M4 - PROCESS VALIDATION

Process Validation

A documented process that provides a high degree of assurance that a facility, laboratory, computer, process or system will consistently produce product, meeting the predetermined specifications & quality attributes

- selection of quality components and materials,

- adequate product and process design,

- statistical control of the process through in-process
and end-product testing

Factors to consider in Process Validation

Process Validation

Action of proving, in accordance with the principles
of GMP, that any procedure, process, equipment,
material, activity or system actually leads to the
expected results

EU / PIC/S

Process Validation

• The collection and evaluation of data, beginning at
the process development stage and continuing
through the production phase, which ensures that
the manufacturing processes -including equipment,
buildings, personnel and materials -are capable of
achieving the intended results on a consistent and
continuous basis.

Process Validation

Validation is the establishment of documented
evidence that a system does what it is supposed to
do

•Processes
•Manufacturing Steps
•Analytical Test methods

General Rule in Process Validation: (3)
anything that can affect patient safety or product quality should be validated

•Processes -

General Rule in Process Validation:
such as manufacturing processes that produce a
product

Manufacturing Steps

General Rule in Process Validation:
each step may be validated separately for
long processes

Analytical Test methods

General Rule in Process Validation:
applicable for raw materials, intermediates,
active pharmaceutical ingredients, finished pharmaceutical products,
method used for stability studies and those methods used in quality
control

Systems and Programs

including those that support
Good Manufacturing Processes (GMP) such as facility
(building specifications), utilities, programs like pest
control, software, hardware (enterprise Resource Platform)
and laboratory information management systems and
water for injection.

Facilities

including rooms and equipment used for
processing products that are sterile must adhere to strict
criteria and be validated before use.

Cleaning processes

- including sterilize in place and clean in
place

Validation

is intended to apply to final verification at the
production scale

Validation

the action of checking the accuracy of something.

Concurrent Validation

is carried out during production. It is
more appropriate to validate process during routine production
due to well understanding of the process.

Concurrent Validation

Extensive testing &
monitoring ensure the desired quality characteristics of product
with high degree of confidence.

Concurrent Validation

In this type, verification of
process still goes on after three initial commercial batches are
taken and process is handled over to manufacturing personnel

Concurrent Validation

batch after batch, the process parameter is evaluated for
manufacturing facilities and studied if there is any change or
deviation is observed

Prospective Validation

Concurrent Validation

Retrospective Validation

Revalidation

Types of Validation

Prospective Validation

-means validation is done during the development
stage.

Prospective Validation

During this step the input resources are selected and clearly specified

Prospective Validation

. During this step the input resources are selected and clearly specified.
Each step in the development of new manufacturing process is required to
be established to give a desired result.

Prospective Validation

The approach in this validation often
leads to transfer of the manufacturing process from the development function
to production.

clearly defined material specification
defined

equipment and process parameter;

specified operating condition, if there is any;

and defined level of training of people

Prospective Validation example:

Retrospective Validation -

is used for facilities, processes and
process control parameters used in operation that have not
undergone in documented validation process but it is possible
using historical data (QA/QC records) to provide the necessary
documented evidence that the process is doing what is believed
to do

Retrospective Validation -

this type of validation is only acceptable for well
established processes.

Revalidation -

is a repetition of the validation process and it is
required under the following circumstances: major changes in
critical process parameters of formula, equipment, procedures, or
quality of raw material or even in physical variation of raw
material like particle size, changes in facilities and installation
which influence process

• Process Design
• Process Qualification
• Continues Process Verification

Process Validation During the Product Life

Quality by Design (QbD)

A systematic approach to ) development that begins with predefined objectives and
emphasizes product and process understanding and process control, based on sound
science and quality risk management. (ICH Q8 R2

Predefined objectives

STAGES OF PROCESS VALIDATION
Quality by Design (QbD)
Systematic Approach

Define Quality Target Product Profile (QTPP)

STAGES OF PROCESS VALIDATION
Quality by Design (QbD)
Systematic Approach

Identify Critical Quality Attributes (CQA)

Product and process
understanding

STAGES OF PROCESS VALIDATION
Quality by Design (QbD)
Systematic Approach

Identify critical material attributes (CMA) and critical process
parameters (CPP)

Product and process
understanding

STAGES OF PROCESS VALIDATION
Quality by Design (QbD)
Systematic Approach

Establish the functional relationships that link CMA/CPP to CQA

Sound science

STAGES OF PROCESS VALIDATION
Quality by Design (QbD)
Systematic Approach

Develop appropriate Control Strategy, including justifications

Process control

STAGES OF PROCESS VALIDATION
Quality by Design (QbD)
Systematic Approach

• Science-driven development (scientific literature, prior
knowledge, DOEs etc.)

Quality risk management

STAGES OF PROCESS VALIDATION
Quality by Design (QbD)
Systematic Approach

Risk-based development (ICH Q9)

STAGE 1 - Process DESIGN

The commercial
manufacturing process is
defined during this stage
based on knowledge gained
through development &
scale-up studies

STAGE 1 - Process DESIGN

STAGE ???

Define commercial-scale process

STAGE 1 - Process DESIGN

STAGE ???

• Define unit operations and process
parameters

STAGE 1 - Process DESIGN

STAGE ???

Identify and understand sources of
variations

STAGE 1 - Process DESIGN

STAGE ???

Identify critical process parameters

ICH Q8(R2)

Definition: A prospective
summary of the quality characteristics of a
drug product that ideally will be achieved to
ensure the desired quality, taking into account
safety and efficacy.

Critical Quality Attributes (CQA)

A physical, chemical, biological, or
microbiological property or
characteristic that should be within
an appropriate limit, range, or
distribution to ensure the desired
product quality (ICH Q8)

Approach to Identify CQAs

Consider all DP quality attributes; physical
attributes, identification, assay, content
uniformity, dissolution and drug release,
degradation products, residual solvents,
moisture, microbial limits, etc.

physical attributes,

identification,

assay,

content uniformity,

dissolution and

drug release,

degradation products,

residual solvents,

moisture,

microbial limits,

Approach to Identify CQAs

Consider all DP quality attributes; _______ etc.

severity of harm

Identify a CQA based on the ____ to
a patient (safety and efficacy) resulting from
failure to meet that quality attribute

Approach to Identify CQAs

Identified before taking into account risk control
– Does not change as a result of risk management

NO

is Physical apperance (apperance, odor, size, score, friability) is a Critical Quality Attributes (CQA)?

YES

is identification is a Critical Quality Attributes (CQA)?

YES

is assay is a Critical Quality Attributes (CQA)?

YES

is content uniformity is a Critical Quality Attributes (CQA)?

YES

is dissolution is a Critical Quality Attributes (CQA)?

Pre roller Compaction Blending and Lubrication

Roller Compaction

Milling

Final Blending and Lubrication

Compression (tableting)

STAGE 1 - Process DESIGN
Process Map

STAGE 2 - Process QUALIFICATION

The process design is
evaluated to determine if
the process is capable of
reproducible
commercial
manufacturing

STAGE 2 - Process QUALIFICATION

STAGE ???

Confirmation at commercial-scale
of process design information

STAGE 2 - Process QUALIFICATION

STAGE ???

Qualification of equipment,
utilities, facilities

STAGE 2 - Process QUALIFICATION

STAGE ???

Identify and understand sources of
variations

STAGE 2 - Process QUALIFICATION

STAGE ???

Identify critical process
parameters

Critical Process Parameter (CPP)

A process parameter whose variability has an impact on a
CQA and therefore should be monitored or controlled to
ensure the process produces the desired quality. (ICH Q8)

Identify drug product

STAGE 2 - Process QUALIFICATION

Step 1

For each procces step, identify intermediate CQAs that impact drug product

STAGE 2 - Process QUALIFICATION

Step 2

Identify materaill attributes and process parameters that may impact the intermediate CQAs of the process step

STAGE 2 - Process QUALIFICATION

Step 3

Control Strategy

“a planned set of controls, derived from current product and
process understanding, that assures process performance and
product quality

STAGE 3 - Continued Process Verification

Ongoing assurance is
gained during routine
production that the
process remains in a
state of control

STAGE 3 - Continued Process Verification

STAGE ???

• Timely monitoring of critical
operating and performance
parameters

STAGE 3 - Continued Process Verification

STAGE ???

monitor product characteristics,
materials, facilities, equipment
and SOP changes

STAGE 3 - Continued Process Verification

STAGE ???

activities to assure process
remains in validated state

• Need to be determined
• Need to be monitored during validation
• May affect the quality of the product

Critical factors or parameters

Regulators
Satisfaction

Consistent
Quality Product

Shareholder
Value

Shareholder
Value

Benefits of Validation

Appropriate level of
qualification for each
process/facility

Established process
control

Reduction/elimination
of uncertainty,
variability, deviations

Reliable, understood
and compliant
processes

Benefits of Validation

Appropriate level of
qualification for each
process/facility

Benefits of Validation

Established process
control

Benefits of Validation

Reduction/elimination
of uncertainty,
variability, deviations

Benefits of Validation

Reliable, understood
and compliant
processes

Drug Product CQA:
Content
Uniformity

Intermediate CQA:
Blend
Uniformity

Process Variables:
Particle size
distribution;
Number of
revolutions

Cleaning Processes

Facilities

Processess

Systems and Programs

Manufacturing Step

Analytical Test Methods

PRODUCT VALIDATION [6]

validation

The term `____’ is intended to apply to final verification at the production scale.

3

The term `validation’ is intended to apply to final verification at the production scale. Typically a minimum of ____ consecutive production batches should be successfully validated prior to the marketing of the product.

Process validation

involves a series of activities taking place over the lifecycle of the product and process.

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.

STAGE 1 - PROCESS DESIGN

is the activity of defining the commercial manufacturing process that will be reflected in planned master production and control records.

STAGE 1 - PROCESS DESIGN

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.

STAGE 1 - PROCESS DESIGN

Although early process design experiments do not need to be performed according to cGMP, they should be conducted under guidelines of sound scientific principles.

STAGE 1 - PROCESS DESIGN

Good documentation practices should be followed. In particular, studies that result in improvement of process understanding are expected to be documented.

STAGE 1 - PROCESS DESIGN

Continuous testing and re-testing at this stage until the process fails is not normally expected by the FDA.

STAGE 1 - PROCESS DESIGN

The establishment of process controls serve to ensure product quality, and by the same token address variability in product. The FDA expects that process controls include examination of material as well as equipment monitoring.

In particular, process control and monitoring is critical when:
the product attribute is either not detectable or otherwise measurable (eg. microbial contamination).
Or when intermediates/products are not well-characterized

STAGE 2 - PROCESS QUALIFICATION

During the process qualification (PQ) stage of process validation, the process design is evaluated to determine if it is capable of reproducible commercial manufacture.

1) design of the facility and qualification of the equipment and utilities

(2) process performance qualification (PPQ).

STAGE 2 - PROCESS QUALIFICATION ELEMENTS

2

During Stage __, CGMP-compliant procedures must be followed.

2

Successful completion of Stage ___ is necessary before commercial distribution.

STAGE 2 - PROCESS QUALIFICATION

Products manufactured during this stage, if acceptable, can be released for distribution.

STAGE 2 - PROCESS QUALIFICATION

Appropriate design of the manufacturing facility is required under cGMP mandates.

STAGE 2 - PROCESS QUALIFICATIONQ

Proper selection of utility systems and equipment that are built according to required design specifications.

STAGE 2 - PROCESS QUALIFICATION

Verifying that systems and equipment operate within required specifications.

STAGE 2 - PROCESS QUALIFICATION

The process performance qualification (PPQ) combined facility, utility, and equipment with properly trained personnel. The FDA highly recommends that objective measures such as statistical metrics be employed whenever possible.

STAGE 2 - PROCESS QUALIFICATION

Written protocols and expected outcomes are very important to this stage of process validation. It's recommended that protocol descriptions include manufacturing conditions, data collection, tests that need to be performed, and sampling plan.

THIRD

The goal of the ____validation stage is continual assurance that the process remains in a state of control (the validated state) during commercial manufacture.

STAGE 3 - CONTINUED PROCESS VERIFICATION

A system or systems for detecting unplanned departures from the process as designed is essential to accomplish this goal.

STAGE 3 - CONTINUED PROCESS VERIFICATION

Adherence to the CGMP requirements, specifically, the collection and evaluation of information and data about the performance of the process, will allow detection of undesired process variability.