Process validation
Wondiyfraw Worku,
Assessor
6th CPH assessment training workshop
May 2014
1
Talk points

Objectives of review of quality(CMC) data- reminder

Process validation, definition and current approaches

Role of dossier assessment in process validation

Risk assessment as part of process validation

Validation scheme: Monitoring and Sampling

Specific topics: Blend uniformity and validation of compression step

Process validation: other dosage forms

Process validation commitment

Retrospective validation

Summary: How to review protocol and report
2
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
3
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)
 Documented evidence which provides a high degree of
assurance that a specific process will consistently result in a
product that meets predetermined specifications and quality
characteristics. (WHO)
 The documented evidence that the process, operated within
established parameters, can perform effectively and
reproducibly to produce a medicinal product meeting its
predetermined specifications and quality attributes.(EMA)
4
Process validation
Traditional vs new paradigm
DevelopmentBasic
Post
approval
changes/ch
ange
controls/risk
analysis
EnhancedDevelopment and
process
qualification
Pilot batch
manufacturing
Process
validation- 3
batches
Continuous and
extensive monitoring
of CQAs and CPPs
for each production
batch
Control
Strategy
ICH Q9
and Q10
5
ICH Q8,
QbD
Latest guidelines
6
FDA, January 2011
WHO, Revised Annex 7 of
WHO GMP guide (draft for
comment)
EMA, February 2014
Continuous process
verification (CPV)
Continuous process
verification (CPV)
Alternative approaches:
-Traditional approach
-Continuous process
verification
-Hybrid approach
Process design and Initial
validation (process
qualification- PPQ) are initial
phases of CPV
Process design and initial
validation (initial process
verification) are initial phases
of CPV
CPV protocol to be supported
by extensive development
information and lab or pilot
scale data. Executed on each
production batch
No mention of number of
batches for initial process
performance
qualification/validation (rather
must be justified based on
overall product and process
understanding)
Mentions data on at least
three pilot or production
batches collected as part of
process design
Number of batches specified
for traditional approach
- minimum of three production
batches unless other wise
justified
Types of process validation and
dossier requirements
Prospective validation
7
Concurrent validation
Retrospective validation
Protocol reviewed and
Protocol reviewed and
accepted, Product PQD; OR accepted, Product PQD
Protocol executed before
submission or PQ
Protocol does not need to
be submitted
Execute and finalize
process validation on the
first three production
batches
Execute and finalize
process validation on the
first three production
batches
Prepare product quality
review report on already
manufactured production
batches
Commercial batches to be
released only after
satisfactorily conclusion of
process validation on three
batches
Each validation batch can
be validated and released.
Applicable for low demand
products (such as NTDs,
orphan drugs or other
seasonal products)
Applicable for submissions
meeting criteria for
established products as
described in Annex 4, TRS
970
Process validation- Role of assessment
Design
qualification
Operational
qualification
Performance
qualification
Dossier
GMP
8
Process
validation
Process validation phases
Pre-validation
phase
Protocol
Preparation
Validation phase
Protocol execution
9
Post valdn phase:
Review of process,
deviations, failures,
need for
improvement,
scale up etc…
Information
from
primary/clinical
manufacturing
(scale up
information)
Information from
product
development
studies
(identification of
critical attributes)
Includes
demonstration of
content uniformity of
the clinical batch
Process risk
assessment
information
(identification
of critical
steps)
Risk assessment
 Part of process development and protocol preparation
 Risk matrix- usually as part of process development
• Critical quality attributes (CQA) vs processing stages, e.g. dissolution vs
granulation
• CQA vs critical process parameters, e.g., dissolution vs kneading time
 Failure mode analysis- usually as part of process validation
 To identify critical attributes, processes and parameters
 Informed validation
 To establish control strategy
10
Example: risk matrix for low dose capsule (CQA vs
process stages)
11
Sifting/sizing
blending
lubrication
Capsule
filling
Assay
Low
Medium
Medium
Medium
Content
uniformity
High
High
High
High
Dissolution
Low
Low
High
Low
Stability
Low
Low
Low
Low
Process steps to be validated
 All steps that are generally considered critical (medium and
high risk steps) should be monitored/scrutinized
 by summarizing actual process parameters applied and observations
recorded
• e.g. sifting stage, wet and dry granulation stages
 observations serve as feedback for future refinement of process
parameters
 In addition, where feasible, sampling and testing should be
performed
• e.g. drying, mixing steps, compression, filling
• results measure effectiveness and consistency of the immediate as
well as preceding steps- e.g. final blend characteristics are mainly
shaped by wet/dry granulation process
12
Validation scheme- example
13
Processing steps
Critical parameters
Validation scheme
Dispensing
Weight checks
Monitored
Sifting
Mesh size
Monitored
Wet Granulation and drying
Amount and addition rate of
granulating agent, mixing speed,
time, as well as sequence of
events
Monitored, Drying uniformity to
be tested
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,
speed, applied pressure,
Monitored; Several samples to be
sampled and tested for IPQC
parameters
Fluidized bed coating
Spray rate, inlet and product
temp, etc…
Monitored; appearance, weight
gain and full testing
Primary packaging, protocol
requested on case by case basis
Sealing temperature, speed
Monitored; leak test
Monitoring- Example:
Compaction
BMR Set
parameters
e.g. of
parameters
Batch 1
Batch 2
Batch 3
Cycle 1
Cycle 2
Cycle 1
Cycle 2
Cycle 1
Cycle 2
Roller
speed
(RPM)
8-15
10
10
10
10
10
10
Roller
pressure
(Bars)
40-60
41-42
42-43
41-43
41-42
41-42
41-43
Vertical
feed screw
(RPM)
50-100
75
75
75
75
75
75
Horizontal
feed screw
(RPM)
10-20
15
15
15
15
15
15
 Any comment vis à vis the difference between BMR set range and actual
applied inputs?
14
Example: Monitoring and sampling:
Drying
Monitoring
Observation
Batch X
Batch Y
Batch Z
62-65
52-63
52-60
Outlet temp
29-44
31-47
28-36
Total drying time
(min) (for
information)
65
65
80
Inlet temperature
15
Set parameter
60+/-10oC
Sampling and Spec
testing
Batch X
Batch Y
Batch Z
Location 1
1.54
1.53
1.70
Location 2
1.94
2.01
1.80
Location 3
2.03
1.30
2.05
Location 4
1.89
1.87
2.20
0.75-2.25%
Blend uniformity
 Early check for content uniformity of the final dosage form
Uniform blend
with good flow
and
compressibility
characteristics
Compression with
optimum
conditions
Tablets meeting
criteria for
uniformity of
dosage units
Note: Blend uniformity is a routine test for low dose products (i.e.
active load <=5% or 5mg)
16
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
 Samples should also be taken from the blend container- to
evaluate impact of transfer
 important for low dose products and particularly for DC processed blend
 Sampling should be done consistently and in away that does not
disturb the bulk blend state – such aspects (e.g. type of sampling
thief used) are better addressed at the time of inspection
17
Blend uniformity- Sample size
 What is an acceptable amount for samples taken at each location?
C. Morten, PIAT programme, University of Manchester
 Normally 1-3 time of the FPP unit dose weight
18
Blend uniformity- acceptance criteria
 Commonly used criteria
 Individual assays: 90.0-110.0% of label claim, RSD NMT 5.0%
 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
 Rarely (in case of very low dose products)
 Individual assays: 85.0-105.0% of the label claim/mean value, RSD: NMT
5.0%
 May be acceptable provided that uniformity of dosage units is
satisfactorily demonstrated on tablets/capsules manufactured from
blend lot with close to limit blend uniformity results
19
Sampling and testing plan- Lubrication- example
Lubrication
Sample
location
Sample size
Sample
analysed
Tests
Acceptance
limits
10 position
from
Octagonal
blender and
blend
container
850-2550mg
in triplicate
10 Individual
samples
Blend
uniformity
Mean: 95.0105.0%,
individual:
90-110%,
RSD: NMT
5%
Samples
from top,
middle and
bottom
50gm
Composite
samples
Complete
analysis as
per routine
blend spec
As per blend
spec
Particle size
distribution,
missing
bulk and
parameter?
tapped
density
What are the
Do you agree with
minimum tests we
the acceptance
expect to see in
criteria?
blend spec?
Acceptable?
20
For
information
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
21
Compression – Sampling frequency and size
 depends on the length of the run time/
batch size
we expect frequent sampling than the normal IPQC
frequency
the number of tablets/capsules taken should be
greater than those taken during a normal IPQC
sampling
22
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)
 Therefore, robustness should be
demonstrated
C. Morten, PIAT programme, University of Manchester
23
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
minutes; others every 1 hour
(at least 3 times)
About 300 tablets
All in process parameters at
start, middle and end of
compression (different
hopper fill levels)
-
Additional samples at high,
low speed; at high and low
hardness levels
-
About 480 samples
300 tablets
1140 tablets
Total number of tablets
sampled
24
About 300 tablets
About 360 tablets
How to demonstrate consistency?

3 sigma
process
25
e.g. 4 sigma
process
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
 Protocol with commitment is acceptable at the
time of review
26
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,
 Protocol with commitment is acceptable at the
time of review
27
Process validation- sterile products
Container and
component sterilization
and depyrogenation
28
Products mfd by
Terminal sterilization
Products mfd by
Aseptic processing
- Depyrogenation by
tunnel depyrogenator
(e.g. ampoules) or
washing (e.g. rubber
stoppers, plastic
bottles)
- Depyrogenation by
washing- for stoppers,
seals, accessories*
- Validation of steam
sterilization – for
stoppers, seals,
accessories*
- Dry heat sterilization
and depyrogenationfor glass vials or
ampoules*
Process validation- sterile products-Contd
Products mfd by
Terminal sterilization
Products mfd by Aseptic
processing
Product sterilization
Terminal sterilization by
Steam sterilization,
radiation or ETO (as
applicable)*
Filter validation (as part of
dev’t pharm)
Process simulation
-
Media fill
Full batch processing
(other aspects of the mfg
process, e.g. valdn of bulk
prepn, filling and sealing
quality)
3 production batches mfd
at proposed scale
3 production batches mfd
at proposed scale
(commitment may also be
accepted).
*validation should be on three runs to demonstrate reproducibility.
29
Dissolution profile comparison with clinical/BE batchsolids 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
 Check if the protocol includes adequate
instruction/provision
30
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
 Primary packaging of tablet/capsule products
blistering of hygroscopic or moisture sensitive products
however should always be individually validated
31
Process validation- commitment
 As described in Annex 4, TRS 970, applicants
are not expected to have process validation
data before PQ
In this case satisfactory PV protocol (PVP) and
appropriately worded commitment are essential
PVP or signed commitment letter should clearly
indicate the need for prospective validation as
finalized on three consecutive production batches,
unless other wise justified.
32
Retrospective validation for established products
 Generally acceptable if condition described in
Annex 4, TRS 970 (generic guide), are met.
 Tries to demonstrate process effectiveness and
consistency via trend analysis:
 extent of deviations
 extent of OOS or OOT
 extent of batch rejection
 extent of product complains
 extent of changes/ improvements introduced
 See Appendix 2 of Annex 4, TRS 970
33
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?
 Reference to current master production record included?
 Summary of critical steps identified? is this convincing ?
 Monitoring and sampling plan provided?- Do you agree with the
steps monitored/sampled?
 Sampling schedule, schematics, tests and acceptance criteria, as well
as current specification codes included ? Are these acceptable?
34
Review of protocol- main aspects to check-contd
 For solid orals: final blending, compression/encapsulation,
coating stages must be adequately sampled and tested. Are
these being reflected?
 Blend uniformity: Sampling schemes and blend uniformity acceptance
criteria specified? Are these acceptable?
 Compression/encapsulation at lower, target and upper speeds included?
 Provision for performance of dissolution profile testing and
comparison with the biobatch included?
 Appropriate commitment (prospective validation on first three
consecutive batches mentioned) provided?
 Protocol reference and version number included in QIS?
35
Review of validation report
 Is the reported data relevant for the proposed manufacturing
process and scale
 equipment used, process parameters applied
 All critical steps adequately monitored/sampled?
 Level of sampling and size are acceptable?
 All results within acceptable limits? Particular trend?
 Deviations appropriately evaluated and discussed?
 Is the overall process in sufficient control? Is there any thing that
should be improved or refined for future production batches
36
Thank you, Questions?
37