ghfghn

1. Stage 3 - Process
Validation: Measuring
what matters
Trevor Schoerie - PharmOut
© PharmOut 2016
www.pharmout.net

2. A quote….
“The company that fails is
the company that comes to
us and says “Just tell us
what to do and we will do
it.”
“The company that
succeeds is the company
that says to us “Here is
what we did and why we
think it is appropriate.”
© PharmOut 2016
www.pharmout.net
Dr. Phillip Minor
National Institute of Biological Standards and Control
A science and risk based approach

3. What the current GMPs say
PIC/S, EU GMPs
§1.1 v. all necessary controls on intermediate
products, and any other in process controls and
validations are carried out.
CFR 211.110(a)
Sampling and testing of in-process materials
and drug products.
To assure batch uniformity … in-process
materials…. Such control procedures shall …
monitor the output and to validate… responsible
for causing variability…
© PharmOut 2016
www.pharmout.net

4. What the current GMPs say – EU/PIC/S
§1.2 ii. critical steps of manufacturing processes and
significant changes to the process are validated;
§1.2 iii. all necessary facilities for GMP are provided including:
a. appropriately qualified and trained personnel; people*
b. adequate premises and space; environment*
c. suitable equipment and services; machines*
d. correct materials, containers and labels; materials*
e. approved procedures and instructions; methods*
f. Suitable storage and transport;
*fishbone (+measurements)
© PharmOut 2016
www.pharmout.net

5. What the current GMPs say - FDA
CFR 211.110(a)
…. such control procedures shall include, but
are not limited to, the following, where
appropriate:
1. Tablet or capsule weight variation;
2. Disintegration time;
3. Adequacy of mixing to assure uniformity and
homogeneity;
4. Dissolution time and rate;
5. Clarity, completeness, or pH of solutions.
© PharmOut 2016
www.pharmout.net

6. Lifecycle concept, but QbD is at the start of the product
lifecycle, i.e. product design, R&D
FDA Process Validation - 3 stages
1. Process Design (QbD & DOE)
2. Process Qualification
3. Continued Process Verification
FDA Process Validation?
© PharmOut 2016
www.pharmout.net

7. EU GMP Guide Annex 15 “Qualification
& Validation”
Concurrent Validation
• May be acceptable in exceptional circumstances "where there is a strong
risk – benefit to the patient"
Traditional Approach
• Produce a number of batches under routine conditions, confirming
reproducibility
Continuous Process Verification
• Science-based control strategy
Hybrid Approach
• The “Traditional Approach” and “Continuous Process Verification” together
© PharmOut 2016
www.pharmout.net

8. EU GMP Guide Annex 15 “Qualification
& Validation
Design
Space
© PharmOut 2016
www.pharmout.net

9. Focus of FDA Process Validation
Guideline
© PharmOut 2016
www.pharmout.net
What is the goal?
Variable or variability - Mentioned 19 times
Control - Mentioned 62 times
Statistics - Mentioned 15 times
Inputs and Outputs
Fishbone Model

10. FDA (& EU) Process Validation Stages
Stage 1 – Process Design: The process is defined during this
stage based on knowledge gained through development and
scale-up activities.
© PharmOut 2016
www.pharmout.net
Stage 2 – Process Qualification: During this stage, the process
design is evaluated to determine if the process is capable of
reproducible commercial manufacturing.
Stage 3 – Continued Process Verification: Ongoing assurance
is gained during routine production that the process remains in a
state of control.
Identify sources of Variability
Control of Variability
Monitoring Variability - remains “in control”

11. Lifecycle
LevelofQCLabTesting
Process
Design
PV
(PPQ)
Commercial
Manufacturing
Could
vary
based on
approach Variability
Estimate
Established
Post
Periodic
Review
Signal
Change
introduced /
CAPA
PAT
Implemented
Monitoring
QC Testing
© PharmOut 2016
www.pharmout.net
Time / Product & Process Knowledge
Control Strategy is dynamic over the lifecycle

12. 3 Stages - Generic Acetriptan Tablets
Define the
Quality Target
Product Profile
(QTPP)
Identify the
CQAs
Define Process
Steps & CPPs
Create a
Control
Strategy
Stage 1
Implement the
Control
Strategy
Qualify Facility,
Utilities,
Systems and
Equipment
Process
Validation
(PPQ)
Continued
Process
Verification
Stage 2
Stage 3
Science and Risk-based Approach at
all Stages of Lifecycle
© PharmOut 2016
www.pharmout.net

13. Quality Risk Management (QRM)
RiskAnalysis
Risk Evaluation
RiskReduction
Begin the QRM Process
RiskAssessment
Risk Identification
RiskControl
Risk Acceptance
Output of the QRM Process
RiskReview
ReviewEvents
QRM
Tools
RiskCommunication
ICH Q9
© PharmOut 2016
www.pharmout.net
Product & Process
Development

14. Initial RA of the formulation variables
DP CQAs
Drug
Substance
PSD
MCC/
Lactose
Ratio
CCS Level Talc
Level
Mag.
Stearate
Level
Assay
Medium Medium Low Low Low
Content Uniformity
High High Low Low Low
Dissolution
High Medium High Low High
Degradation Products Low Low Low Low Medium
High Risk is unacceptable. Further investigation is needed to reduce the risk.
Medium Risk is acceptable. Further investigation may be needed in order to reduce the risk.
Low Broadly acceptable risk. No further investigation is needed.
© PharmOut 2016
www.pharmout.net

15. Design of Experiments (DoE)
• A designed experiment allows understanding of how
input variables are related to output variables
Input Process Output
• Experimental units are units to which one treatment is
assigned or applied
• Input variables are called factors-controlled independent
variables whose levels are set by the experimenter
• Levels of a factor are the settings that are tested in an
experiment
© PharmOut 2016
www.pharmout.net

16. Defining CPPs
Process
Variable
Can variable
be
controlled?
NO
Process
Performance
Attribute
OR
Product Quality
Attribute
Process
Input
YES
Potential
Impact to
CQAs?
NOYES
Potentially
a CPP
Potentially
NOT a CPP
Risk
Assessment.
CPP?
YESCritical Process
Parameter
NO
© PharmOut 2016
www.pharmout.net
Key Process
Parameter
OR
Non-Key Process
Parameter

17. Equipment & fixed process parameters
used in the formulation studies
Process Step Equipment
Pre-Roller Compaction
Blending and Lubrication
4 qt V-blender
• 250 revolutions for blending (10 min at 25 rpm)
Roller Compaction and
Integrated Milling
Alexanderwerk WP120 with 25 mm roller width
and 120 mm roller diameter
• Roller surface: Knurled
• Roller pressure: 50 bar
• Roller gap: 2 mm
• Roller speed: 8 rpm
• Mill speed: 60 rpm
• Coarse screen orifice size: 2.0 mm
• Mill screen orifice size: 1.0 mm
Final Blending and
Lubrication
4 qt V-blender
• 100 revolutions for granule and talc blending (4
min at 25 rpm)
• 75 revolutions for lubrication (3 min at 25 rpm)
Tablet Compression 16-station rotary press (2 stations used)
• 8 mm standard round concave tools
• Press speed: 20 rpm
• Compression force: 5-15 kN
• Pre-compression force: 1 kN
© PharmOut 2016
www.pharmout.net

18. Tablet Compression Process
Development
Effect of Main Compression Force, Press Speed
and Ribbon Relative Density:
• Compression force and press speed (related to
dwell time) can affect numerous quality attributes
including hardness, disintegration, dissolution, assay,
content uniformity, friability, weight variability &
appearance.
• The density of the ribbon following roller compaction
may also impact the compressibility and
compactability of the granules which would then
impact tablet hardness & dissolution.
© PharmOut 2016
www.pharmout.net

19. Tablet Compression Process
Development
© PharmOut 2016
www.pharmout.net
A 23 full factorial DoE with three centre points was performed
to understand the effects of these parameters on tablet
quality attributes
Factors: Formulation Variables
Levels
-1 0 +1
A Main compression force (kN) 5 10 15
B Press Speed (rpm) 20 40 60
C Ribbon relative density (no units) 0.68 0.75 0.81
The press was run at the speed of the specified DOE for at
least five minutes prior to any sampling. Tablet samples were
then pulled at the beginning, middle and end of each run
(except one Batch which was sampled every 20 min).

20. Tablet Compression Process
Development
• The results obtained from the development work
identify acceptable ranges
• Feeder frame paddle speed (8-20rpm)
• Press speed (20-60rpm)
• The data also allows potential In-Process Controls to
be identified for the compression step:
© PharmOut 2016
www.pharmout.net
Test Frequency Limits
Individual tablet weight (n =10) 30 min 200.0 mg ± 10.0 mg
Composite tablet weight (n =20) 30 min 4.00 g ± 0.12 g
Hardness (n = 10) 30 min Target: 8.0-10.0 kP
Limits: 5.0-13.0 kP
Thickness (n = 10) 30 min 3.00 mm ± 0.09 mm
Disintegration* (n = 6) 3 x per run NMT 5 min
Friability* (sample weight = 6.5 g) 3 x per run NMT 1.0%

21. Scale-Up from Lab to Pilot Scale and
Commercial Scale
• Scale-up information is usually limited at the time of
submission.
• The principles of scale-up should be detailed as part
of a planned approach.
• It is the firm’s discretion to submit scale-up data such
as actual process verification information at the time
of submission for a complex drug product which has a
high risk of scale-up failure.
© PharmOut 2016
www.pharmout.net
Scale Batch Size Units
Development (Lab) 5Kg 25,000
Pilot (Exhibit) 50Kg 250,000
Commercial (Proposed) 150Kg 750,000

22. Scale-Up of the Roller Compaction &
Integrated Milling Process
Several process parameters to consider when scaling up
to a larger, wider roller. The strategy employed should
be documented.
• Roller Gap, Roll Force or Roll Pressure
• Screw Speed and Roll Speed
• Mill Screen Size and Mill Speed
© PharmOut 2016
www.pharmout.net
Scale Model Roller
width
(mm)
Roller
diameter
(mm)
Roller Gap
(mm)
Roller
Pressure
(bar)
Mill screen
orifice
(mm)
Lab WP120 25 120 1.2-2.4 20-77 1.0
Pilot WP120 40 120 1.8 50 1.0
Commercial WP200 75 200 2.0-2.4 31-121 1.0

23. Initial Risk Assessment of the
Manufacturing Process
© PharmOut 2016
www.pharmout.net
DP CQAs
Pre-RC
Blending &
Lubrication
Roller
Compaction
Milling
Final
Blending
&
Lubrication
Compression
Assay
Low Low* Low Low* Low
Content Uniformity
Low Low Low Low* Low
Dissolution
Low Low Low Low Low
Degradation Products Low* Low* Low* Low* Low*
High risks identified during development
Scientific knowledge & understanding gained
Appropriate controls developed to reduce risk to an
acceptable level documented
*The level of risk was not reduced from the initial risk assessment

24. Other items for consideration
Container Closure system:
• Round white opaque HDPE bottles with an induction
seal liner and child resistant (CR) closure
• Labelled for storage at 25°C with excursions
permitted to 15-30 °C
Microbiological Attributes:
• An accelerated stability study of the exhibit batch
demonstrated that the drug product has low water
activity and is not capable of supporting microbial
growth. Routine testing of tablets unnecessary
© PharmOut 2016
www.pharmout.net

25. Control Strategy
• Built up based on previous knowledge and the
outcome of extensive product & process studies
• Investigation of material attributes and process
parameters that were deemed high risk to the CQAs
of the DP during initial risk assessment
• Critical Material Attributes (CMAs) and Critical
Process Parameters (CPPs) were determined
• Acceptable Operating Ranges were identified
• All variables that were deemed high risk are included
in the control strategy
• Can be further refined as process knowledge
increases over time
Create a
Control
Strategy
© PharmOut 2016
www.pharmout.net

26. Quality Risk Management (QRM)
Risk Acceptance
Begin the QRM Process
RiskAssessment
Risk Identification
Risk Analysis
RiskEvaluation
RiskControl
Risk Reduction
Output of the QRM Process
RiskReview
ReviewEvents
QRM
Tools
RiskCommunication
ICH Q9
© PharmOut 2016
www.pharmout.net
Control Strategy
Development

27. Control Strategy Examples
© PharmOut 2016
www.pharmout.net
Factor Attributes
or
Parameters
Range
Studied
Actual data
for the
exhibit
batch
Proposed
range for
commercial
scale
Purpose of
control
Raw Material Attributes
Acetriptan
particle size
distribution*
d90 10-45 μm 20 μm 10-30 μm To ensure in
vitro
dissolution,
in vivo
performance
and batch-
to-batch
consistency
d50 6-39 μm 12 μm 6-24 μm
d10 3.6-33.4 μm 7.2 μm 3.6-14.4 μm
Talc,
Grade D04
Particle size
distribution
> 75μm:
NMT 0.2%
> 75μm:
0.1%
>75μm:
NMT 0.2%
To ensure
batch-to-
batch
consistency
*Critical input Material Attributes (CMA)

28. Control Strategy Examples
© PharmOut 2016
www.pharmout.net
Factor Attributes
or
Parameters
Range
Studied
Actual
data for
the exhibit
batch
Proposed
range for
commercial
scale
Purpose of
control
Pre-Roller Compaction Blending and Lubrication In-Process Controls
Blend
uniformity*
Blend to endpoint: < 5.0% RSD (In-line NIR method) In-line NIR
method is used
for endpoint
determination
to ensure BU is
met consistently
Tablet Compression Process Parameters
Rotary press Feeder frame
paddle speed
8-20 rpm 15 rpm 8-20 rpm To ensure all
tablet CQAs are
met consistently
*critical process parameter (CPP)

29. Stage 2 Process Qualification
• Demonstrate that the process is capable of
reproducible commercial manufacture
• It should be completed before product is
released commercially
• Two parts to this Stage:
Design &
Qualification
of FSE
Process
Performance
Qualification
Product that meets
predetermined quality
attributes
© PharmOut 2016
www.pharmout.net

30. Process Validation
• Demonstrates the validity of the process design
and the suitability of the process control
strategy
• At full-scale (commercial manufacture)
• Provides confidence (documented evidence)
that systems of monitoring, control and SOPs in
production are capable of detecting and
compensating for potential sources of process
variability over the product lifecycle
• The number of PV batches to be produced
should be justified
© PharmOut 2016
www.pharmout.net

31. Knowledge vs # of PV batches
Prior Knowledge Process Design
Prior
Knowledge
PV
Process Design PV
Comprehensive Prior Knowledge may support fewer PV batches
Limited Prior Knowledge may require more PV batches
© PharmOut 2016
www.pharmout.net

32. Stage 3 (a) and (b)
How many PPQ batches?
This depends on the risk and the following elements could be
applied to make the decision:
Rationale and experience-based justifications
Based on Target Process Confidence and Target Process
Capability
Based on expected coverage
© PharmOut 2016
www.pharmout.net

33. Quality Risk Management (QRM)
RiskReduction
Begin the QRM Process
RiskAssessment
Risk Identification
Risk Analysis
RiskEvaluation
RiskControl
Risk Acceptance
Output of the QRM Process
RiskReview
ReviewEvents
QRM
Tools
RiskCommunication
ICH Q9
Continual
Improvement
© PharmOut 2016
www.pharmout.net

34. Maintenance of the Validated State
• “Continued Process Verification”
• Change in the validated state of the process
could impact product
• Monitored via:
• Change Control
• Periodic Monitoring
• Data Trending Review
• Calibration and PM
• Knowledge of operational parameters (Control
Strategy) and Design Space (if applicable)
© PharmOut 2016
www.pharmout.net

35. © PharmOut 2016
www.pharmout.net
Thank you for your time.
Questions?
Trevor Schoerie
Executive Consultant
trevor.schoerie@pharmout.net
www.pharmout.net