VALIDATION &

QUALIFICATION

RITESH SINGH
FLOW OF PRESENTATION
 GMP
 History of GMP- Timeline
 What is Validation
 Why Validation
 Four (4) Approaches to Validation
 CMA, CPP, CQA
 What is Qualification
 Phases of Qualification
 Types of Validation/Qualification
 Validation Documentation (VMP,
Protocol & Reports)
 Significance of Validation
 Role of Engineers in Validation
 Good manufacturing practice is that part of
quality assurance which ensures
that products are consistently produced and
controlled to the quality standards
appropriate to their intended use and as
required by the marketing authorization
~ WHO TRS 961 ANNEX 3
 Good Manufacturing
Practice

GMP States that every step in the Production

including “Who” did “What” and “When”
must be documented and fully traceable.
or
It is the documented way of using your
“COMMON SENSE”
 HISTORY OF GMP
Concept of
Federal Food, “Validation“
Bureau of Drug & introduced by Ted
Biologics Chemistry Cosmetic Act First GMP Buyer & Bud
Control Act becomes FDA • Proof of Safety Regulations issued Loftus in mid
1902 1930 1938 1963 1970’s

1906 1937 1956 1969 1987

Pure Food & Drug Sulfonamide Thalidomide WHO First “Process
Act Elixir Tragedy Tragedy adopted Validation”
• Consumer Protection Diethylene Glycol Caused Congenital GMP with a
Law (DEG)- Poisonous Guideline-FDA
Disabilities draft text
• Bureau of Chemistry Solvent was added
 What is Validation?
According to European Commission:
• “Act of proving, in accordance of GMPs that Any process actually leads to expected results”.
(1991)
• “Documented evidence that the process operated in accordance with established parameters can
effectively and reproducibly produce a medicinal product in accordance with its predetermined
specifications and quality attributes.” (2000)

According to US FDA:
"Process validation provides documented evidence that provides a high degree of assurance that a
specified process will consistently produce a product that meets its pre-determined
specifications and quality features."

According to ICH (International Conference on Harmonization):

"Process Validation is the means to ensure and provide documentary evidence that processes within
their design parameters can produce a finished product of the required quality repeatedly and
reliably."

According to WHO:
"The documented act of proving that any procedure, process, equipment, material, activity, or
system actually results in the expected outcome."
Why Validation?
Let’s just rephrase the question, “Validation, Why Not?”

Validation is based on, but not prescribed by, regulatory requirements and is best viewed as
an important and integral part of cGMP (Current Good Manufacturing Practices). It plays a
vital role in Pharmaceutical and Medical Device Industry specifically.

Validation simply means an evaluation of validity or an intervention to show

effectiveness.
 APPROACHES TO VALIDATION
There are four (4) approaches to Validation according to NAFDAC (National Agency for Food and
Drug Administration and Control)- Nigeria

1. PROSPECTIVE VALIDATION
• Prospective validation occurs before the system is used in production
• It is proactive approach of documenting the design, specifications and performances before the system is
operational
• New Facility, New Equipment, New Product and New Process

2. CONCURRENT VALIDATION
• Concurrent validation occurs simultaneously or parallel with production
• Existing Facility, Existing Equipment, Existing Product and Process.

3. RETROSPECTIVE VALIDATION
• Based on review and Analysis of Historical data
• The source of this data is Production and QA/QC record.
4. RE-VALIDATION
Required when there is are changes in,
• Any of the critical process parameters (CPP).
• Formulation.
• Primary Packaging Components.
• Raw Material.
• Change in major component of Equipment or Premises.
• Failure to meet product and process specifications in batches would also require process re-
validation or re-qualification
 CMA, CPP, CQA
 CRITICAL MATERIAL ATTRIBUTES (CMA)
A physical, chemical, biological or microbiological property or characteristic of an input material
that should be within an appropriate limit, range, or distribution to ensure the desired quality of
output material.
 CRITICAL PROCESS PARAMETERS (CPP)
Any parameter whose variability has direct impact on Quality of product. Example: Temperature,
Humidity, Mixing time, drying Temperature, machine Speed, Mesh Size, Steam pressure of
autoclave, Sterilization temperature. (According ICH Q8)
 CRITICAL QUALITY ATTRIBUTES (CQA)
Any Physical, Chemical, Biological or Microbiological property or characteristics which should be
within appropriate limit, range or distribution to assure product of desired quality. Example: Assay,
Content Uniformity, pH, Osmolarity, Sterility, F˚ etc. (According ICH Q8)
RELATIONSHIP BETWEEN CMA, CPP & CQA
 QUALIFICATION
• Qualification is defined as an action of providing that equipment or ancillary
systems are properly installed, work correctly, and actually lead to the
expected results.
• The term “Qualification” generally applies on Facility, Utilities, and
Equipment.

NOTE:
Qualification is actually part of Validation where applicable, but not vice versa.
Example: Humans may not be validated, Perhaps can be trained to qualify for particular job.
 PHASES OF QUALIFICATION
• User Requirement Specification (URS) is a list of all the requirements from the user, like
equipment to be purchased. which include the functional and technical specifications for the
machine equipment or software. This specification in the written format is defined as URS. It shall
be very specific.
• Design Qualification (DQ) includes activities that define the design elements of the instruments
such as functional and operational specifications as well as vendor selection criteria. DQ can be
performed by the manufacturers, developers, or even the end-users.
• FAT (Factory Acceptance Test) is where the supplier tests the system in accordance with the
clients approved specifications to show that system is at a point to be installed and tested on site.
It is usually preformed at the vendor prior to shipping to a customer.
• SAT (Site Acceptance Test) is when the system is tested in accordance to the client approved test
plans / specifications, and demonstrate the system is installed properly and interfaces with other
systems and peripherals in its working environment.

NOTE: DQ can be performed prior to FAT as per revised Baseline ISPE Guide Vol. 5 2019
• Installation Qualification (IQ) comprises all activities during the installation
of the instrument. IQ checks whether the environment where it is installed
is suitable if the instrument is in accordance with the desired specifications
and if the installation procedures have been complied with.
• Operational Qualification (OQ) involves collecting documentary evidence
showing that the installed instrument’s performance in the chosen
environment will be according to the criteria specified in operational
specifications.
• Performance Qualification (PQ) requires measuring if the instrument is
performing its intended purpose against the activities documented in the
PQ stage, which consists of maintenance, change control, and calibration.
 TYPES OF
VALIDATION/QUALIFICATION
• Facility/Area Qualification • Analytical Method Validation

• Utility Qualification • Computer System Validation

• Equipment Qualification (CSV)

• Process Validation • Cleaning Validation

 FACILITY/AREA QUALIFICATION
Facilities Qualification validates the overall manufacturing / testing / production
environment.

• “The requirement is as usual driven Good engineering principles and

from the product processes”. Where
the product process calls for specific practice must be used to protect this
room condition, as defined in ISO conditions as required, using
14644 and was in Federal Standard • Approved Area Dimensions & Specs
209E, the engineers must design the
respective process area to enable • Quality of Air Filtration
these conditions to be achieved and • Temperature & Humidity control
maintained. • Air Flows Control
• Differential Air pressures Controls.
 UTILITY QUALIFICATION
All Utilities must pass a string of Some Critical Utilities at Pharmaceutical
Qualitative and Quantitative specifications Plant:
to be considered satisfactory.
 HVAC System
Steps in Utility System Qualification include:  Water System (i.e. DI, WFI)
• Implementing strong operating procedures.  Pure Steam
• Establishing extensive quality control systems.  Nitrogen System
• Extensive Sampling on regular intervals.  Compressed Air System
• Maintaining dependable testing labs.
Note: All the above utilities directly have an
impact on Product Quality (affecting Quality
Attributes).
 EQUIPMENT QUALIFICATION
• As per definition, Equipment LEVELS OF EQUIPMENT/SYSTEM
Qualification is documented evidence
which provides assurance that the Level I
equipment or system is commissioned Equipment systems with highest degree of
properly, operates and performs Product Quality & Regulatory impact. Eg. Steam
consistently as per their intended Sterilizers, Dry Heat Sterilizers etc.
purpose. Level II
Equipment System that may not have a direct
impact on product quality, but typically will
• Qualification starts from URS to the support Level I Equipment. E.g. Compressed air.
Decommissioning of Equipment. Level III
Equipment systems representing processes with
low Regulatory and Product Quality impact.
 PROCESS VALIDATION

• Process Validation is defined as the The process validation activities can be

collection and evaluation of data, described in three stages.
from the process design stage Stage 1 – Process Design
throughout production, which This is the R&D phase and involves defining a
establishes scientific evidence that a process for manufacturing the product. It usually
process is capable of consistently includes the following:
delivering quality products. • Creation of a Quality Target Product Profile
(QTPP)
• Identifying Critical Quality Attributes (CQAs)
• Defining Critical Process Parameters (CPPs)
• Conducting risk assessments
Stage 2 – Process Validation or Process Qualification Stage 3 – Continued Process Validation
This stage evaluates/qualifies the process designed Continued Process Verification involves ongoing
earlier to ensure it can reproduce consistent and validation during production of the commercial product
reliable levels of quality.
to ensure the process designed and qualified in the
It involves collecting and evaluating data on all aspects previous stages continues to deliver consistent quality.
and stages of the manufacturing process. This includes:
One of the main aims of this stage is to detect and
• The building and facilities, i.e. ensuring they adhere resolve process drift.
to local regulations as well as pharmaceutical
manufacturing regulations The stage involves product sampling, analysis, and
verification at various points in the manufacturing
• Transportation & Storage of raw materials process, and requires the involvement of employees
• Training of production line employees with quality control training.

• Every step of the process to turn raw materials into

the finished product. This includes having pre-
defined sampling points at various stages of the
process.

• Finished product packaging, storage, and distribution

How many Product Batches could be taken for
Process Validation?
Answer: Three consecutive batches are enough to identify trend analysis and
provide adequate evaluation and reproducibility data.
1) First batch quality assumes to be accidental (CO-INCIDENTAL)
2) Second batch quality assumes as regular (ACCIDENTAL),
3) Third batch quality shows the Validation (CONFORMATION).
Nevertheless,
According to regulatory authorities, 3 batches no longer required – other approaches
can be used based on the Manufacturer, while providing a sound scientific rationale.
Quality Myths!!!!
03 Batches- Not appropriate
30 Batches required for 90% reliability & 95% confidence (Practically Impossible)
 ANALYTICAL METHOD VALIDATION
• Method Validation confirms that the analytical procedure employed for a specific test is
suitable for its intended purpose.
Strategy for Method Validation
1. Develop Validation Protocol and define scope of the method
2. Define Performance parameters and acceptance criteria
3. Define Validation Experiments
4. Select Quality Material- (Standards & Reagents)
5. Perform Full Validation Experiments & Develop SOPs for method execution routinely
6. Define criteria for revalidation
7. Define type & frequency of system suitability tests and/or Analytical Quality Control (AQC)
8. Document Validation Experiments and Generate Validation Report
 COMPUTER SYSTEM VALIDATION
Computer Systems Validation (CSV) – is a process used to test, validate and formally document that a regulated computer-based system does
exactly what it is designed to do in a consistent and accurate manner that is secure, reliable and traceable.
Usually, while validating computer systems, companies stick to the Good Automated Manufacturing Practice V-Model, also known as GAMP-5.

Step-by-Step Breakdown of Computer System Validation

• Planning — at this stage, deadlines and the budget needed to carry out CSV are set. Also, all stages are broken down by time and
monetary estimates in form of Gantt Chart.
• Defining URS- Basically, this includes all the functions a system needs to carry out.
• Design Specifications. At this point, a team involved in CSV decides the look of a given function and the way it should function in
order to complete all tasks outlined during the previous stage.
• Configuring a System build. This stage consists of writing configure scripts that will design the software for a computer system.
• IQ tests. test a range of scripts to determine if they have chosen the correct way to install the system into the user environment.
• PQ tests — test worst-case scenarios to ensure a system would still work properly under poor conditions.
• Reporting. All planned activities are reviewed. A tester has to document the result of validation and organizes them as proof that a
system is ready for release.
 CLEANING VALIDATION

• Documented evidence to establish that cleaning procedures are

removing residues to predetermined levels of acceptability, taking
into consideration factors such as batch size, dosing, toxicology and
equipment size.
Cleaning Validation Sampling Worst Case Selection:
Methods:
1. Visual Inspection 1. Toxicity
2. Swabbing Method 2. Difficult To Clean (Cleanability)
3. Rinse Sampling 3. Therapeutic Dose

4. Placebo Sampling Method 4. Solubility

 VALIDATION MASTER PLAN
• Validation Master Plan (VMP) is a COMPONENTS OF VMP
document which outlines the principles
tied to the qualification of a certain
facility, defining the systems and areas
which need validation and provides a
written guideline on how to achieve and
then maintain a qualified facility.
 SIGNIFICANCE OF VALIDATION

• Improve the use of Technology

• Improve Operational Efficiency
• Improve compliance with
Regulations
• Increase Productivity
• Reduce the risk of Failure
• Reduce the Cost
• Process Optimization
• Increased Customer Satisfaction
 ROLE OF ENGINEERS IN VALIDATION

Engineers contribute a significant portion to the Validation Team. They

are entitled with the following responsibilities:
• Commissioning and Qualification of Equipment/Utilities
• Monitoring Area/System/Equipment/Utilities Specifications
• Directing Validation Activities and Preparing Compliance Reports
• Auditing and Calibrating Equipment
• Analyzing test results and compiling of technical reports.
• Providing evidence of regulatory compliance
• Bridge the Gap between Quality Operations and Engineering
Department
 REFERENCES
[1] Drug Act 1976, Drugs Licensing, Registering and Advertising Rules, 1976, Schedule B
[2] USP-NF General Chapters
[3] British Pharmacopoeia
[4] The International Pharmacopoeia
[5] EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 15:
Qualification and Validation
[6] FDA Current Good Manufacturing Practice for Finished Pharmaceuticals, 21 CFR, Part 211
[7] WHO TRS 937, Annex 4, Supplementary Guidelines on Good Manufacturing Practices: Validation
[8] Baseline Guide Volume 5, ISPE Commissioning and Qualification
[9] Good Manufacturing Practices (GMP) Guidelines – 2009 Edition, Version 2, Health Canada, GUI-0001
[10] PIC/S Guide to Good Manufacturing Practice for Medicinal Products, Annex 15, Qualification and Validation.