This document discusses process validation for pharmaceutical products. It defines process validation, outlines current regulatory approaches, and describes the role of dossier assessment in process validation. Key points covered include risk assessment as part of process validation, validation schemes involving monitoring and sampling, specific topics like blend uniformity and compression step validation, and process validation for different dosage forms. Guidelines from FDA, WHO, and EMA on process validation approaches like traditional, continuous, and hybrid are summarized. The document provides examples of process validation protocols, monitoring plans, sampling methods and acceptance criteria for various steps in manufacturing like blending, drying, lubrication, and compression.

1. 6th
CPH assessment training workshop
May 2014
Process validation

2. 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

3. 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

4. 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)

5. Process validation
Traditional vs new paradigm
Post approval
changes/chan
ge
controls/risk
analysis
Development-
Basic
Process
validation- 3
batches
Pilot batch
manufacturing
Enhanced-
Development and
process qualification
Control
Strategy
Continuous and extensive
monitoring of CQAs and
CPPs for each production
batch
ICH Q9
and Q10
ICH Q8,
QbD

6. Latest guidelines
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

7. Types of process validation and
dossier requirements
Prospective validation Concurrent validation Retrospective validation
Protocol reviewed and
accepted, Product PQD; OR
Protocol executed before
submission or PQ
Protocol reviewed and
accepted, Product PQD
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

8. Process validation- Role of assessment
Design
qualification
Operational
qualification
Performance
qualification
Process
validation
GMP
Dossier

9. Process validation phases
Pre-validation phase
Protocol Preparation
Information from
product development
studies (identification
of critical attributes)
Information from
primary/clinical
manufacturing
(scale up
information) Process risk
assessment
information
(identification of
critical steps)
Validation phase
Protocol execution
Post valdn phase:
Review of process,
deviations, failures,
need for improvement,
scale up etc…
Includes demonstration of
content uniformity of the
clinical batch

10. 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

11. Example: risk matrix for low dose capsule (CQA vs
process stages)
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

12. 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

13. 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
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

14. Monitoring- Example:
Compaction
Any comment vis à vis the difference between BMR set range and actual applied
inputs?
BMR Set
parameters
Batch 1 Batch 2 Batch 3
e.g. of
parameter
s
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

15. Example: Monitoring and sampling:
Drying
Monitoring Set parameter Observation
Batch X Batch Y Batch Z
Inlet temperature 60+/-10o
C 62-65 52-63 52-60
Outlet temp 29-44 31-47 28-36
Total drying time
(min) (for
information)
65 65 80
Sampling and
testing
Spec Batch X Batch Y Batch Z
Location 1 0.75-2.25% 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

16. 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)

17. 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

18. Blend uniformity- Sample size
 What is an acceptable amount for samples taken at each location?
Normally 1-3 time of the FPP unit dose weight

19. 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

20. Sampling and testing plan- Lubrication-
example
missing parameter?Do you agree with the
acceptance criteria?
Sample
location
Sample size Sample
analysed
Tests Acceptance
limits
Lubrication 10 position
from
Octagonal
blender and
blend
container
850-2550mg
in triplicate
10 Individual
samples
Blend
uniformity
Mean: 95.0-
105.0%,
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,
bulk and
tapped
density
For
information
What are the
minimum tests we
expect to see in
blend spec?
Acceptable?

21. 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

22. 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

23. 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

24. 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
About 300 tablets
All in process parameters at
start, middle and end of
compression (different
hopper fill levels)
-
About 360 tablets
Additional samples at high,
low speed; at high and low
hardness levels
- About 480 samples
Total number of tablets
sampled
300 tablets 1140 tablets

25. How to demonstrate consistency?
3sigma
process
e.g. 4 sigma
process

26. 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

27. 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

28. Process validation- sterile products
Products mfd by
Terminal sterilization
Products mfd by
Aseptic processing
Container and
component sterilization
and depyrogenation
- 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 depyrogenation-
for glass vials or
ampoules*

29. 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.

30. 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
Check if the protocol includes adequate
instruction/provision

31. 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

32. 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.

33. 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
SeeAppendix 2 of Annex 4,TRS 970

34. 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?

35. 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?

36. 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