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PROCESS VALIDATION
A Roadmap to Success
By Sambhujyoti Das,
Quality Assurance

PROCESS VALIDATION (yesterday)
Sambhujyoti Das
FDA (US) published its first process validation guidance on
May1987.
Definition:
Establishing documented evidence that a process is able to produce
products meeting its predetermined acceptance criteria,
consistently.
Focus:
• Meeting acceptance criteria.
• Repeatability.

Sambhujyoti Das
Options:
• Prospective – first time before commercialization.
• Concurrent – during commercial manufacturing.
• Retrospective – based on historic data of process performance.
Validity:
3 final scale batches.

Sambhujyoti Das
ABC Company: Product XYZ
Our first 3 batches were okay ……. produced 50+ batches last year
……. 6 batches were 100% inspected ……. less yield …… OOS in 4
batches ……. 1 batch failure ……. deviation ……. investigation …….
CAPA …… not sure about conformity …… market complain may
come …….. regulatory issues ???
SOMETHING TERRIBLY WORNG !!

PROCESS VALIDATION (critical formulations)
Sambhujyoti Das
• OSD: (i) Modified released products.
(ii) Low drug concentration.
(iii) Microencapsulated products.
(iv) Unconventional processes.
• Parenteral: (i) Lyophilized products.
(ii) Molecular inclusion products.

PROCESS VALIDATION (today)
Sambhujyoti Das
After 24 years of long wait, finally FDA (US) published new guidance
on January 2011.
WHAT’S NEW
OR
JUST ANOTHER
GUIDANCE

Sambhujyoti Das
What FDA tells:
“This revised guidance conveys FDA’s current thinking on process
validation and is consistent with basic principles first introduced in
the 1987 guidance. The revised guidance also provides
recommendations that reflect some of the goals of FDA’s initiative
entitled “Pharmaceutical CGMPs for the 21st Century ― A Risk-
Based Approach,” particularly with regard to the use of
technological advances in pharmaceutical manufacturing, as well as
implementation of modern risk management and quality system
tools and concepts.”
This revised guidance replaces the 1987 guidance.

Sambhujyoti Das
Sources:
• Product LIFECYCLE concept.
• Q8(R2) Pharmaceutical Development.
• (Q9) Quality Risk Management.
• (Q10) Pharmaceutical Quality System.
and the last but not least……….
• More than 20 years of industry experience.
• Audit observations.
• Technology advancements.

Product life cycle (PLC) , Q8, Q9 & Q10: simplified
Formulation
Development
Process
Characterization
Process
Optimization
Process
Scale up
Product
Discontinuation
QQUALITY
RISK
MANAGEMENT
(Q9)
PHARMACEUTICAL
DEVELOPMENT (Q8)
Sambhujyoti Das
PHARMACEUTICAL
QUALITY SYSTEM
(Q10)
Comm.
Manufacturing
Process
Change

PROCESS VALIDATION (the paradigm shift)
Sambhujyoti Das
Process Validation 1987 Process Validation 2011
Number of repeated batches. Confidence on product quality.
Control on process by meeting
acceptance criteria.
Control on process by controlling
response variability.
Terminal in nature. Continuous in nature.
Satisfying requirements. Managing knowledge.
Criticality based. Risk analysis based.
Largely standalone in nature. Highly integrated in nature.
Conceptual differences:

PROCESS VALIDATION (the paradigm shift)
Sambhujyoti Das
Guess:
• The approx. age ?
• How she looks ?
• Which movie would
she prefer ?
Courtesy:
7 Habits of Highly Effective People.
STEPHEN R COVEY.

Sambhujyoti Das
Definition:
It is 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
product.
Process validation involves a series of activities taking place over
the lifecycle of the product and process.

Sambhujyoti Das
Three stages of process validation activity
Stage 1 – Process Design:
The commercial manufacturing process is defined during this stage
based on knowledge gained through development and scale-up
activities.
Stage 2 – Process Qualification:
During this stage, the process design is evaluated to determine if
the process is capable of reproducible commercial manufacturing.
Stage 3 – Continued Process Verification:
Ongoing assurance is gained during routine production that the
process remains in a state of control.

Sambhujyoti Das
Process Validation Roadmap:

Sambhujyoti Das
STAGE 1 – PROCESS DESIGN (Normative) :
Defining the commercial manufacturing process that will be
reflected in planned master production and control records. The
goal of this stage is to design a process suitable for routine
commercial manufacturing that can consistently deliver a product
that meets its quality attributes.
• Building and Capturing Process Knowledge and Understanding
intended dosage form - the quality attributes - manufacturing
pathway - predicted contributions to variability.
establishing ranges of incoming component quality – equipment
parameters - in-process material quality attributes – clear
documentations.

Sambhujyoti Das
STAGE 1 – PROCESS DESIGN (Normative) :continues....
• Establishing a Strategy for Process Control
strategy design to reduce input variations – incorporation of
process controls by risk assessments – control on material quality
– equipment monitoring.
Master Manufacturing Record with operational limits & process
control strategy.

Sambhujyoti Das
STAGE 1 – PROCESS DESIGN (Informative) :
Identify the Key Process Input Variables (KPIV) that affect Critical-
to-Quality (CTQ) for a product.
• Product Design
The rationale will define how the formulation, raw materials and
processing steps are related to achieving the desired product
performance.
• Process Risk Assessment
(1) Creation of process map that captures all inputs, outputs and
control variables.
(2) A pFMEA can be used to prioritize which key process steps
(KPIVs).

Sambhujyoti Das
STAGE 1 – PROCESS DESIGN (Informative) : continues....
• Equipment/Process Characterization studies
(1) Ensure that equipment performance is stable and reproducible.
(2) Design Space to Control Space determination.
(3) Smaller batch size with larger sampling plans.
(4) Validated analytical and in-process methods with appropriate
accuracy and precision.

Sambhujyoti Das
• Design Space Establishment
To identify the boundaries and variables that drive process stability.
(1) Focus on the Key Process Output Variables (KPOVs) that affect
the product quality.
(2) Explore boundary limits by Design Space.
• Validation Master Plan
Sufficient details to approach, justification and rationale for Process
Qualification.

Sambhujyoti Das
• Tools & Techniques
Process & Variability
 Ishikawa diagram
 KPIVs – KPOVs
 Variance
 Capability
 Freq. Histogram
 ____________
Design & Analysis
 OFAT
 DOE
 ANOVA
 Correlation
 __________
Sampling
 AQL
 LTPD
 OC curve
 _________

Sambhujyoti Das
STAGE 2 – PROCESS QUALIFICATION (Normative) :
The process design is evaluated to determine if it is capable of
reproducible commercial manufacture (before commercial
distribution).
• Design of a Facility and Qualification of Utilities and Equipment
proper Facility and equipment design – commissioning activities –
operation in all anticipated operating ranges – performance of
challenges and interventions.
• Process Performance Qualification =
Facility + Utilities + Equipments + Trained personnel +
Commercial manufacturing process + Process controls + Product
components.

Sambhujyoti Das
STAGE 2 – PROCESS QUALIFICATION (Normative) : continues....
Commercial
Batch(s)
Pilot Batch(s)
Laboratory
Batch(s)
Designed
Experiments
PPQ APPROACH
P
R
O
C
E
S
S
U
N
D
E
R
S
T
A
N
D
I
N
G

Sambhujyoti Das
• Design of a Facility and Qualification of Utilities and Equipment
Qualification of utilities and equipment can be covered under
individual plans or as part of an overall project plan.
The plan should identify the following items:
1. the studies or tests to use,
2. the criteria appropriate to assess outcomes,
3. the timing of qualification activities,
4. the responsibilities of relevant departments and the quality
unit, and
5. the procedures for documenting and approving the
qualification.

Sambhujyoti Das
• Process Performance Qualification
A manufacturer must successfully complete PPQ before
commencing commercial distribution of the drug product. The
decision to begin commercial distribution should be supported by
data from commercial-scale batches.
 Higher level of sampling, additional testing and greater scrutiny
of process performances than routine production.
 Confirmation of uniform product quality throughout the batch.
 Demonstration of process consistency by using of statistical
matrices.

Sambhujyoti Das
• PPQ Protocol contents
1. The manufacturing conditions, including operating parameters,
processing limits, and component inputs.
2. The data to be collected and when and how it will be evaluated.
3. Tests to be performed and acceptance criteria for each
significant processing step.
4. The sampling plan, including sampling points, number of
samples, and the frequency of sampling for each unit operation
and attribute. The number of samples should be adequate to
provide sufficient statistical confidence of quality both within a
batch and between batches.

Sambhujyoti Das
• PPQ Protocol contents
5. A description of the statistical methods to be used in analyzing
all collected data (statistical metrics).
6. Design of facilities and the qualification of utilities and
equipment, personnel training and qualification, and
verification of material sources (if not performed previously).
7. Status of the validation of analytical methods used in measuring
the process, in-process materials, and the product.
8. Review and approval of the protocol by appropriate
departments and the quality unit.

Sambhujyoti Das
STAGE 2 – PROCESS QUALIFICATION (Informative) :
The PPQ is intended to subsume all of the known variability from
the manufacturing process and demonstrate that the process
predictability is sufficient to ensure the product performs as it
claims to do.
The PPQ exercise focuses on demonstrating process control.
STAGE 1 STAGE 2
PROCESS PREDICTIBILITY

Sambhujyoti Das
 Evaluation and managing the risks associated with each
processing steps.
 The old rule of “three lots and we are done” goes out the
window.
 Simple processes with a low risk of process excursion, e.g. High
loaded dose, direct blend formulations, the PPQ may be three
lots or less.
 Complex processes, e.g. low dose controlled release spray
drying processes or mammalian cell processing, the number of
demonstration lots will likely be higher.
 The PPQ will challenge the process control space (process limits).

Sambhujyoti Das
 Process Capability is a fundamental metric that can be used to
compare process variability and process centering against
allowable specifications.
 At the end of the PPQ is to go back to the risk management
evaluation and demonstrate that the process risk elements
identified at the outset of Stage 1 have been mitigated.
 Change control system can help in process improvement.

THE ICEBREAKER
Sambhujyoti Das
There is something about Mary
Mary's mum has four children.
The first child is called April.
The second May.
The third June.
What is the name of the fourth child?

Sambhujyoti Das
STAGE 3 – CONTINUED PROCESS VERIFICATION (Normative) :
The goal of the third validation stage is continual assurance that
the process remains in a state of control (the validated state) during
commercial manufacture.
o Prepare an ongoing system for detecting unplanned departures
from the process.
o Systematic collection of process data.
o Evaluation of process information.
o Identify the problem(s) that caused undesirable variability.
o Correct / anticipate / prevent the problem(s).

Sambhujyoti Das
Data trending & evaluation
 The relevant process data.
 The quality of incoming materials or components.
 In-process materials and finished products.
 The data should be statistically trended and reviewed.
 The information collected should verify that the quality
attributes are being appropriately controlled throughout the
process.
Focus should be on process stability and process capability.

Sambhujyoti Das
FDA says –
“We recommend that a statistician or person with adequate training
in statistical process control techniques develop the data collection
plan and statistical methods and procedures used in measuring and
evaluating process stability and process capability.”
Reaction
on
Individual
Events
Detection of
unintended
process
variability

Sambhujyoti Das
Anticipate significant sources of variability,
Establish appropriate detection,
Prepare control, and/or mitigation strategies,
Develop appropriate alert and action limits.
Scrutiny of intra-batch as well as inter-batch variation should be
part of a comprehensive continued process verification program.

Sambhujyoti Das
Variation can also be detected by:
 Assessment of defect complaints,
 Out-of-specification findings,
 Process deviation reports,
 Process yield variations,
 Review of Batch records,
 Incoming raw material records,
 and adverse event reports.
QUALITY
REVIEW
MEETING

Sambhujyoti Das
STAGE 3 – CONTINUED PROCESS VERIFICATION (Informative) :
We have used the product stability program,
change control process and the Annual
Product Review Process as vehicles for monitoring
and assessing process stability.
But the challenges with this approach has always been when
dealing with process drift.

Sambhujyoti Das
STAGE 3 – CONTINUED PROCESS VERIFICATION (Informative) :
• Tools & Techniques
Process Monitoring & Sampling
Sampling Matrix
KPIVs and CTQs
Statistical Process Control
Moving Range Charts
X Bar-R charts
Process Capabilities
__________________
Statistical software packages such as Minitab and JMP can make
analysis simple and reproducible.

Sambhujyoti Das
Qualification
Process Validation stage gate approach:

Sambhujyoti Das
Process Validation stage gate approach:
 The new Process Validation guidance represents a dramatic shift
from the 1987 FDA guidance issued to industry.
 Less prescriptive guidance but sufficiently descriptive
framework to create a scientifically driven approach.
 No single answer but clearly defined deliverables at each
milestone.
 A more focused validation effort, potentially reducing the cost.
FDA expects –
PPQ study needs to be completed successfully before commercial
distribution of a product. concurrent release will be used rarely.

PROCESS VALIDATION
Sambhujyoti Das
even Einstein
used to ask
QUESTIONS.

REFERENCES
Sambhujyoti Das
 ICH Guidance for Industry - Q7, Q8(R2), Q9, Q10.
 ASTM E2474-06 Standard Practice for Pharmaceutical Process Design
Utilizing PAT.
 ASTM E2476-09 Standard Guide for Risk Assessment and Risk Control as
it Impacts the Design, Development, and Operation of PAT Processes for
Pharmaceutical Manufacture.
 ASTM E2281-03 Standard Practice for Process and Measurement
Capability Indices.
 ASTM E2500-07 Standard Guide for Specification, Design, and
Verification of Pharmaceutical and Biopharmaceutical Manufacturing
Systems and Equipment.
 ASTM E2709-10 Standard Practice for Demonstrating Capability to
Comply with a Lot Acceptance Procedure.

REFERENCES
Sambhujyoti Das
Minitab 16.2.0 - for SPC, SQC and Six Sigma

PROCESS VALIDATION
Sambhujyoti Das
THANK YOU
FOR YOUR
PARTICIPATION

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