CONTINUOUS PROCESS

VERIFICATION –
A HOLISTIC APPROACH

Raktim Dey
Dy. Manager – Validations and Qualifications
Granules India Limited
 What is continuous Process Verification?
• Continuous Process Verification ( CPV here in after) is the third phase of a Product
lifecycle management.
• CPV ensures the product remains in a state of control from date of dispatch till the
end of its expiry.
• The 3 main pillars of a CPV report are CPPs (Critical Process Parameters or the input
variables), CQAs ( Critical Quality Attributes or the desired Output) and CMAs (Critical
Material Attributes-A CMA is a physical, chemical, biological or microbiological
property or characteristic of an input material that should be within an appropriate
limit, range, or distribution to ensure the desired quality of output material.)
• The CPV involves a scientific and risk-based approach, wherein the manufacturing
process performance is continuously monitored and evaluated, and documented to
prove that the process operates within the specified parameters and consistently
produces material which meets all its CQAs and control strategy requirements as
intended.
 How to plan for a Continuous Process Verification?
• As already discussed , Continued Process Verification (CPV) provides a means to
ensure that processes remain in a state of control following the first 2 stages of
Process validation i.e. Process Design ( Stage-I) and Process Performance
Qualification ( Stage-II)
• Stage –I and Stage-II lay down the core of determining the CPPs , CQAs and
CMAs of a particular product manufacturing process which in turn assists in
monitoring a product as a part of CPV.
• The co-relation between process inputs (CPPs) and corresponding outputs
(CQAs) established in earlier stages ( Stage-I & II) is fundamental to the success
of the CPV program.
 How to document a CPV program?
• Planning for CPV commences during the Stage –I itself. High-level quality system policies and
documents should outline how various departments interact and how information is compiled
and reviewed in order to ensure maintenance of the validated state.
• Generally a product specific CPV report comprises the following elements (not limited to):
Roles and responsibilities of various functional groups.
Sampling and testing strategy.
Data analysis methods (e.g., statistical process control methods).
Acceptance criteria (where appropriate).
Strategy for handling Out-of-Trend (OOT) and Out-of-Specification (OOS) results.
Mechanism for determining what process changes and/or trends require going back to Stage 1
and or Stage 2.
Timing for re-evaluation of the CPV testing plan.
 Development of a CPV Plan
• Planning for CPV commences during the Stage –I itself. High-level quality system policies and
documents should outline how various departments interact and how information is compiled and
reviewed in order to ensure maintenance of the validated state.
• The figure below illustrates an example of the development of a CPV monitoring strategy
throughout the lifecycle stages.
• Statistical methods
Stage
• Data to trend
I Draft a CPV Plan • Ensuring confidence in the process
based upon small batches

II •
Based upon the learning Revise commitment to suitable No. of
batches under CPV prior to reassessing
during PPQ stage adjust acceptance criteria
the CPV plan • Update statistical strategy based on
• knowledge/confidence gained from
PPQ
• Update frequency of data review based
III on relevant statistical tools

Approve the plan prior to

start further Periodic review to
Manufacturing ensure State of
control
 Determination of CPV for Legacy products
• For CPV of Legacy product , the historical data is used to determine the current state of control of the process.
• Measures like , performance capability (Ppk) and other statistical approaches should be considered for assessment of the
process.

Refer the IPA document of Process

Validation for details of CPV for legacy
documents.
 Assessment of CPV data and its trending

• The CPV plan should clearly state how the data collected will be analyzed.
• It may be compared to pre-defined acceptance criteria, e.g., a gradient elution slope
for a critical column chromatography step, unit operation yields, data may be
statistically assessed to evaluate process trends.
• Control charts are commonly used to evaluate process control over time.
• They are appropriate for both evaluating statistical process control and for
detecting process trends.
• Under CPV, control charts are generated and evaluated on a per batch basis.
 CPV report preparation
• The CPV plan needs to include a frequency of review of the information from data
collection mechanisms as well as Quality Systems.
• Generally industrial practice is to prepare CPV report on a Quarterly basis and
minimum batch numbers to consider for a particular product to prepare a CPV report
is 3o batches.
• However, The frequency of data review will depend primarily on risk. The starting
point for defining the review period will be the most recent process risk
communication document.
• As more production data is generated, deeper process understanding is gained and
control is likely to be more easily demonstrated.
 Briefing the 3 stages of Product Life Cycle Management
Stage 1 — Process design:
• Identification of product attributes that may affect quality and patient safety.
• Criticality analysis of product quality attributes (CQA identification).
• Cause and Effect Analysis or Risk Ranking and Filtering, which link the process
steps and parameters to process performance or product quality attributes.
These can be used to screen potential variables for future process
characterization (e.g., DoE) and testing.
• Preliminary Hazards Analysis (PHA) or early FMEA.
• Determining process control strategies that address the risk of failure for each
process step
 Briefing the 3 stages of Product Life Cycle Management
Stage 2 — Process Performance Qualification:
• Determination of process steps and parameters to test in PPQ, including
sampling plans and sample quantity.
• Facility and equipment readiness checks. Prior batch manufacturing Facility
and Equipment shall be qualified.
• Determination of effective acceptance criteria for each test function.
• Analytical test results and deviations.
Briefing the 3 stages of Product Life Cycle Management
Stage 3 — Continuous Process Verification:
• Determination of parameters that should be monitored as well as how they
should be sampled and analyzed (e.g., sampling plans, confidence required
and length of enhanced sampling).
• Evaluation of commercial manufacturing data to determine the best course
for process improvement.
• Continuous monitoring of batches to assess the process capability.
Flow diagram for a typical QRM tool for Process
development & Validation

Refer the IPA document of

Process Validation for
details of Risk Assessment
 Process Capability
• In process improvement efforts, the process capability index or process capability ratio is a statistical
measure of process capability: the ability of a process to produce output within specification limits. The
concept of process capability only holds meaning for processes that are in a state of statistical control.
• In simple words, it measures producer's capability to produce a product within a pre determined tolerance
range.
• The two most common process capability statistics are Cp and Cpk.
• Cpk is more widely used than Cp, since it takes into account the mean and the standard deviation in its
calculation. The difference between Cp and Cpk is an indicator of how far the average of the process is
from the target specification.

Refer the IPA document of Process

Validation for details of Process Capability
Few Essential Flow Diagrams

Refer the IPA document of

Process Validation for details
of Process validation lifecycle
flow chart
Few Essential Flow Diagrams

Refer the IPA document of

Process Validation for details
of Process validation lifecycle
flow chart
Few Essential Flow Diagrams

Refer the IPA document of Process

Validation for details of CPV work flow
Stage wise CPPs and CQAs for a Product ( Not limited to.)
Operation Process parameter Quality attributes
 Area Temperature
 Area RH
 Impeller Speed
 (RPM)
 BD of Dry Mix
 Impeller Tip
Dry Mixing  LOD of Dry Mix
 Speed (m/s)
 Ampere Load
 Chopper Speed
 Binder Addition
 Time
 Ampere Load
 Area Temperature
 Area RH
Binder  Binder Quantity  Homogeneity of Binder Solution
Preparation  Solvent Quantity  No Lumps or Agglomerates in Binder solution
 Stirring Time
 Stirring Speed
 Area Temperature
 Area RH
 Impeller speed
 (RPM)  Ampere Load
Binder  Impeller Tip  Torque Value
Addition and Granulation  Speed (m/s)  Process Time
 Chopper Speed
 RPM of Peristaltic Pump
 Binder Addition Rate (gm/min)
 Extra Solvent Quantity (if any)
 Area Temperature
 Area RH
Wet Milling NA
 Screen Size
 Speed (RPM)
Stage wise CPPs and CQAs for a Product ( Not limited to.)
Operation Process parameter Quality attributes

 Area Temperature
 Area RH
 Air Drying Time
 Inlet Temperature
Drying  LOD
 Inlet Air CFM
 Outlet Temperature
 Drying Time
 Racking/Other Requirement

 Area Temperature
 Area RH
Dry Milling NA
 Screen Size
 Speed (RPM)

 Area Temperature
 Area RH
 Blender RPM  Yield
Blending and Lubrication
 No of Rotations  Blend Uniformity
 Blending time
 Lubrication Time
Stage wise CPPs and CQAs for a Product ( Not limited to.)
Operation Process parameter Quality attributes

 Area Temperature
 Area RH
 No of station
 No of punches
 Type of tooling
 (D/B/BB)
 Tooling MOC/Coating
Tablets meeting all in process parameters like ( DT, Friability,
 Turret RPM
Compression Hardness, Thickness, Weight variation , Dissolution, Description
 Type of feeder
etc.)
 Feeder RPM
 Compaction force
(Main Roller)
 Compaction force
(Pre-compression)
 Ejection force
 Dwell Time

 Area Temperature
 Area RH
Coating Solution  Binder Quantity  Homogeneity of Coating Solution
preparation  Solvent Quantity  No Lumps or Agglomerates in Coating solution
 Stirring Time
 Stirring Speed
Stage wise CPPs and CQAs for a Product ( Not limited to.)
Operation Process parameter Quality attributes
 Area Temperature
 Area RH
 Occupancy %
 Pan Diameter
 No of Guns
 Type of Gun
 Bed- to- gun
 Distance
 Pan Coating and/
 or other requirements
 Inlet Temperature  Tablets meeting all in process parameters like (DT, Friability,
 Inlet Air RH Hardness, Thickness, Weight variation, Dissolution, Description
Coating Process
 Inlet air Dew Point etc.)
 Outlet Temperature  Tablet meeting Finished product specification
 Product Temperature
 Spray Rate (Gm/Min)
 Atomization
 Pan RPM
 Pan DP
 Drying Temperature
 Drying Time
 Drying Pan RPM
 Pan Coating and/ or other
requirements

Refer the IPA document of Process Validation for details of CPPs and CQAs
 DATA COLLECTION FOR A CPV REPORT
• Furnished below are a typical example of the parameters to be considered
for a CPV report preparation.

Limits mentioned are just for example

DATA COLLECTION FOR A CPV REPORT

Limits mentioned are just for example

DATA COLLECTION FOR A CPV REPORT

Limits mentioned are just for example

DATA COLLECTION FOR A CPV REPORT

Limits mentioned are just for example

DATA COLLECTION FOR A CPV REPORT

Limits mentioned are just for example

DATA COLLECTION FOR A CPV REPORT

Limits mentioned are just for example

 DATA COLLECTION FOR A CPV REPORT
 Details of Deviations, Change Controls , Market complaints , OOT and OOS may also be considered as
a part of CPV report.

 However, these details are generally elaborated in APQR.

THANK YOU !

OPEN FOR DISCUSSIONS