Module 4: Introduction and Objectives
Processes - such as manufacturing
Process validation is establishing documented
evidence which provides a high degree of
assurance that a specific process (such as the
manufacture of pharmaceutical dosage forms)
will consistently produce a product meeting its
predetermined specifications and quality
characteristics.
According to the FDA, assurance of product
quality is derived from careful and systemic
attention to a number of important factors,
including: selection of quality components and
materials, adequate product and process
design, and (statistical) control of the process
through in-process and end-product testing.
Thus, it is through careful design (qualification)
and validation of both the process and its
control systems that a high degree of
confidence can be established that all individual
manufactured units of a given batch or
succession of batches that meet specifications
will be acceptable. Discuss the regulatory
guidelines and technical references for
equipment, analytical method, process and
cleaning validation.
Module 4: Lesson 1 - Introduction To Process
Validation
Process Validation is a means of ensuring that
manufacturing processes are capable of
consistently producing a finished product of the
required quality. It involves providing
documentary evidence that key steps in the
manufacturing process are consistent and
reproducible. A validated manufacturing
process is one that has been proven to do what
it purports or is presented to do.
As a general rule, anything that can affect
patient safety or product quality should be
validated including the following:
1.
processes that produce a product
2. Manufacturing Steps - each step may be
validated separately for long processes
3. Analytical Test methods - applicable for
raw materials, intermediates, active
pharmaceutical ingredients, finished
pharmaceutical products, method used
for stability studies and those methods
used in quality control.
4. 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.
5. Facilities - including rooms and
equipment used for processing
products that are sterile must adhere to
strict criteria and be validated before
use.
6. Cleaning processes - including sterilize
in place and clean in place process
validation for intro
The term `validation’ is intended to apply to
final verification at the production scale.
Typically a minimum of three consecutive
production batches should be successfully
validated prior to the marketing of the product.
Types of Process Validation: changes in facilities and installation which
influence process.
a. Prospective Validation -means validation
done during the development stage. During this Process Validation During the Product Life
step the input resources are selected and
Process validation involves a series of activities
clearly specified. Each step in the development
taking place over the lifecycle of the product
of new manufacturing process is required to be
and process. These stages are:
established to give a desired result. The
approach in this validation often leads to
transfer of the manufacturing process from the
development function to production. Examples
are clearly defined material specification;
defined equipment and process parameter;
specified operating condition, if there is any;
and defined level of training of people

b. Concurrent Validation - is carried out during

production. It is more appropriate to validate
process during routine production due to well Stage 1 – Process Design: The commercial
understanding of the process. Extensive testing manufacturing process is defined during this
& monitoring ensure the desired quality stage based on knowledge gained through
characteristics of product with high degree of development and scale-up activities.
confidence. In this type, verification of process
Stage 2 – Process Qualification: During this
still goes on after three initial commercial
stage, the process design is evaluated to
batches are taken and process is handled over
determine if the process is capable of
to manufacturing personnel. So, batch after
reproducible commercial manufacturing.
batch, the process parameter is evaluated for
manufacturing facilities and studied if there is Stage 3 – Continued Process Verification:
any change or deviation is observed. Ongoing assurance is gained during routine
production that the process remains in a state
c. Retrospective Validation - is used for facilities,
of control.
processes and process control parameters used
in operation that have not undergone in Module 4: Lesson 2.1 - STAGES OF PROCESS
documented validation process but it is possible VALIDATION
using historical data (QA/QC records) to provide
STAGE 1 - PROCESS DESIGN
the necessary documented evidence that the
process is doing what is believed to do. Process design is the activity of defining the
Therefore this type of validation is only commercial manufacturing process that will be
acceptable for well established processes. reflected in planned master production and
control records. The goal of this stage is to
d. Revalidation - is a repetition of the validation
design a process suitable for routine
process and it is required under the following
commercial manufacturing that can consistently
circumstances: major changes in critical process
deliver a product that meets its quality
parameters of formula, equipment, procedures,
attributes.
or quality of raw material or even in physical
variation of raw material like particle size,
  Although early process design manufactured during this stage, if acceptable,
experiments do not need to be can be released for distribution.
performed according to cGMP, they
 Appropriate design of the
should be conducted under guidelines
manufacturing facility is required under
of sound scientific principles.
cGMP mandates.
 Good documentation practices should
 Proper selection of utility systems and
be followed. In particular, studies that
equipment that are built according to
result in improvement of process
required design specifications.
understanding are expected to be
 Verifying that systems and equipment
documented.
operate within required specifications.
 Continuous testing and re-testing at this
 The process performance qualification
stage until the process fails is not
(PPQ) combined facility, utility, and
normally expected by the FDA.
equipment with properly trained
 The establishment of process controls
personnel. The FDA highly recommends
serve to ensure product quality, and by
that objective measures such as
the same token address variability in
statistical metrics be employed
product. The FDA expects that process
whenever possible.
controls include examination of
 Written protocols and expected
material as well as equipment
outcomes are very important to this
monitoring. In particular, process
stage of process validation. It's
control and monitoring is critical when:
recommended that protocol
o the product attribute is either
descriptions include manufacturing
not detectable or otherwise
conditions, data collection, tests that
measurable (eg. microbial
need to be performed, and sampling
contamination).
plan.
o Or when
intermediates/products are not Module 4: Lesson 2.3 - STAGES OF PROCESS
well-characterized. VALIDATION
Module 4: Lesson 2.2 - STAGES OF PROCESS STAGE 3 - CONTINUED PROCESS VERIFICATION
VALIDATION
The goal of the third validation stage is
STAGE 2 - PROCESS QUALIFICATION continual assurance that the process remains in
a state of control (the validated state) during
During the process qualification (PQ) stage of
commercial manufacture. A system or systems
process validation, the process design is
for detecting unplanned departures from the
evaluated to determine if it is capable of
process as designed is essential to accomplish
reproducible commercial manufacture. This
this goal. Adherence to the CGMP
stage has two elements: (1) design of the facility
requirements, specifically, the collection and
and qualification of the equipment and utilities
evaluation of information and data about the
and (2) process performance qualification
performance of the process, will allow detection
(PPQ). During Stage 2, CGMP-compliant
of undesired process variability. Evaluating the
procedures must be followed. Successful
performance of the process identifies problems
completion of Stage 2 is necessary before
and determines whether action must be taken
commercial distribution. Products
to correct, anticipate, and prevent problems so understanding and process control, based on
that the process remains in control. sound science and quality risk management.

 cGMP requirements include an on-

going program to collect and analyze
data relating to product quality.
 Adherence to cGMP processes and
principles will be critical in identifying
areas of variability that need to be
analyzed and/or corrected.
 The FDA recommends that monitoring
and sampling at the level determined
during the process qualification stage
be pursued until sufficient data is
available.
 Maintenance of the facility, utilities, and
equipment should not be overlooked.

Module 4: Lesson 3 - QUALITY BY DESIGN

QbD
Quality by design (QbD) is a concept first
developed by the quality pioneer Dr. Joseph M.
Juran who believed that quality should be
designed into a product, and that most quality
crises and problems relate to the way in which a
product was designed in the first place.
This involves designing and developing
manufacturing processes during the product
development stage to consistently ensure a
predefined quality at the end of the
manufacturing process. It emphasizes product
and process understanding and process control
which is based on sound science and quality risk
management (QRM).
The concept of QbD was mentioned in the
International Council for Harmonization (ICH)
Q8 guideline, which states that “quality cannot
be tested into products i.e., quality should be
built in by design.” According to ICH Q8 QbD is
defined as a systematic approach to
development that begins with predefined
objectives and emphasizes product and process
Quality by Design (QbD) has become a new
concept for development of quality
pharmaceutical products, It is an essential part
of the modern approach to pharmaceutical
quality, QbD is a best solution to build a quality
in all pharmaceutical products but it is also a
major challenge to the Pharmaceutical industry
whose processes are fixed in time, despite
inherent process and material variability, Under
this concept of QbD throughout designing and
development of a product, it is essential to
define desire product performance profile or
Target product Profile (TPP), Target Product
Quality Profile (TPQP)] and identify critical
quality attributed (CQA). On the basis of this we
can design the product formulation and process
to meet the product attributes. This leads to
recognize the impact of raw materials [critical
material attributes (CMA), critical process
parameters (CPP) on the CQAs and
identification and control sources of variability.
QbD is an emerging idea which offers
pharmaceutical manufacturer with increased
self-regulated flexibility while maintaining tight
quality standards and real time release of the
drug product.
QbD is:
• A Quality System for managing a product’s
lifecycle
• A regulatory expectation
• Intended to increase process and product
understanding and thereby decrease patient
risk
• A multifunctional exercise

Principle of QbD Concepts include risk and

knowledge based decisions, systematic
approaches process development, continuous
Improvement, and this leads to “capable”
processes.

Advantages of Quality by Design:

1. Higher level of product and process

understanding, which can lead to:

 Increased success rate in development

and manufacturing
 Increased process robustness, less
manufacturing deviations and
failed/reworked batches

2. Potential regulatory flexibility, which can

lead to:

 Ease of post approval changes for

movements within an approved design
space
 Real time release testing (RTRT)
resulting in lower analytical testing
costs, lower cycle times, etc.