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

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

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

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

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

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
parameter
s

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 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 containerto 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- Lubricationexample

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 distributiongranulation
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 timewhich 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?

sigma 3
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 productsContd

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

devt 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 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
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