Professional Documents
Culture Documents
Wondiyfraw Worku,
Assessor
1
Talk points
Objectives of review of quality(CMC) data- reminder
Retrospective validation
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Reminder
Objectives of assessment of quality part
To provide the highest assurance that all production
batches (unit doses) will be consistently efficacious as the
clinical batch(es)
To reduce risk to safety via the highest assurance of
acceptable and consistent quality of the product and its
components
Process
validation
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Process validation
The collection and evaluation of data, from the process
design stage through commercial production, which establishes
scientific evidence that a process is capable of consistently
delivering quality products. (FDA)
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Process validation
Traditional vs new paradigm
ICH Q8,
Development- QbD
Enhanced-
Basic Development and
process
qualification
Pilot batch
Post manufacturing
approval
changes/ch
ange Continuous and
controls/risk extensive monitoring Control
analysis Process of CQAs and CPPs Strategy
validation- 3 for each production
batches batch
ICH Q9
and Q10
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Latest guidelines
FDA, January 2011 WHO, Revised Annex 7 of EMA, February 2014
WHO GMP guide (draft for
comment)
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Process validation- Role of assessment
Dossier
GMP
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Process validation phases Includes
demonstration of
content uniformity of
the clinical batch
Pre-validation
phase
Protocol Information
Preparation from
primary/clinical
manufacturing
(scale up Process risk
information) assessment
information
Validation phase (identification
Protocol execution Information from of critical
product steps)
development
studies
Post valdn phase: (identification of
Review of process, critical attributes)
deviations, failures,
need for
improvement,
9 scale up etc
Risk assessment
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Example: risk matrix for low dose capsule (CQA vs
process stages)
Sifting/sizing blending lubrication Capsule
filling
Assay Low Medium Medium Medium
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Process steps to be validated
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Validation scheme- example
Processing steps Critical parameters Validation scheme
Dispensing Weight checks Monitored
Sifting Mesh size Monitored
Wet Granulation and drying Amount and addition rate of Monitored, Drying uniformity to
granulating agent, mixing speed, be tested
time, as well as sequence of
events
Dry Granulation Slugging /compaction parameters Monitored only or Monitored and
sampled?
Blending mixing speed, time Monitored; Blend uniformity to be
established
Lubrication mixing speed, time Monitored; Blend uniformity from
mixer and bulk container
Compression Initial set up parameters, Monitored; Several samples to be
speed, applied pressure, sampled and tested for IPQC
parameters
Fluidized bed coating Spray rate, inlet and product Monitored; appearance, weight
temp, etc gain and full testing
Primary packaging, protocol Sealing temperature, speed Monitored; leak test
requested on case by case basis
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Monitoring- Example:
Compaction
BMR Set Batch 1 Batch 2 Batch 3
parameters
Horizontal 10-20 15 15 15 15 15 15
feed screw
(RPM)
Any comment vis vis the difference between BMR set range and actual
applied inputs?
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Example: Monitoring and sampling:
Drying
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Blend uniformity
Early check for content uniformity of the final dosage form
Uniform blend
with good flow Compression with Tablets meeting
and optimum criteria for
compressibility conditions uniformity of
characteristics dosage units
Note: Blend uniformity is a routine test for low dose products (i.e.
active load <=5% or 5mg)
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Blend uniformity- Sampling
location and method
Sampling location -usually predetermined as part of qualification
of the mixer (i.e. mostly GMP issue)
But, in the dossier, we at least check if periphery, center positions and
various other positions are considered
Samples from each location are usually taken in triplicate
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Blend uniformity- Sample size
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Blend uniformity- acceptance criteria
Less common
Individual assays:90.0-110.0% of the mean value, RSD NMT 5.0%
In this case, setting mean = 95.0-105.0% of the label claim appears
reasonable
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Sampling and testing plan- Lubrication- example
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Compression
Good compression outcome is a measure of (it depends
on):-
Granule/powder mix properties
bulk and tapped density-granulation
particle size and particle size distribution-granulation
moisture content- drying
extent of lubrication- lubrication time
Machine and tooling attributes
appropriate selection and adequate lubrication of punches
and dye
machine speed
applied compression pressure
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Compression Sampling frequency and size
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Compression- Challenge studies
Certain variations in
compression speed and
hardness than the target set
points may happen
what would be the impact of such
variations?
speed affects dwell time- which
intern affects several tablet
parameters (thickness, hardness,
as well as weight variation)
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Extensive sampling- example
(there are several other approaches)
IPQC testing schedule Normal production batch Validation batches
48 station machine, batch size of 170,000 tabs, target speed 25rpm
Group weight and
appearance, every 30 About 300 tablets
minutes; others every 1 hour About 300 tablets
(at least 3 times)
All in process parameters at -
start, middle and end of About 360 tablets
compression (different
hopper fill levels)
Additional samples at high, - About 480 samples
low speed; at high and low
hardness levels
Total number of tablets 300 tablets 1140 tablets
sampled
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How to demonstrate consistency?
3 sigma
process
e.g. 4 sigma
process
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Process validation-oral solutions
Validation focuses on
mixing time and conditions to clear solution, if deemed
relevant
bulk liquids: pH, specific gravity, clarity of solutions;
assay
filling process
filled units:- Volume/Wt variation and as per FPP specs
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Process Validation- Oral suspensions
Focuses on
API micronization processes (if applicable)
colloidal milling process (as applicable),
homogenization
filling
Viscosity, fill volume/weight variation,
Other critical attribute that may be affected by filling process?
Other parameters as per FPP spec including, PSD, pH, dissolution,
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Process validation- sterile products
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Process validation- sterile products-Contd
Products mfd by Products mfd by Aseptic
Terminal sterilization processing
Product sterilization Terminal sterilization by Filter validation (as part of
Steam sterilization, devt pharm)
radiation or ETO (as
applicable)*
Process simulation - Media fill
Full batch processing 3 production batches mfd 3 production batches mfd
(other aspects of the mfg at proposed scale at proposed scale
process, e.g. valdn of bulk (commitment may also be
prepn, filling and sealing accepted).
quality)
*validation should be on three runs to demonstrate reproducibility.
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Dissolution profile comparison with clinical/BE batch-
solids and suspensions (as part of process validation)
A good check point to verify performance relative
to the biobatch
All validation batches should be profiled in the routine
media on 12 units, using time points as used for
biobatch
Comparison with historical biobatch profile, with
calculation of f2 (as necessary), should be performed
and results discussed
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Matrixing/bracketing approach
Multiple strengths of same product (common
blend)
until stages of final granules: 3 consecutive batches of the
common blend (instead of 3 separate blend batches for each
strength)
compression: 3 consecutive batches of each strength
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Process validation- commitment
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Retrospective validation for established products
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Review of protocol- main aspects to check
Scope of the validation (type, batch size, reason)- do they reflect the
planned validation? Highest batch size to be validated?
Major equipments identified (in line with BMR) and a provision for
recording their Q status included?
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Review of protocol- main aspects to check-contd
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Review of validation report
Is the reported data relevant for the proposed manufacturing
process and scale
equipment used, process parameters applied
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Thank you, Questions?
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