4/4/2019

Process validation
Wondiyfraw Worku,

Assessor

6th CPH assessment training workshop

May 2014

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
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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Process validation‐ Role of assessment

Fase prevalidació Fase execució

Design Operational
Performance Process
qualification qualification
qualification validation

1. Recerca i desenvolupament de la FF
2. Formulació 1. Verificació procés
3. Lots pilots 2. Paràmetres crítics
4. Escalatges 3. “condicions worst case”
5. Transferència a lots comercials
6. Condicions estabilitat i conservació
7. Qualificacions d’equips Dossier
8. Documentació: guies,
Post valid phase:
9. Capacitat procés
Review of process,
GMP deviations, failures,
need for
improvement,
7 scale up etc…

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Risk assessment (ICH Q9)

 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

Example: risk matrix for low dose capsule

(CQA vs process stages)
Sifting/sizing blending lubrication Capsule
filling
Assay Low Medium Medium Medium

Content High High High High

uniformity

Dissolution Low Low High Low

Stability Low Low Low Low

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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

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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

e.g. of Cycle 1 Cycle 2 Cycle 1 Cycle 2 Cycle 1 Cycle 2

parameters
Roller 8-15 10 10 10 10 10 10
speed
(RPM)
Roller 40-60 41-42 42-43 41-43 41-42 41-42 41-43
pressure
(Bars)
Vertical 50-100 75 75 75 75 75 75
feed screw
(RPM)

Horizontal 10-20 15 15 15 15 15 15
feed screw
(RPM)

 Any comment vis à vis the difference between BMR set range and actual
applied inputs?

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Example: Monitoring and sampling:

Drying

Monitoring Set parameter Observation

Batch X Batch Y Batch Z
Inlet temperature 60+/-10oC 62-65 52-63 52-60

Outlet temp 29-44 31-47 28-36

Total drying time 65 65 80

(min) (for
information)

Sampling and Spec Batch X Batch Y Batch Z

testing
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

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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

 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

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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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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

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Thank you, Questions?

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