loading
    dock.
  • They often would like to equip the receiving area
    with an NIR to be used by technicians who are not
    trained as scientists.
  • The instrument will be used to confirm the
    identity of each container of material that is
    received. This would otherwise have to be done in
    the QC lab by wet chemical techniques.

26
Library Samples
  • One lot each of the following substances was
    provided for the construction of the raw material
    library

D-Glucose D-Fructose Sucrose D-Mannitol D-Sorbitol
?-D-Lactose Monohydrate Acetylsalicylic
Acid Acetaminophen L-Ascorbic Acid Citric Acid
27
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28
Glucose Library and Validation
29
Fructose Library and Validation
30
Qualitative Analysis to Protect Your Processes
  • Your process has changed without explanation and
    is offline until the problem is resolved
  • Find that one raw material supplier has recently
    changed
  • Did supplier B send the same material that
    Supplier A did?
  • Qualitative FT-NIR analysis will show chemical
    differences between two different lots of, for
    example, HPMC, a common industrial raw material.

31
Different Manufacturers of HPMC
32
Qualitative Analysis Can Differentiate Subtle
Differences in Physical Properties
  • Different physical properties in batches of the
    same chemical compound can affect reaction
    parameters like dissolution or reaction rate
  • Particle size, crystal geometry or packing,
    hydration
  • Your process has been set up to use only 50
    micron Microcrystalline Cellulose
  • Spectral information alone will show the same
    chemical Qualitative Analysis can show particle
    sizes

33
Particle Size and NIR
34
Risk Blended Materials
  • During formulation the API and excipients are
    dispensed then blended into a homogenous mixture.

35
Blending
36
Blend Uniformity in Tablets
  • Achieving proper blend uniformity for tablets
    prior to pressing is critical to achieve proper
    distribution of actives and excipients.
  • Under-blending results in inhomogeneous
    distribution of active ingredients in tablet
  • Over-blending leads to unrecoverable material
  • Example shows how blend uniformity can be
    successfully monitored in seconds using FT-NIR
    technology

37
Region of Interest for Component 2
Component 1
Component 2
38
FT-NIR Predictions for Blending
Sample ID Component 1 Component 2 Sample
1 Top 47.6 51.2 Sample 1 Middle
47.9 51.0 Sample 1Bottom
48.0 50.8 Sample 2a Top 53.4 45.5 Sampl
e 2a Middle 49.2 49.6 Sample 2a Bottom
53.7 45.2 Sample 2b Top 52.3 46.6 Sampl
e 2b Middle 48.8 50.2 Sample 2b Bottom
50.6 48.3
39
Tablet pressing
40
Tablet Coating
41
Show Concentration Differences in Tablets
  • Can use both Transmission and Reflection
    measurements to analyze tablets. Can be done
    without removing the tablets from the Antaris
  • Distinguish different clinical tablet
    formulations by amount of active ingredient
  • Finished product is a tablet and manufacturing
    protocols need independent verification of amount
    of active ingredient.

42
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43
Reflectance Spectra for Clinical Tablets
44
Tablet Reflectance Results
45
Tablet Transmittance Results
30
20
R 0.99965 RMSEC 0.0561
NIR Calculated (Rel. Units)
10
Calibration
Validation
0
0
10
20
30
Label Claim (Rel. Units)
46
Tablet Transmission Data Classification Using
Discriminant Analysis
47
Effective Risk reduction using PAT
  • PAT is not just about measurement
  • Its a whole lot more
  • Requires a toolbox of PAT sensors
  • NIR
  • Mid-IR
  • Raman
  • Fluorescence
  • Acoustic
  • Thermal
  • And many more!
  • Process and system integration
  • Process modelling
  • Informatics and Knowledge Management
  • 24/7/365 Global Support for mission critical
    implementations

48
Summary How PAT will reduce Risk
  • True Process Knowledge.
  • Raw Materials
  • Work in progress
  • Finished product
  • Designed in quality measurement systems
  • Future Pharma products will have PAT in the
    licencing applications
  • Right 1st Time for current Pharma products.
  • Real time or near-real time product quality
    monitoring.
  • Feed back and feed forward process control.
  • Integrated systems for risk reduction via
    knowledge acquisition and management.

49
Measurements across the process
Process Monitoring (PAT)
  • Reaction monitoring
  • Blending and mixing
  • Fermentation
  • Drying

50
Desired State
  • Product quality and performance achieved and
    assured by design of effective and efficient
    manufacturing processes
  • Product specifications based on mechanistic
    understanding of how formulation and process
    factors impact product performance
  • Continuous "real time" assurance of quality

http//www.fda.gov/cder/gmp/21stcenturysummary.htm
51
Desired State
  • Regulatory policies tailored to recognize the
    level of scientific knowledge supporting product
    applications, process validation, and process
    capability
  • Risk based regulatory scrutiny relate to the
  • level of scientific understanding of how
    formulation and manufacturing process factors
    affect product quality and performance, and
  • the capability of process control strategies to
    prevent or mitigate risk of producing a poor
    quality product

http//www.fda.gov/cder/gmp/21stcenturysummary.htm
52
PAT Definition
  • PAT is 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
  • The term analytical in PAT is viewed broadly to
    include chemical, physical, microbiological,
    mathematical, and risk analysis conducted in an
    integrated manner

53
Acknowledgements
  • Steve Hammond
  • Director of the Process Analytical Support Group,
    Pfizer Global Manufacturing Services
  • Scot Ellis
  • NIR Product Manager, Thermo Electron Corporation
  • Dave Edwards
  • Product Specialist, Thermo Electron Corporation

54
  • Questions?

55
Thank you
  • Brian Davies
  • Director Process Analytical Technology
  • brian.davies_at_thermo.com
  • www.thermo.com
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