003 Qualification and Validation an Overview1

7/30/2019 003 Qualification and Validation an Overview1

1/45

Qualification and

Validation

An Overview


2/45

Contents

Training Objectives

References

Qualification and Validation Definitions

Order of Q and V Activities Validation Responsibilities

Important Validation Considerations

Basic Checking of Validation Documentation Revalidation

Typical Validation Errors

Conclusion


3/45

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.


4/45

References (1)

References EU GMP volume 4Annexe 15 Qualification & Validation

Qualification: Action of proving that any EQUIPMENT

works correctly and actually leads to the expectedresults. The word Validation is sometimes widened toincorporate the concept of qualification

Validation: Action of proving, in accordance with the

principles of GMPs, that any PROCEDURE, PROCESS,MATERIAL, ACTIVITYorSYSTEMactually leads to theexpected results


5/45

References (2)

References EU GMP volume 4 (1997)Chapter 5 Production, Validation : 5.225.24

When any new manufacturing formula or method of preparation isadopted (after validation), steps should be taken to demonstrate its

suitability for routine processing. The defined process, using thematerials and equipment specified, should be shown to yield aproduct consistently of the required quality

Significant amendments to the manufacturing process, includingany 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 criticalrevalidation to ensure that they remain capable of achieving theintended results.


6/45

Qualification and Validationdefinitions (1)

Qualification

Identification of particular attributes of equipment, utilities orprocesses related to the performance of a particular function, suchas design (DQ), Installation (IQ) or Operation (OQ) and the

allocation of certain limits or restrictions to those attributes andfinally, the measurement of those attributes in those ranges forthose functions, such as performance (PQ)

Validation

Documented evidence that the item under consideration does whatit purports to do. Validation includes but is not limited to:Manufacturing processes, cleaning procedures, ComputerizedSystems, facilities, utilities and analytical methods.


7/45

Qualification and Validationdefinitions (2)

So let us simplify these definitions by the following practicalfacts:

The term Qualification tends to get used when discussingpersonnel , equipment and utilities (e.g. filling machines,

laboratory equipment, nitrogen systems)

The term Validation tends to get used when discussingmethods 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 validatedwhen all phases of the IQ, OQ, and PQ are completed.


8/45

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 asongoing commercial production

Retrospective (not recommended)

Validation of a Process already in use based uponaccumulated historical datas conformance topredetermined acceptance criteria. Use of RetrospectiveValidation is restricted to APIs under limited circumstanceswithout significant changes.


9/45

Order of Q and V Activities (1)

There are distinct phases that relate to Qualification and these take place inthe following order - using equipment as an example:

Design Qualification (DQ) ensures the critical design requirements havebeen met during equipment construction (e.g. grade of stainless steelspecified)

Installation Qualification (IQ) ensures that the equipment has been installedcorrectly (e.g. correctly electrical wiring, piping etc versus approveddrawings)

Operational Qualification (OQ) ensures that the equipment can perform thebasic operations across its operating range (e.g. motors operate acrossdefined speed range)

Performance Qualification (PQ) ensures that an operation, when carried outversus a defined protocol, will consistently perform its intended function tomeet pre-determined acceptance criteria.


10/45


The following Q and V documentation is normally generated

Qualification/Validation Plan that sets out the overall plan of thequalification or validation, and includes responsibilities, number ofbatches etc

Qualification/Validation Protocol that details the work that mustbe performed for each batch/run, the tests to be performed, andclearly shows the acceptance criteria

Qualification/Validation Report that documents the obtainedresults, and assesses them versus the acceptance criteria

Qualification/Validation Summary Report this documentsummarises the overall validation, and provides a conclusion aboutthe validation status.


11/45


It is essential that Qualification and Validation are performed in thecorrect order within the site otherwise the work will be invalid

If we consider a new product as an example, we need to ensurethat key equipment, utilities, computer systems are

qualified/validated prior to trying to validate our product

In addition, there is no point in QC testing the validation samples ofthe new product if they have not qualified their laboratoryequipment nor validated their QC testing method

This is shown diagrammatically on the following slide, indicating theactivities that are pre-requisites to process validation.


12/45


Manufacturing Quality ControlDepartment Department

Facilities and UtilitiesQualification IncludingAssociated Computer

System validation(CSV)

Quality ControlEquipment

Qualification Including

Associated CSV

Processing EquipmentQualification Including

Associated CSV

QC Test MethodsValidation

Process Validation and Cleaning Validation


13/45

Qualification: DQ, IQ, OQ, PQ

Organisation Validation

Conception Qualification

Conclusion Validation

Performance Qualification

Operational Qualification

Installation Qualification

Final ValidationReport

PerformanceQualification Report

OperationalQualification Report

InstallationQualification Report

ConceptionQualification Report


14/45

Qualification: IQ, OQ, PQ (1)

IQ- Each element of the system is: adequately installed,

in conformity with user needs, supplier technical specificationsand the regulatory requirements

Protocol

description of the system to be validated

Technical verification tests (individual component, criticalparameters, control and functioning systems, systemenvironment, power, and utilities, accessibility / material flow,safety)

documentation checking.


15/45


OQ- Each element of the system workswithin 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).


16/45


PQ - The system or the product processwill regularly produce the expected resultswithin the predefined limits

Protocol :

verification of the documents of validation achieved andapproved

verification of the presence of all organisational procedures,operational documents and training documents

verification tests for the general process during a determinedperiod or on defined batches and acceptance criteria.


17/45

Validation Responsibility (1)

Site validation activities need to be well coordinated to ensure theyare performed in a suitable and timely manner

The validation work needs to include the appropriate cross-functional expertise from the planning stage

A cross-functional Site Validation Forum may well exist,

To publish Site Validation Master Plan To generate validation SOPs 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 anddocumenting their validation work within their area using theapproved site systems, SOPs, and templates

QA are responsible for final approval of the validation plans,protocols, and reports.


18/45


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 qualificationand validation (e.g. inventory list)

Qualification and validation status and history of eachsystem or equipment unit

Site Qualification and Validation Plan (See next slide)


19/45


A site qualification and validation master planthat includes, but is not limited to:responsibilities for Q&V and organizational

structure for validation activities

definition of terms used in the site qualificationand validation master plan

methodology and/or procedures that govern thequalification and validation master plan

identification of revalidation or requalificationrequirements, the change control process andevidence that will maintain validationdocumentation in a current state of control.


20/45

Important Process Validation

Considerations (1)

Process Validation is not to be used as process developmentor 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 orinconsistent 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 goodstatistics and be designed to ensure that quality is consistentthroughout the batch.


21/45

Important Process Validation

Considerations (2)

A minimum of three consecutive validationbatches are normally used to consider aprocess validated

All deviations from the validation protocolneed to be fully justified, and approved byQuality Assurance

Process Validation batches are normallyplaced on the stability testing program.


22/45


23/45

Basic Checking of ValidationDocumentation (2)

Look for examples of the following generaldocument 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 anddates ?

Do the results make common sense ?

Do the dates make sense ? Is there a trace to the raw data, measuring equipment,

calibration certificates etc.


24/45

Basic Checking of Validation

Documentation (3)

Ensure that you start by reviewing theapproved validation plans and protocolsIdentify precisely what was being planned:

Does validation mimic production process?

How many batches/runs? (normally minimum 3 consecutivebatches) 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,

temperature) What are the acceptance criteria? (e.g. 30 minutes, 25

30oC)Are batches being put onto stability testing program?


25/45


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

status?


26/45


Documentation (5) A useful check for an established process is to check the

actual process (reality) versus the validation documentationand the submitted registration dossier

This will identify whether the actual process still matches theone that has been validated and registered

For the chosen product, compare in detail the following threekey 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 thechange control documents to understand why there is adifference.


27/45

Revalidation

Changes to processes must be handled via change control system

Changes must be assessed both for their impact on the registrationdossier 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 whenconsidered in isolation, numerous minor changes may cumulativelyimpact 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 changesthat may have an impact on the status of process validation.


28/45

Typical Validation Pitfalls

The next few slides will cover some of the mostfrequent pitfalls noted during review of validationdocumentation

We will consider the generalities of validation inthe following distinct phasesValidation planningValidation protocols

Sampling and TestingDocumentingReview and Sign offWhat happens after validation


29/45

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 validationactivities

The validation activities nearly always take longer andutilise more resource than originally thought

Validation activities are therefore on many occasionsunder resourced

Each validation does not have an identified owner todrive the process (organisation)

Major reason : Lack of realistic validation planning?


30/45

Validation Planning (1)

In many cases validation protocols:

do not embrace all of the validation requirements are too complicated for people to follow (toowordy) 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 thetechnical aspects of a process are ok, but the validationfailed 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.


31/45

Validation Planning (2)

There is sometimes no clear indication of all the identified criticalprocess parameters mixing speed mixing time water temperature

Operating conditions are not specified sometimes because theprocess 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 NOTuse validation as Process Development Acceptance Criteria are not clearly defined so people do not know the

parameters to work within.


32/45

Validation Planning: Process

validation Method The validation protocol should be prepared by the technical

personnel responsible for carrying out the validation exercise. Itshould state the way in which the process is to be operated, identifythe controls to be exerted, specify the variables to be monitored,state the samples to be taken for subsequent testing, specify theproduct performance characteristics/attributes to be monitored

along with acceptable limits and refer to the test methods to beused

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.


33/45

Critical Process Parameters:

Example process Mixing of Solids

Equipment: Blade mixers, Free fall mixers

Variables of Process: type, shape and position of mixingblades, 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 withlubricant)

Control of the Process variables or IPC of the process step:Time; rate/rpm; power consumption; temperature

Control of the characteristics of the Product: Contentuniformity; particles size analysis; disintegration time;dissolution rate.


34/45

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 atinlet/outlet; spraying rate; material temperature; filter shaking period;drying time; filter bags; climatic conditions

Product properties affected by these variables: particles sizedistribution; bulk/tapped density; flow properties; hardness;homogeneity; residual moisture

Control of the Process variables or IPC of the process step: airflowmeter; 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; particlesize analysis; bulk/tapped density; flow properties; granule friability;yield; disintegration time.


35/45

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-compressionpressure; compression pressure; percent hopper fill; feedingrate/speed of feeder

Product properties affected by these variables: weight; weightdistribution; 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 speedcontrol; 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.


36/45

Critical Process Parameters:Example process Steam Sterilization

Equipment:Autoclave Variables of Process: Type, size, temperature,

pressure, cycle time, load and arrangement ofload, distribution and penetration of heat, cooling

system Product properties affected by these variables:

Sterility 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).


37/45

Critical Process Parameters:Example process Lyophilising

Equipment: Freeze-drier

Variables of Process: Type; capacity; temperature of shelf / product/condenser; distribution of temperature; time; vacuum; closingmechanism (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 forreconstitution; moisture content; head space pressure; sterility test(where applicable).


38/45

Validation Planning Worse Case

scenarios The earlier part of the Qualification process should help you

to better understand your equipment and processes, whichwill help you to identify any potential weaknesses

Early Qualification work does not always consider thepotential worse case scenarios:

What happens if the power fails to the mixer? What happens if the water temperature goes above 30 degrees

centigrade?

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 saveexpensive product when there are problems when runninglive product.


39/45

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.


40/45

Failure to Record Key Information

During Validation

There is no documented evidence within thevalidation to support the validation parameters, forexample:Actual machine speed

Actual mixer speedActual water temperature

There is no direct audit trail to support thevalidation work, for example:No cross reference to measuring devicesMeasuring devices are not calibratedRaw data is missingA protocol or report is missing.


41/45

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 metbut some trickery wordsused to justify why this was ok.


42/45

Inadequate Conclusion and

Sign Off There is no clear statement or conclusion in the

validation report to indicate the status - such as theprocess for product X is considered validated

Work is not performed in sequence, or work is notsigned 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 runningparameters actually reflect your process

validation parameters ! Validated rinse time for cleaning vessel = 30 minutes Routine Production rinse time 20 minutes !!.


43/45

What Happens After

Validation? 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 asfilling/Packaging line speed, washing machine temperature/time,heat sealing temperature/time? unfortunately they do !!!


44/45

Conclusion

Validation is simple if planned properly

Validation does not always require masses of documentation ifperformed correctly

Validation plans/protocols need to be very clear to enable people tofollow them precisely, and for reviewers to check the key pieces of

data

Once the validated conditions have been established consider howthe equipment controls can belocked

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 anddocumented.


45/45

Thank You

Any Questions

Documents

003 Qualification and Validation an Overview1