Process validation

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 Talk points
 Objectives of review of quality data- reminder
 Process validation, definition and current approaches
 Risk assessment as part of process validation
 Validation scheme: Monitoring and Sampling
 Specific topics: Blend uniformity and validation of compression step
 Process validation commitment
 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)
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)

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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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FDA, January 2011
Latest guidelines
WHO, Revised Annex 7 of
WHO GMP guide (draft for
EMA, February 2014

comment)

Continuous process verification Continuous process verification Alternative approaches:

(CPV) (CPV) -Traditional approach
-Continuous process
verification
-Hybrid approach

Process design and Initial Process design and initial CPV protocol to be supported
validation (process validation (initial process by extensive development
qualification- PPQ) are initial verification) are initial phases of information and lab or pilot
phases of CPV CPV scale data. Executed on each
production batch

No mention of number of Mentions data on at least three Number of batches specified for
batches for initial process pilot or production batches traditional approach
performance collected as part of process - minimum of three production
qualification/validation (rather design batches unless other wise
must be justified based on justified.
overall product and process
understanding)
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 Types of process validation
Prospective validation Concurrent validation Retrospective validation

Protocol reviewed and Protocol reviewed and Protocol does not need to be
accepted, Product PQD; OR accepted, Product PQD submitted
Protocol executed before
submission or PQ
Execute and finalize process Execute and finalize process Prepare product quality
validation on the first three validation on the first three review report on already
production batches production batches manufactured production
batches

Commercial batches to be Each validation batch can be Applicable for submissions

released only after validated and released. meeting criteria for
satisfactorily conclusion of Applicable for low demand established products as
process validation on three products (such as NTDs, described in Annex 4, TRS
batches orphan drugs or other 970
seasonal products)

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 Process validation- Role of assessment

Design Operational Performance Process

qualification qualification qualification validation

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

 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

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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 Monitored only or Monitored and

parameters 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

speed, applied pressure, be sampled and tested for IPQC
12 parameters
 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

parameter
s

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)
 Any comment vis à vis the difference between BMR set range and actual
applied inputs?
Horizontal 10-20 15 15 15 15 15 15
feed screw
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(RPM)
 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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 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

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 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

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 Sampling and testing plan- Lubrication- example
Sample Sample size Sample Tests Acceptance
location analysed limits

Lubrication 10 position 850-2550mg 10 Individual Blend Mean: 95.0-

from in triplicate samples uniformity 105.0%,
Octagonal individual:
blender and 90-110%,
blend RSD: NMT
container 5%

Do you agree
What Samples
are the 50gmwith Composite missing
Complete As per blend
minimum tests
fromwetop, samples parameter?
analysis as spec
expect tomiddle
the acceptance
see in and
criteria? per routine
?blend spec
bottom blend spec
?Acceptable

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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 samples 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

Group weight and

appearance, every 30
minutes; others every 1 hour About 300 tablets
(at least 3 times)

All in process parameters at -

start, middle and end of
(different hopper fill levels)

Additional samples at high, -

low speed; at high and low
hardness levels

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 How to demonstrate consistency?

3
sigma
process e.g. 4 sigma
process
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 Process validation- material type

 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.

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 Process Validation- material type

 Focuses on
 homogenization
 filling
• Viscosity, fill volume/weight variation,
• Other critical attribute that may be affected by filling process?

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 Matrixing/bracketing approach
 Multiple strengths of same product (common
blend)
 until stages of final blend: 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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 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?

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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

 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

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 Thank you,

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