pv roadmap

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.


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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


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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

ProductDiscontinuati

on

QQUALITYRISK

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


• 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.


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• 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 Experimen

ts

PPQ APPROACH

PROCESS

UNDERSTANDING


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• 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 processpredictability 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

STAGE 3 – CONTINUED PROCESS VERIFICATION (Normative) : 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 AnnualProduct 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 & TechniquesProcess Monitoring & Sampling

Sampling MatrixKPIVs 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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