Validation and Qualification of

Pharmaceutical Products
 Introduction
VALIDATION
 The process of providing documented evidences, that provides
high degree of assurance that a specific process will
consistently produce a product meeting its predetermined
specifications and quality attributes.
 It is the total life cycle of the product from its
development which specifically focuses on the methods and
processes of production
 Introduction

QUALIFICATION
 Qualification is the part of validation process which
verifies module or system functional performance
prior to being placed on line
 It is the part of validation which generally focuses
on equipments and facilities
 Regulatory Basis for pharma products
 FDA regulations describing CGMP for finished pharmaceuticals
are provided in 21 CFR parts 210 and 211.
 It states that there shall be written procedures for
production and process control designed to assure that the
drug products have the identity, strength, quality, and purity
they purport or are represented to possess
 The regulation requires manufacturers to design a process,
including operations and controls, which results in a product
meeting these attributes.
 Regulatory Basis for pharma products...
 A drug . . . shall be deemed to be adulterated . . . if . . . the
methods used in, or the facilities or controls used for, its
manufacture, processing, packing, or holding do not conform to
or are not operated or administered in conformity with
current good manufacturing practice to assure that such drug
meets the requirements of this Act as to safety and has the
identity and strength, and meets the quality and purity
characteristics, which it purports or is represented to
possess.
 Regulatory Basis for pharma products...

In summary, the CGMP regulations require that

manufacturing processes be designed and controlled to
assure that in-process materials and the finished
product meet predetermined quality requirements and
do so consistently and reliably.
Types of validation and qualifications

 process validation
 cleaning validation
 analytical method validation
 sterilization validation
 equipment and facility qualification
 sterilization validation
1. Process validation

 Is defined as 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.
 It involves a series of activities taking place over the
lifecycle of the product and process and the activities
can be described in three stages.
2. Process validation...
 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.
Types of process validation
1. Prospective Validation( premarket validation)
 usually carried out prior to distribution either of a new
product or a product made under a revised manufacturing
process into commercial use.
 Should include, but not be limited to the following:
 Short description of the process.
 List of the equipment/facilities
Finished product specifications for release.
 List of analytical methods, as appropriate.
 Functions and responsibilities...
Types of process validation...
2. Retrospective Validation
 It is defined as the established documented evidence that a
system does what it purports to do on the review and analysis
of historical information. This is achieved by the review of the
historical manufacturing testing data to prove that the
process has always remained in control.
 It is only acceptable for well established processes and will be
inappropriate where there have been recent changes in the
composition of the product, operating procedures or
equipment
Types of process validation...

3. Concurrent Validation
 carried out during normal production
 is similar to prospective, except the operating firm
will sell the product during the qualification runs, to
the public at its market price.
 It involves in-process monitoring of critical processing
steps and product testing which helps to generate
documented evidence to show that the production
process is in a state of control.
Types of process validation...
4. Revalidation
 provides the evidence that changes in a process and/or the
process environment that are introduced do not adversely
affect process characteristics and product quality.
 Some of the changes that require revalidation
 Changes in raw materials, change in source of active raw
material manufacturer, change in packaging material, change in
process, change in equipments, change in plant/facility.
2. Cleaning Validation
 Cleaning validation is the process of assuring that cleaning
procedures effectively remove the residue from
manufacturing equipment / facilities below a predetermined
level.
 The reasons for validating the cleaning procedure:
 It is a customer requirement.
 It ensures the safety and purity of the product.
 It is regularity requirement in active pharmaceutical
ingredient product manufacture.
 2. Cleaning Validation...

The objective of the cleaning validation is to verify the effectiveness of cleaning

procedure for removal of product residues, degradation products, preservatives,

excipients and/ or cleaning agents as well as the control potential microbial

contamination.

Elements of Cleaning Validation;

→Establishments of acceptance criteria

→Cleaning procedure

→Residues to be cleaned
3. Analytical Methods
 Specific and non-specific are the two analytical methods used
widely to detect any compound.
 If a drug active is highly toxic, a specific method is always
recommended
Specific method
 method that detects a unique compound in the presence of
potential contaminants.
Examples; HPLC, Ion chromatography, Atomic absorption,
3. Analytical Methods...
b. Non-specific method
 Detects any compound that produces a certain response.
Examples; Total Organic Carbon (TOC), pH, Titration, and
conductivity
 The method shall be practical and rapid, and, as much as
possible shall use instrumentation existing in the company,and
shall be validated in accordance with USP, EP requirements
Analytical Method Validation

 All analytical methods that are intended to be used

for analyzing any clinical samples will need to be
validated to meet the requirements for its intended
use.
 Validation of analytical methods is an essential but
time - consuming activity for most analytical
development laboratories.
Analytical Method Validation...
Why Validate Analytical Procedures?
 Reasons;
→ regulatory requirements,
→good science, and
→ quality control requirements.
 The Code of Federal Regulations (CFR) 311.165c explicitly
states that “the accuracy, sensitivity, specificity, and
reproducibility of test methods employed by the firm shall be
established and documented.
Characteristics ofAnalytical Method Validation
 Accuracy
 Precision ( Repeatability, Intermediate precision and
reproducibility)
 Specificity
 Detection limit
 Quantitation limit
 Linearity
 Range
 Robustness.
Process of Analytical Method Validation
 The typical process that is followed in an analytical method
validation is:
1. Planning and deciding on the method validation experiments
2. Writing and approval of method validation protocol
3. Execution of the method validation protocol 4. Analysis of the
method validation data
5. Reporting the analytical method validation
6. Finalizing the analytical method procedure
Facility and equipment qualification
 Design Qualification (DQ)
 The documented verification that the proposed design of the facilities,
systems and equipment is suitable for the intended purpose
 What to be considered during DQ
→Contamination control concept → Personnel/materials flow

→Materials of construction →Air supply/return

→Environmental monitoring → Operations in separate areas
→Differential pressures, air change rates
Facility and equipment qualification
 Installation Qualification (IQ)
 The documented verification that the facilities, systems and
equipment, as installed or modified, comply with the approved
design and the manufacturers recommendations
 What to consider during IQ
→Verify Materials of Construction – Walls, floors, ceilings,
→Correct installation of door interlocks & alarms
→ Facility lights, sprinklers, fire detection
→Completion of HEPA filter integrity (leak) testing – Other
work that could impact filter integrity must be first completed
Facility and equipment qualification
 Operational Qualification (OQ)
 The documented verification that the facilities, systems and
equipment, as installed or modified, perform as intended
throughout the anticipated operating ranges.
 OQ considerations include:
 Process control limits (time, temperature, pressure, line speed,
setup conditions, etc.)
 Raw material specifications
 Process operating procedures.
 Material handling requirements.
Facility and equipment qualification
 Performance Qualification (PQ)
 The documented verification that the facilities, systems and
equipment, as connected together, can perform effectively
and reproducibly, based on the approved process method, and
product specification.”
 OQ considerations include:
→Actual product and process parameters and procedures
established in OQ.
→Acceptability of the product.
→Process repeatability, long term process stability