Process validation.pptx_Process validation and inspection method with Example of Process validation protocol and report

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Zerlealem Tsegaye
February 2024
Process validation and inspection method with Example of
Process validation protocol and report

Presentation outline
 Process validation, definition and purpose
 General principle
 Traditional vs new paradigm
 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: sterile products
 Process validation : Biological products
 Retrospective validation
 Summary: How to review protocol and report
 List of References used

Process validation Definition
 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)
Which one of the 3 definition is Ethiopian FDA PV definition????

Purpose of PV
 To show that critical steps are under control and
lead continuously to the desirable quality
 Mandatory for processes including all critical steps
Examples of critical steps ????

General principle
• Manufacturing processes may be developed using a traditional
approach or a continuous verification approach.
– Irrespective of the approach used, processes must be shown to be
robust and ensure consistent product quality before any product is
released to the market
• Manufacturing processes using the traditional approach should
undergo a prospective validation programme.
– Retrospective validation is no longer an acceptable approach.

General principle
• Process validation of new products should cover all
intended marketed strengths and sites of manufacture.
• Bracketing could be justified for new products based on
extensive process knowledge from the development stage
in conjunction with an appropriate ongoing verification
programme.

General principle
• Normally batches manufactured for process validation should be
the same size as the intended commercial scale batches and the use
of any other batch sizes should be justified
• Equipment, facilities, utilities and systems used for process
validation should be qualified.
• Test methods should be validated for their intended use.

General principle
• Process validation batches should only be manufactured by trained
personnel in accordance with GMP using approved documentation.
• It is expected that production personnel are involved in the
manufacture of validation batches to facilitate product
understanding.
• The suppliers of critical starting and packaging materials should be
qualified prior to the manufacture of validation batches; otherwise
a justification based on the application of quality risk management
principles should be documented.

General principle
• For process validation of products which are transferred
from one site to another or within the same site, the
number of validation batches could be reduced by the use
of a bracketing approach.
– However, existing product knowledge, including the content of
the previous validation, should be available.
• Different strengths, batch sizes and pack sizes/container
types may also use a bracketing approach, if justified.

Traditional vs new paradigm
• Traditional process validation is normally performed
when the pharmaceutical development and/or
process development is concluded, after scale-up to
production scale and prior to marketing of the
finished product.
• Process validation studies may be conducted on
pilot scale batches if the process has not yet been
scaled up to production scale.

• Formal process validation studies to be
conducted on production scale batches
• The number of batches used would depend on
the variability of the process, the complexity
of the process / product and the experience of
the manufacturer but would usually be a
minimum of 3 consecutive batches.

• Continuous process verification is an alternative approach
to traditional process validation in which manufacturing
process performance is continuously monitored and
evaluated .
• Continuous process verification may be applicable to both a
traditional and enhanced approach to pharmaceutical
development.
• Continuous process verification can be used in addition to,
or instead of, traditional process validation.

• Companies should perform, as relevant, extensive in-
line, on-line or at-line controls and monitor process
performance and product quality on each batch.
• Data on quality attributes of incoming materials or
components, in-process material and finished products
should be collected.
– This should include the verification of attributes,
parameters and end points, and assessment of CQA and
critical process parameter (CPP) trends.

Ongoing Process Verification Lifecycle
• Manufacturers should monitor product quality to ensure that a state of control is
maintained throughout the product lifecycle with the relevant process trends
evaluated.
• The extent and frequency of ongoing process verification should be reviewed
periodically.
• At any point throughout the product lifecycle, it may be appropriate to modify the
requirements taking into account the current level of process understanding and
process performance.
• Ongoing process verification should be conducted under an approved protocol or
equivalent documents
• Statistical tools should be used, where appropriate, to support any conclusions
with regard to the variability and capability.

• The first stage in the product lifecycle.
process design
• the second stage in the product lifecycle.
Continuous process verification
• The third stage
on-going process verification

 Enabler
• Process analytical technology (PAT) applications
• The use of PAT enables disturbances to be detected in real
time.
• Example applications include
 in-line UV flow cells to monitor therapeutic protein
concentration
 in-line near-infrared spectroscopy to assess blend uniformity or
water content
 on-line HPLC to monitor conversion of a chemical reaction.
• Multivariate Statistical Process Control (MSPC)

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…

Process validation protocols
 A short description of the process and a
reference to the respective MasterBatch
Record;
 Functions and responsibilities;
 Summary of the CQAs to be investigated;
 Summary of CPPs and their associated
limits;
 Summary of other (non-critical) attributes
and parameters which will be investigated
or monitored during the validation
activity, and the reasons fortheir
inclusion;
 List of the equipment/facilities to be used
(includingmeasuring/monitoring/recordin
g equipment) together with the
calibration status;
 List of analytical methods and method
validation, as appropriate.
 Proposed in-process controls with
acceptance criteria and the reason(s) why
each in-process control is selected.
 Additional testing to be carried out with
acceptance criteria;
 Sampling plan and the rationale behind it;
 Methods for recording and evaluating
results;
 Process for release and certification of
batches (if applicable).

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
• 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
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
– 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

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

Monitoring- Example:
Compaction
– Any comment with the difference between BMR set range and actual
applied inputs?
BMR Set
parameters
Batch 1 Batch 2 Batch 3
e.g. of
parameters
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

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
(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

Blend uniformity
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)

Blend uniformity- Sampling
location and method
• Sampling location -usually predetermined as part of
qualification of the mixer
– 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

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

Blend uniformity- acceptance criteria
• Commonly used criteria
– Individual assays: 90.0-110.0% of label claim, RSD NMT
5.0%
• 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

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?

Compression
• Good compression outcome is a measure of
– 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

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

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

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

How to demonstrate consistency?

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

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,

Process validation- sterile products
Products mfd by Terminal sterilization and
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*

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) Pseudomonas
diminuta.
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
*validation should be on three runs to demonstrate reproducibility.

Process validation : Biological products
• Flow of Manufacture for Biotechnological Products Manufactured in
a Microbial Cells e.g. E. Coli, Human insulin.
– Develop host cell
– Develop expression vector
– Establish a cell bank
– Protein production
– Purification(DSP)
– Characterization/Analysis
– Formulation of DP(Drug Product)

 Control of al starting materials, (medium nutrients, cell viability &
density).
 Cell expansion using shake flask(125ml, 500ml 2000L;
Contamination Check, pH, Wet Cell Weight ).
 Fermentation – (critical process parameters eg , pH, PCO2, temp,
stir rate, batch phase, fed batch phase(fed rate NMT 11 g/Llh),
continuous cell density, viability, Contamination Check, pH, Wet Cell
Weight , Product content of Insulin).
 Centrifugation – rpm
 Lysis crude – (Temperature, time, pH, endotoxin level, yield etc.)

 Capture and Elucidation –columns/resins for capture, Buffer, flow rate of
buffers, Load, viscosity, pH, conductivity & temperature, Bioburden.
 Purification – Chromatography
 Enzymatic conversion of human proinsulin to human insulin– type of
enzyme used (Pancreatic Porcine trypsin, recombinant porcine trypsin.
Pancreatic Bovine trypsin and recombinant bovine trypsin.
 Multimodal Chromatographic Purification of human insulin :
UF/DF – Concentration of product
 Crystallization of insulin with zinc solution(pH, % solids, Product content,
purity and impurity profile)
 Drug substance → Human insulin

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

Retrospective validation for
established products
• 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 medicine registration guideline

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?

Review of protocol- main
aspects to check-cont.
• 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?

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

Some of the References used to
prepare the PPT
• Guideline for Registration of Medicines fourth edition
• EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human
and Veterinary Use volume 4 EudraLex
https://health.ec.europa.eu/system/files/2016-11/2015-10_annex15_0.pdf
• Guideline on process validation for finished products - information and data to be
provided in regulatory submissions
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-
process-validation-finished-products-information-and-data-be-provided-
regulatory-submissions-revision-1_en.pdf
• Guideline on manufacture of the finished dosage form
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-manufacture-finished-
dosage-form-revision-1_en.pdf
• WHO published PPT

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