Qualification And Validation In

Pharmaceutical Manufacturing

KHADIJAH ADE-ABOLADE MPH. FPCPharm.

Chief Regulatory Officer/Lead Inspector
Drug Evaluation & Research
NAFDAC
 OBJECTIVES
• Discuss the requirements for
Qualification and Validation in
Pharmaceutical Manufacturing
• Appreciate the need for Validation
 OUTLINE
• Definitions
• Validation documentation
• Qualification
• Types of validation
• Approaches
• Life cycle concept of validation
• Conclusion
 INTRODUCTION
• Safety, quality and efficacy are built
into the product – cannot be
"inspected or tested into a product"
• Need for confidence that the product
will consistently meet predetermined
specifications and attributes
 WHAT IS VALIDATION?
• “Validation is defined as the collection &
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.”
• Documenting that a process or system
meets its pre-determined specifications
and quality attributes
 WHAT IS VALIDATION?
• EU GMP - it is “Action of proving, in accordance
with the principles of Good Manufacturing
Practice (GMP), that any procedure, process,
equipment, material, activity or system actually
leads to expected results.”
• The US FDA defines “Validation as establishing
documented evidence which provides high
degree of assurance that a specific process will
constantly produce a product meeting its pre-
determined specification and quality
attributes.”
 WHAT IS QUALIFICATION
• Performed to establish confidence that process
equipment and ancillary systems are capable of
consistently operating within established limits
and tolerances.
• Provides documented evidence that the subject
equipment has been installed as per
specification (manufacturer’s recommendation)
and will attain and maintain critical process
parameters repeatedly and reliably.
• A subset of validation, typically done as part of
a larger validation effort.
 Comparison between Qualification and
Validation
• Validation and Qualification are essentially
components of the same concept.
• Qualification is normally used for equipment,
utilities and systems
• Validation is normally used for processes and
methods
• In this sense, qualification is often a part (the
initial stage) of validation but the individual
qualification steps alone do not constitute
process validation.
• Process validation cannot take place without first
carrying out qualification
 WHY VALIDATION?

• Assures Quality

• Regulatory Requirement

• Reduces Cost

• It’s the LAW !

 Consequences of NOT Validating Systems
and Processes

Poor Product Quality

Death Bad Publicity

Financial losses
 Systems

equipment
• What to
Qualify/Validate
 Responsibility
✓ Responsibility for
qualification and
validation is a multi-
disciplinary one which
includes:
✓ Heads of
Production and QC
✓Heads of
Engineering and
Contractors/suppliers
✓Respective
responsibilities
clearly defined in the
VMP.

Pharm.(Mrs) Edosa Ogbeide 12

 Validation Life Cycle Process
Validation should not be
viewed as a one-off event.
Validation must follow a
structured documented
process applying a lifecycle
approach having the Structured
following key elements: Documented
Lifecycle
✓ Initial Validation
Approach
✓ Validation Review and
✓ Change Management Validation Review

Validation encompasses the entire life of the system

from the initial requirements definition through to
maintenance and eventual decommissioning of the
system

Pharm.(Mrs) Edosa Ogbeide 13

 Validation Documentation
• Validation Master Plan (VMP)
• Validation Protocols (VP)
• Validation Reports (VR)
• Standard Operating Procedures
(SOPs)
 Validation Documentation
Validation Master Plan
• Contains key elements of the validation program.
• Concise, clear, contains at least:
❑a validation policy
❑organizational structure of validation activities
❑summary of facilities, systems, equipment and
processes validated (and to be validated)
❑documentation format (e.g. protocol and report)
❑planning and scheduling
❑change control and references to existing
documents
 Validation Documentation
Validation Protocol
• A validation protocol is a detailed document relating
to a specific part of the validation process.
• Outlines tests to be carried out, the acceptance
criteria and the information that must be recorded.
• Defines the approval process for the validation.
• Describes the procedure to be followed for
performing validation.
• Objectives of the validation/qualification study, the
site of the study, the responsible personnel
 Validation Documentation
Validation Protocol
• Description of the equipment to be used (including
calibration before and after validation)
• SOPs to be followed (e.g. the operation and cleaning
of the equipment) and the standards and criteria for
the relevant products and processes.
• Type of validation and time/frequency should also
be stipulated.
• Processes and/or parameters to be validated (e.g.
mixing times, drying temperatures, drying times,
physical characteristics, content uniformity, etc.)
 Validation Documentation
Validation Report
• Record of results obtained during the performance
of the validation.
• Reflects the final test results and other documents
such as instrument calibration certificates.
• Basis on which the decision is taken on whether a
particular process is judged to be validated.
• Includes evaluation, analysis and comparison of
results with acceptance criteria by the responsible
personnel.
• Results should meet acceptance criteria and satisfy
the stated objective.
 Validation Documentation
Validation Report
• Refer to the protocol, state details of material,
equipment, programs and cycles used, together
with details of procedures and test methods.
• Include recommendations on the limits and criteria
to be applied to all future production batches.
• Protocol and the report may be combined into a
single set of documents.
• The protocol is approved as a form on which the test
results are recorded as they become available.
 QUALIFICATION
Types (Stages) of Qualification

• Design qualification (DQ)

• Installation qualification (IQ)
• Operational qualification (OQ)
• Performance qualification (PQ)
 QUALIFICATION
DQ IQ OQ PQ

Training
Calibration Certification

Change
control GMP Process
under control
Review
periodically
Pharm.(Mrs) Edosa Ogbeide 22
 Commissioning
• Include equipment • Supplements validity
start-up, adjustments, and regulatory
fine-tuning, cycle compliance
development, testing • checks to verify the
and documentation system or equipment is
flexibility. built to design
• Leaves the equipment specifications
in a “State of Control”, • No safety issues
which ensures the • Takes place at the
equipment is ready for manufacturer’s premise
formal qualification, (FAT) or User/Client’s
testing, and approval. Premise (SAT)
 Design qualification (DQ)
• Process of completing and documenting
design reviews to illustrate that all quality
aspects have been fully considered at the
design stage.
• To ensure that all the requirements for the
final systems have been clearly defined at
the start.
• In other words, has it been designed and
selected correctly?
 Design qualification (DQ)
Before purchasing, a manufacturing
equipment
• Collection of data about similar equipment
available in the market
• Assessing your needs
• Resources to buy, operate, space and
maintenance they would need, etc.
• Making the decision
 Installation Qualification (IQ)
• Process of checking the installation, to
ensure that the components meet the
approved specification and are
installed correctly, and to see how that
information is recorded.
• To ensure that all aspects (static
attributes) of the facility or equipment
are installed correctly and comply with
the original design.
 Installation Qualification (IQ)
Considerations include:
• Equipment design features (i.e. materials of
construction cleanability, etc.)
• Installation conditions (functionality, utilities, wiring,
etc.)
• Calibration, preventative maintenance, cleaning
schedules; safety features
• Supplier documentation, prints, drawings and
manuals, software documentation
• Environmental conditions (such as clean room
requirements, temperature, humidity)
• Spare parts list
 Installation Qualification (IQ)
E.g., a manufacturing equipment

• After purchasing (or critical repair)

• Place it on its intended place
• Connect with other equipment, electric power,
material flow devices.
• Collect its documents including Operation Manual,
etc.
• Its formally “released”: it is ready for working with
 Operational Qualification
• Process of testing to ensure that the
individual and combined systems
function to meet agreed performance
criteria and to check how the result of
testing is recorded.
• To ensure that all the dynamic attributes
comply with the original design.
• Does it work correctly?
 Operational Qualification
• Assuring that the critical components and
systems are capable of operating within
established limits and tolerances
• “Worst case” (Proven Acceptable Range)
demonstration that the equipment will
perform as expected while operating at the
extremes of the proposed range of operation.
 Operational Qualification
Considerations include:
• Process control limits (e.g. time, temperature,
pressure, line speed, setup conditions)
• Software parameters; starting material
specifications
• Process operating procedures; material handling
requirements
• Process change control; training; short term
stability and capability of the process, (latitude
studies or control charts)
• Risk analysis and potential failure modes, action
levels and worst-case conditions (Failure Mode and
Effects Analysis, Fault Tree Analysis
 Operational Qualification
E.g., a manufacturing equipment
• ”Model manufacturing” experiments
with model materials, similar to those
to be used in the real manufacture
• E.g. qualifying an autoclave, we use
culture-media
• Permit the acceptable fluctuations of
parameters, even set the ”worst
conditions”
 Operational Qualification
Worst Conditions
• For example, if an equipment is to be
operated within the limits of:
– Temperature: 20 and 35 oC
– Pressure: 0.9 and 1.2 atm
• The worst cases are when it operates at
– 20 oC and 0.9 atm
– 35 oC and 1.2 atm
– 20 oC 0.9 and 1.2 atm
– 35 oC and 0.9 atm
 Performance Qualification
• Also called process qualification
• Process of testing to ensure that the
individual and combined systems function to
meet agreed performance criteria on a
consistent basis and to check how the result
of testing is recorded.
• To ensure that the criteria specified can be
achieved on a reliable basis over a period of
time.
• Does it produce the product correctly.
 Performance Qualification
PQ includes:
• Actual product and process parameters and
procedures established in OQ
• Assurance of process capability as
established in OQ
• Acceptability of the product
• Process repeatability, long term process
stability
 Performance Qualification
• Similar to the Operational Qualification, but the
real manufacture is running
• Permits accepted fluctuations up to their limits
(incl. worse conditions, if occur)
• Integrates procedure, personnel, systems, and
materials to verify that the pharmaceutical grade
utility, environment, equipment, or support
system produces the required output
• Production is done under conditions that simulate
those planned to be used during actual
manufacturing
 Change Control
• Policy and procedure
• Risk assessment
• Authorization
• Failure to properly document changes
to the system means invalidation of the
process
 Change Control
Changes that require revalidation
• Software changes; Controllers
• Site changes; Operational changes
• Change of source of material
• Change in the process
• Significant equipment change
• Production area changes
• Support system changes
 Validation
Types
• Process Validation
• Analytical Method Validation
• Cleaning Validation
• Water Systems Validation
• Computerized System Validation
 Process Validation
• Means of ensuring, and providing documentary
evidence that processes (within their specified
design parameters) are capable of repeatedly
and reliably producing a finished product of the
required quality.
• PV should be completed prior to commercial
manufacturing
• Where this is not possible, it may be necessary
to validate processes during routine production
 Approaches to Validation
Prospective Validation
• Prospective validation is carried out during the
development stage.
• Includes division of the production process into
separate steps
• Analysis of potentially critical points in the
manufacturing process e.g. mixing times, or
temperature.
• Trials are carried out in which these steps and
critical points are simulated and the effect on the
process is assessed.
 Approaches to Validation
Prospective Validation
❑ Each step should be
evaluated on the basis ❑ Representatives
of experience or from Production,
theoretical QC/QA,
considerations to Engineering, and
determine the critical in some cases
factors/parameters
❑ May incorporate Research and
that may affect the Development (if
a challenge element
quality of the finished available) will
to determine the
product. normally be
robustness of the
process. involved in this
❑ Such a challenge process.
is generally referred
to as a "worst case"
exercise.
Pharm.(Mrs) Edosa Ogbeide 42
 Approaches to Validation
Concurrent Validation
• Carried out during normal production.
• Requires full understanding of the
process based on prospective work.
• Involves very close and intensified
monitoring of the steps and critical
points in at least the first three
production-scale batches
 Approaches to Validation
❑ Documentation
Concurrent Validation requirements are the
❑ In certain same as specified for
circumstances it may Prospective Validation
not be possible to and the testing to be
complete a validation carried out in-process
programme before and on the finished
routine production ❑ It is important however, product will be as
starts. In these cases it that the premises and specified in approved
will be known in equipment to be used protocols.
advance that the have been qualified ❑ The completed
finished product will be previously and that the protocols and reports
for sale or supply. decision to carry out should be reviewed
Concurrent Validation is and approved before
made by appropriately product is released
authorised people. for sale or supply.
Pharm.(Mrs) Edosa Ogbeide 44
 Approaches to Validation
Retrospective Validation
• The analysis of accumulated results from past
production to assess the consistency of a process.
• Includes trend analysis on test results and a close
examination of all recorded process deviations.
• It is important to analyze 10 to 25 batches
manufactured over a period of 12 months to provide
a statistically significant picture.
• It is not the preferred method of validation and
should be used in exceptional cases only and never
for sterile products
 Approaches to Validation
Retrospective Validation
❑ There are many
processes in routine ❑ This type of validation
use in many exercise is only
companies that have Data acceptable for well
not undergone a established processes
formally documented and will be
validation process. inappropriate where
❑ Validation of these there have been recent
processes is possible,
❑ The steps involved in this changes in the
using historical data composition of the
type of validation still
to provide the
require the preparation product, operating
necessary procedures or
of a protocol, the
documentary
reporting of the results equipment.
evidence that the
of the data review,
process is doing
leading to a conclusion
what it is believed to
and recommendation.
do. Pharm.(Mrs) Edosa Ogbeide 46
 REQUIREMENTS FOR PROCESS VALIDATION
Fully qualify all equipment, the production
1 environment and analytical testing methods
Operatives taking part in the validation work should
2 have been appropriately trained

3 Calibration and maintenance schedule developed

4 Standard Operating Procedures followed

5 Materials (APIs and Excipients) must meet Raw

Material specifications

6 Analytical methods must be fit for the purpose

7 Pre-approved validation protocol

Pharm.(Mrs) Edosa Ogbeide 47

The Lifecycle concept of Process
Validation
Stage 1: Process Design
•Define Process Knowledge Space
•Identify Critical Process Parameters
•Determine Control Strategy

Process Stage 2: Process Qualification

Validation •Equipment/Utility/Facility
Qualification
Lifecycle •Identify Critical Process Parameters
•Process Performance Qualification

Stage 3: Process Maintenance

•Monitoring of Critical Process
Parameters

48
Pharm.(Mrs) Edosa Ogbeide
The Lifecycle concept of Process
Validation
• The Lifecycle concept links product and
process design, qualification of the
commercial manufacturing process and
maintenance of the process in a state of
control during routine production
• A science- and risk-based approach to verify
and demonstrate that a process operating
within predefined specified parameters
consistently produces material that meets all
its critical quality attributes.
 Validation Maintenance
V M
A 1
A
I Change
2 Management Program
L
I N
D T
3 re-qualification
Periodic
A E
T N
I A
Periodic Validation Review
O N
N C
E

Pharm.(Mrs) Edosa Ogbeide 50

 Validation Maintenance
• Change Management is • Changes should be
the primary mechanism formally documented
by which validation is and approved before
maintained implementation and
• Effective change records maintained
control system must be • Commitment of the
in place to control company to control is
changes to validated essential to ensure a
systems continued validation
status of the systems
concerned.
 Validation Maintenance
Revalidation
➢change in operating
parameters
➢component
specifications have
changed
➢new accessories or
components are added
to previously qualified
equipment
➢process changes that
potentially impact
product effectiveness or
quality
 Decommissioning
• Documented
demonstration that at
the time of removal from
routine operational use,
system was operating in
compliance with specific
requirements and fit for
purpose
• Should be planned
• Requirements depends
on system complexity
• Outcome should be
reported and provide
conclusion
Continuous Process Verification
• Introduced to cover an alternative approach to
process validation based on a continuous
monitoring of manufacturing performance
• Based on the knowledge from product and
process development studies and / or previous
manufacturing experience.
• Can be introduced at any time in the lifecycle of
the product. It can be used for the initial
commercial production, to re-validate
commercialized products as part of process
changes or to support continual improvement
Continuous Process Verification
• Involves extensive in-line, on-line or at-line
controls and monitoring process performance
and product quality on each batch.
• Relevant data on quality attributes of
incoming materials or components, in-process
material and finished products should be
collected.
• Verification of attributes, parameters and end
points, and assessment of CQA and critical
process parameter (CPP) trends
 Cleaning Validation
• Establishing documented evidence that the
equipment is consistently cleaned of product,
microbial and cleaning agent residues to
predetermined acceptable levels
• Provides a high degree of assurance that the
Cleaning procedure can effectively remove
residues of a product and a cleaning agent from
the manufacturing equipment, to a level that
does not raise patient safety concerns
 Cleaning Validation
Basic Considerations
• Cleaning mechanisms: Mech. action,
dissolution, chem. reaction, detergency
• Cleaning Procedure: SOPs, tools & materials
• Cleaning method: CIP, COP, manual cleaning
• Determination of contamination limits: TD,
blanket spec.
• Worst case selection
• Clean Hold times
• Sampling: swab, rinse, location, surface area,
swab recovery, analytical method
 Analytical Method Validation
ICH Q2 (R1)
• Specificity
• Linearity
• Accuracy
• Precision
• Robustness
• LOD
• LOQ
 Water Systems Validation
Conducted in 3 phases:
• Phase 1: 2-4 weeks - intensive system
monitoring, develop operating ranges,
implement & refine SOPs
• Phase 2: 2-4 weeks – deploy refined SOPs,
demonstrate operation within established
ranges, demonstrate production of required
quality & quantity
• Phase 3: 1 year – verify long-term control,
demonstrate consistent production of
required quality & quantity
• Ongoing system monitoring
Computerized Systems Validation
Basic Considerations
• System specification – hardware, software,
user training
• Functional specification – testing, operating
& maintaining the system
• Security – controls against unauthorized
data manipulation, audit trail
• Back-ups – secure data storage
 Conclusion
▪ Validation is an essential component of GMP
▪ Helps to achieve goal of is assuring product
quality, safety and efficacy
▪ Offers huge business benefits
▪ Lifecycle approach covers entire systems
and processes and must be structured,
planned and documented
▪ Validation maintenance is essential element
of validation lifecycle
 Benefits of
Validation and
Qualification

Eqmt
Facilities ****Note: Eqmt= equipment
Utilities
Processes
VALIDATION

Pharm.(Mrs) Edosa Ogbeide 62

 References
• NAFDAC cGMP for Medicinal Products Regulations 2009
• WHO Supplementary Training Modules on GMP. WHO TRS No.
937, 2006. Annex 4
• ICH Tripartite Guidelines: Validation of Analytical Procedures:
Text and Methodology Q2(R1)
• WHO TRS 986 Annex 2; Good manufacturing practices for
pharmaceutical products: Main principles
• NAFDAC Good manufacturing Practice for Pharmaceutical
Products Guidelines 2016
• Chukwumerije O. (2016). Presentation on Pharmaceutical
Qualification & Validation
• Ogbeide E. (2013). Presentation on Equipment Qualification &
Process Validation
THANK YOU
QUESTIONS?