003 Qualification and Validation An Overview1
003 Qualification and Validation An Overview1
003 Qualification and Validation An Overview1
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
Training Objectives
To provide a high level introduction to the principles of
References (1)
References EU GMP volume 4
Annexe 15 Qualification & Validation
works correctly and actually leads to the expected results. The word Validation is sometimes widened to incorporate the concept of qualification
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.
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.
personnel , equipment and utilities (e.g. filling machines, laboratory equipment, nitrogen systems) methods and processes (e.g. manufacturing, packaging, cleaning, sterilization and computer systems), and can sometimes include Qualification activities when all phases of the IQ, OQ, and PQ are completed.
accumulated historical datas conformance to predetermined acceptance criteria. Use of Retrospective Validation is restricted to APIs under limited circumstances without significant changes.
Installation Qualification
Installation Qualification Report
Operational Qualification
Operational Qualification Report
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, safety) documentation checking.
(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).
approved 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.
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 and documenting their validation work within their area using the approved site systems, SOPs, and templates QA are responsible for final approval of the validation plans, protocols, and reports.
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.
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.
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.
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.
batches) 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?
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?
Revalidation
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.
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.
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.
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 lubricant) 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.
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.
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:
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.
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.
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.
running process
Validated rinse time for cleaning vessel = 30 minutes Routine Production rinse time 20 minutes !!.
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 !!!
Conclusion
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 data 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 documented.
Thank You
Any Questions