Company name DEPARTMENT Management of GMP

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Transcript Company name DEPARTMENT Management of GMP

Qualification and
An Overview
Training Objectives
Qualification and Validation Definitions
Order of Q and V Activities
Validation Responsibilities
Important Validation Considerations
Basic Checking of Validation Documentation
Typical Validation Errors
Training Objectives
• To provide a high level introduction to the principles of
Qualification and Validation for people not working directly
with this area
• To cover the main aspects associated with each element of
Qualification and Validation and how they inter-relate
• To provide an indication of things to look for when reviewing
validation documentation
• To provide further reference for people who are interested to
learn more about the topic.
References (1)
• References EU GMP volume 4
 Annexe 15 “Qualification & Validation”
• Qualification: Action of proving that any EQUIPMENT
works correctly and actually leads to the expected
results. The word Validation is sometimes widened to
incorporate the concept of qualification
• Validation: Action of proving, in accordance with the
principles of GMPs, that any PROCEDURE, PROCESS,
MATERIAL, ACTIVITY or SYSTEM actually leads to the
expected results
References (2)
• References EU GMP volume 4 (1997)
Chapter 5 Production, Validation : 5.22 – 5.24
“When any new manufacturing formula or method of preparation is
adopted (after validation), steps should be taken to demonstrate its
suitability for routine processing. The defined process, using the
materials and equipment specified, should be shown to yield a
product consistently of the required quality”
“Significant amendments to the manufacturing process, including
any change in equipment or materials, which may affect product
quality and/or the reproducibility of the process should be validated”
“Processes and procedures should undergo periodic critical
revalidation to ensure that they remain capable of achieving the
intended results.”
Qualification and Validation
definitions (1)
• Qualification
Identification of particular attributes of equipment, utilities or
processes related to the performance of a particular function, such
as design (DQ), Installation (IQ) or Operation (OQ) and the
allocation of certain limits or restrictions to those attributes and
finally, the measurement of those attributes in those ranges for
those functions, such as performance (PQ)
• Validation
Documented evidence that the item under consideration does what
it purports to do. Validation includes but is not limited to:
Manufacturing processes, cleaning procedures, Computerized
Systems, facilities, utilities and analytical methods.
Qualification and Validation
definitions (2)
• So let us simplify these definitions by the following practical
• The term Qualification tends to get used when discussing
personnel , equipment and utilities (e.g. filling machines,
laboratory equipment, nitrogen systems)
• The term Validation tends to get used when discussing
methods and processes (e.g. manufacturing, packaging,
cleaning, sterilization and computer systems), and can
sometimes include Qualification activities
• For example, a purified water system is considered “validated”
when all phases of the IQ, OQ, and PQ are completed.
Qualification and Validation
definitions (3)
• There are a few important process validation terms
that can be explained as follows:
• Prospective
 Validation required to be completed before a process is
used, or before a Product is released
• Concurrent
 A Validation exercise performed at the same time as
ongoing commercial production
• Retrospective (not recommended)
 Validation of a Process already in use based upon
accumulated historical data’s conformance to
predetermined acceptance criteria. Use of Retrospective
Validation is restricted to APIs under limited circumstances
without significant changes.
Order of Q and V Activities (1)
There are distinct phases that relate to Qualification and these take place in
the following order - using equipment as an example:
Design Qualification (DQ) ensures the critical design requirements have
been met during equipment construction (e.g. grade of stainless steel
Installation Qualification (IQ) ensures that the equipment has been installed
correctly (e.g. correctly electrical wiring, piping etc versus approved
Operational Qualification (OQ) ensures that the equipment can perform the
basic operations across its operating range (e.g. motors operate across
defined speed range)
Performance Qualification (PQ) ensures that an operation, when carried out
versus a defined protocol, will consistently perform its intended function to
meet pre-determined acceptance criteria.
Order of Q and V Activities (2)
The following Q and V documentation is normally generated
 Qualification/Validation Plan – that sets out the overall plan of the
qualification or validation, and includes responsibilities, number of
batches etc
 Qualification/Validation Protocol – that details the work that must
be performed for each batch/run, the tests to be performed, and
clearly shows the acceptance criteria
 Qualification/Validation Report – that documents the obtained
results, and assesses them versus the acceptance criteria
 Qualification/Validation Summary Report – this document
summarises the overall validation, and provides a conclusion about
the validation status.
Order of Q and V Activities (3)
• It is essential that Qualification and Validation are performed in the
correct order within the site otherwise the work will be invalid
• If we consider a new product as an example, we need to ensure
qualified/validated prior to trying to validate our product
• In addition, there is no point in QC testing the validation samples of
the new product if they have not qualified their laboratory
equipment nor validated their QC testing method
• This is shown diagrammatically on the following slide, indicating the
activities that are pre-requisites to process validation.
Order of Q and V Activities (4)
Quality Control
Facilities and Utilities
Qualification Including
Associated Computer
System validation
Quality Control
Qualification Including
Associated CSV
Processing Equipment
Qualification Including
Associated CSV
QC Test Methods
Process Validation and Cleaning Validation
Qualification: DQ, IQ, OQ, PQ
Organisation Validation
Conception Qualification
Qualification Report
Installation Qualification
Qualification Report
Operational Qualification
Qualification Report
Performance Qualification
Conclusion Validation
Qualification Report
Final Validation
Qualification: IQ, OQ, PQ (1)
• IQ - Each element of the system is:
 adequately installed,
 in conformity with user needs, supplier technical specifications
and the regulatory requirements
• Protocol
 description of the system to be validated
 Technical verification tests (individual component, critical
parameters, control and functioning systems, system
environment, power, and utilities, accessibility / material flow,
 documentation checking.
Qualification: IQ, OQ, PQ (2)
• OQ - Each element of the system works
within the predefined limits
• Protocol:
 description of the system to be validated
 technical verification tests and acceptance criterion
(individual functions, calibration of the critical
measurement systems, working of the whole system,
control and working systems, system environment,
power and utilities, safety and alarms)
 documentation checking (operational documents).
Qualification: IQ, OQ, PQ (3)
• PQ - The system or the product process
will regularly produce the expected results
within the predefined limits
• Protocol :
 verification of the documents of validation achieved and
 verification of the presence of all organisational procedures,
operational documents and training documents
 verification tests for the general process during a determined
period or on defined batches and acceptance criteria.
Validation Responsibility (1)
• Site validation activities need to be well coordinated to ensure they
are performed in a suitable and timely manner
• The validation work needs to include the appropriate crossfunctional expertise from the planning stage
• A cross-functional Site Validation Forum may well exist,
To publish Site Validation Master Plan
To generate validation SOP’s and templates
To agree validation priorities and timings
To review completed validation documents
To plan re-validation activities
• Process owners are generally responsible for performing and
documenting their validation work within their area using the
approved site systems, SOP’s, and templates
• QA are responsible for final approval of the validation plans,
protocols, and reports.
Validation Responsibility (2)
• Each site must develop, and keep current, a Site
Qualification and Validation Master Plan that
includes, but is not limited to:
Site description
Site or global project description as applicable
List of systems and equipments requiring qualification
and validation (e.g. inventory list)
Qualification and validation status and history of each
system or equipment unit
Site Qualification and Validation Plan (See next slide)
Validation Responsibility (3)
• A site qualification and validation master plan
that includes, but is not limited to:
 responsibilities for Q&V and organizational
structure for validation activities
 definition of terms used in the site qualification
and validation master plan
 methodology and/or procedures that govern the
qualification and validation master plan
 identification of revalidation or requalification
requirements, the change control process and
evidence that will maintain validation
documentation in a current state of control.
Important Process Validation
Considerations (1)
• Process Validation is not to be used as process development
or optimisation
 Development and scale up work should be used to fix the
process before validation commences
• Process Validation must never be used to justify a bad or
inconsistent process
 The process must be based on good science and meet cGMP
before validation commences
• Process Validation must be based upon additional work and
more samples than are taken for a regular production batch
• Process Validation samples should be based upon good
statistics and be designed to ensure that quality is consistent
throughout the batch.
Important Process Validation
Considerations (2)
• A minimum of three consecutive validation
batches are normally used to consider a
process validated
• All deviations from the validation protocol
need to be fully justified, and approved by
Quality Assurance
• Process Validation batches are normally
placed on the stability testing program.
Basic Checking of Validation
Documentation (1)
• Validation documents are often reviewed by regulatory
authorities either as part of product registration dossiers or
during audits
• Any validation activity should be able to be read like a book
 A beginning (a clear and precise plan, requirements, and acceptance
 A middle (documented results versus the acceptance criteria)
 An end (a summary and clear conclusion)
• The next few slides indicate basic checks that should be
performed to ensure that the most commonly found validation
documentation errors are not present - even if you are not an
expert in that area or product.
Basic Checking of Validation
Documentation (2)
• Look for examples of the following general
document errors:
 Was the Q and V work performed in the correct order ?
 Was one phase completed before the next commenced ?
 Is the report completed with results, signatures and
dates ?
 Do the results make common sense ?
 Do the dates make sense ?
 Is there a trace to the raw data, measuring equipment,
calibration certificates etc.
Basic Checking of Validation
Documentation (3)
• Ensure that you start by reviewing the
approved validation plans and protocols
Identify precisely what was being planned:
– Does validation mimic production process?
– How many batches/runs? (normally minimum 3 consecutive
How many samples will be taken, and from where?
How will samples be tested? (individual or pooled)
What specification will the samples be tested against?
Are critical process parameters defined? (e.g. mix time,
What are the acceptance criteria? (e.g. 30 minutes, 25 –
Are batches being put onto stability testing program?
Basic Checking of Validation
Documentation (4)
• Review the validation reports and summary report, and
compare the actual data versus the plan:
Were there the required number of batches/runs?
Were the batches/runs consecutive?
Were the required number (and location) of samples taken?
Were the samples tested individually or pooled?
Was the correct test specification used?
Were there records for all of the critical process parameters?
Did all results meet the pre-determined acceptance criteria?
Are all deviations from the protocol fully justified?
Have process validation batches been put on stability program?
Is there a clear summary/concluding statement on validation
Basic Checking of Validation
Documentation (5)
• A useful check for an established process is to check the
actual process (reality) versus the validation documentation
and the submitted registration dossier
• This will identify whether the actual process still matches the
one that has been validated and registered
• For the chosen product, compare in detail the following three
key documents:
 The batch record from the most recently released batch
 The most recent process validation report/summary report
 The most recently submitted CMC part of the dossier
• Ideally, the reality should match theory. If not then review the
change control documents to understand why there is a
• Changes to processes must be handled via change control system
• Changes must be assessed both for their impact on the registration
dossier and their impact on the validation status
• Minor changes may not require the process to be re-validated,
whereas some more significant changes will require re-validation
• Even if individual minor changes do not require re-validation when
considered in isolation, numerous minor changes may cumulatively
impact the process
• Therefore, all processes need revalidation at some time to ensure
that the process is still under control
• Annual Product Reviews are a useful way to review recent changes
that may have an impact on the status of process validation.
Typical Validation Pitfalls
• The next few slides will cover some of the most
frequent pitfalls noted during review of validation
• We will consider the generalities of validation in
the following distinct phases
 Validation planning
 Validation protocols
 Sampling and Testing
 Documenting
 Review and Sign off
 What happens after validation
Which of These Validation
Statements is True?
• Validation is generally the final stage of a project and
there is always a lot of pressure to just “make it happen”
• Generally, too little time is spent planning the validation
• The validation activities nearly always take longer and
utilise more resource than originally thought
• Validation activities are therefore on many occasions
under resourced
• Each validation does not have an identified owner to
drive the process (organisation)
• Major reason : Lack of realistic validation planning?
Validation Planning (1)
• In many cases validation protocols:
do not embrace all of the validation requirements
are too complicated for people to follow (too “wordy”)
are not specific enough in terms of samples (e.g. size, location)
Are not specific enough about QC testing (e.g. individual assays)
do not specify clear responsibilities
are not communicated to involved parties
• We can probably all think of examples where the
technical aspects of a process are ok, but the validation
failed or was severely delayed because:
The people took the wrong sample
The samples were inadequately labelled and were mixed up
Not all samples were taken as required
The samples were inappropriately tested.
Validation Planning (2)
• There is sometimes no clear indication of all the identified critical
process parameters
 mixing speed
 mixing time
 water temperature
• Operating conditions are not specified – sometimes because the
process has not yet been fixed. We see examples as follows:
Validation Batch A 15 minutes mixing – failed assay
Validation Batch B 20 minutes mixing – failed assay
Validation Batch C 25 minutes mixing – satisfactory assay
Validation status : Passed !!!
• Do NOT use validation as Process Development
• Acceptance Criteria are not clearly defined – so people do not know the
parameters to work within.
Validation Planning: Process
validation Method
• The validation protocol should be prepared by the technical
personnel responsible for carrying out the validation exercise. It
should state the way in which the process is to be operated, identify
the controls to be exerted, specify the variables to be monitored,
state the samples to be taken for subsequent testing, specify the
product performance characteristics/attributes to be monitored
along with acceptable limits and refer to the test methods to be
• Examples of process variables are:
-Temperature - Time - Volume - Capacity - Appearance Cooling/Heating rate - Heat distribution - Particles size - Chemical
composition of the environment in contact with the product (e.g.
oxygen, carbon dioxide, water vapour) – power consumption pressure - humidity - vacuum - materials - speed.
Critical Process Parameters:
Example process “Mixing of Solids”
• Equipment: Blade mixers, Free fall mixers
• Variables of Process: type, shape and position of mixing
blades, sequence of addition; capacity; percent fill; time;
blade/container rpm or peripheral speed
• Product properties affected by these variables: Homogeneity;
particles size; drug release (wear of coats or coating with
• Control of the Process variables or IPC of the process step:
Time; rate/rpm; power consumption; temperature
• Control of the characteristics of the Product: Content
uniformity; particles size analysis; disintegration time;
dissolution rate.
Critical Process Parameters:
Example process “Wet Granulation”
Equipment: Fluidized bed granulator
Variables of Process: Type; capacity; position; angle & bore of nozzle;
spray cone; batch size; inlet/outlet temperature; airflow rate at
inlet/outlet; spraying rate; material temperature; filter shaking period;
drying time; filter bags; climatic conditions
Product properties affected by these variables: particles size
distribution; bulk/tapped density; flow properties; hardness;
homogeneity; residual moisture
Control of the Process variables or IPC of the process step: airflow
meter; temp. of air at inlet & outlet; feeding rate; pressure of air;
process timing; humidity of air at outlet
Control of the characteristics of the Product: residual moisture; particle
size analysis; bulk/tapped density; flow properties; granule friability;
yield; disintegration time.
Critical Process Parameters:
Example process “Tableting/Slugging”
• Equipment: tableting machines (reciprocating & rotating)
• Variables of Process: Type of machine; shape & material of tools;
condition of tools; machine speed; filling depth; pre-compression
pressure; compression pressure; percent hopper fill; feeding
rate/speed of feeder
• Product properties affected by these variables: weight; weight
distribution; thickness; hardness; friability; disintegration time;
dissolution time
• Control of the Process variables or IPC of the process step:
inspection of tools; machine speed control; volume fill/feeder speed
control; compression pressure; ejection force; metal detection
• Control of the characteristics of the Product: hardness; thickness;
weight; uniformity of weight & contents; appearance; yield;
(moisture content); disintegration time; dissolution rate.
Critical Process Parameters:
Example process “Steam Sterilization”
• Equipment: Autoclave
• Variables of Process: Type, size, temperature,
pressure, cycle time, load and arrangement of
load, distribution and penetration of heat, cooling
• Product properties affected by these variables:
• Control of the Process variables or IPC of the
process step: temperature, pressure, cycle time,
bio indicator
• Control of the characteristics of the Product:
sterility, apyrogenicity (where applicable).
Critical Process Parameters:
Example process “Lyophilising”
• Equipment: Freeze-drier
• Variables of Process: Type; capacity; temperature of shelf / product
/condenser; distribution of temperature; time; vacuum; closing
mechanism (for sterile products); air filter
• Product properties affected by these variables: uniformity of weight;
residual solvent; microbial contamination
• Control of the Process variables or IPC of the process step: vacuum
– temperature (shelf, product, condenser) – time profile
• Control of the characteristics of the Product: uniformity of weight
and content; solvent residues; time of dissolution in the solvent for
reconstitution; moisture content; head space pressure; sterility test
(where applicable).
Validation Planning – Worse Case
• The earlier part of the Qualification process should help you
to better understand your equipment and processes, which
will help you to identify any potential weaknesses
• Early Qualification work does not always consider the
potential worse case scenarios:
 What happens if the power fails to the mixer?
 What happens if the water temperature goes above 30 degrees
 What happens if the operator tries to modify data and save it?
 What happens if a re-print is requested?
• Knowing the answers to key questions can help to save
expensive product when there are problems when running
live product.
Inappropriate Sampling and
Testing: Some Real Life Examples
• Inadequate sampling:
 The quantity of validation samples are the same number as
routine production samples
 The samples are not statistically valid
 The sampling details are not specified in the validation
protocol (sample size, location, sample container, etc.)
• Inadequate testing:
 Validation samples are pooled although validation protocol
requires individual testing
 Cleaning validation samples are not tested for all active materials
and residual cleaning agents
 Test method used for testing of validation samples is not
developed / validated.
Failure to Record Key Information
During Validation
• There is no documented evidence within the
validation to support the validation parameters, for
 Actual machine speed
 Actual mixer speed
 Actual water temperature
• There is no direct audit trail to support the
validation work, for example:
 No cross reference to measuring devices
 Measuring devices are not calibrated
 Raw data is missing
 A protocol or report is missing.
Inappropriate Review/Sign off
(Some Real life Examples)
• The review of validation data is sometimes poor:
 Deviations from the validation protocol are not noticed
 Validation results do not meet acceptance criteria but no
comment is made
• Examples of Deviations from Validation Protocol:
 Machine running speed only 2/3 of speed required within
protocol, but signed off with no comments
 two validation batches instead of three that were required
in the protocol, but signed off with no comment
 One acceptance criteria required the equipment to be
visually clean. This was not met – but some trickery words
used to justify why this was ok.
Inadequate Conclusion and
Sign Off
• There is no clear statement or conclusion in the
validation report to indicate the status - such as “the
process for product X is considered validated”
• Work is not performed in sequence, or work is not
signed off in a timely manner
 PQ commenced before IQ signed off
 Work performed but not signed off for months (or years !)
• Make sure the routine batch
parameters actually reflect your
validation parameters !
 Validated rinse time for cleaning vessel = 30 minutes
 Routine Production rinse time 20 minutes !!.
What Happens After
• Do clean room operators change the clean room air pressure?
– definitely not as they should not have access
• Do process operators change the granulation blending time?
– highly unlikely because of:
 Pre-set Programmable Logic Controller (PLC)
 Requirement to record actual value in batch documentation
 Operators generally understand the consequences of not mixing for
long enough
• Do operators/technicians change equipment parameters such as
filling/Packaging line speed, washing machine temperature/time,
heat sealing temperature/time?
– unfortunately they do !!!
• Validation is simple if planned properly
• Validation does not always require masses of documentation if
performed correctly
• Validation plans/protocols need to be very clear to enable people to
follow them precisely, and for reviewers to check the key pieces of
• Once the validated conditions have been established – consider how
the equipment controls can be “locked”
• Minor deviations from the validation protocol may happen
occasionally, and need to be properly explained and justified
• The protocol sets the critical parameters and acceptance criteria.
Failure to meet these acceptance criteria must be investigated and
Thank You
Any Questions