Process Validation Guidance & compliance publication: General Principles & Practices introduces a life cycle approach to process verification. While the guidelines no longer think the use of traditional three-batch process validation appropriate, it does not stipulate the number of validation batches appropriate for a prospective validation protocol, nor does it provide a rationale to determine it. This could; and has, left many manufacturers in a dilemma
The way forward must be by utilizing a continuing activity that constantly verifies process compliance?
The secret to success is going to be in selecting the single parameter robust enough to be used as yard stick for the process efficacy. Once this can be achieved preventative measures will become routine practice as operators use predictive analysis to execute routine maintenance - before product drifts out production tolerances. The whole process validation even for life cycle evaluation can be monitored with suitable data capture systems. Which will be be used in product release and simplification of end-product release analysis and process validation.
PC systems use statistics to monitor the quality of products
created by a process and send alerts when something abnormal is detected. Control charts are pretty good at showing
when process validation is behaving normally and are usually the first step in
R2R control involves the use of measurement data to optimize
a particular process step or set of steps
This is an example a feedback control system. R2R control systems generally start off
controlling a single process validation task, but can be grown to achieve factory-wide control
FDC systems monitor the performance of manufacturing
equipment during operation and detect events that might affect the quality of
the product. When an issue is detected a
warning message is raised.
APC brings together all of these pieces of software. In a fully realized APC system, each
component (SPC, R2R, FDC) can interact with the others to form a comprehensive
factory control system.
For Process Validation to be successfully executed then critical quality characteristics and critical process parameters must be derived from research and development scale-up, or existing commercial production history. If these parameters do not exist, it is necessary to establish them through either designed experiments or planned review of commercial history prior to the start of process validation.
Although often combined in the same protocol, the purposes of PQ and PV for products differ. PQ starts to address the ruggedness of each of the process steps While PV puts all the parts together to verify that the process can consistently and accurately be replicated.
The performance of certain support processes can be proven for multiple products without having any product involved. Examples of these include sterilization of stoppers and glassware, aseptic processes, and cleaning validation. The specifics of these are discussed in other chapters.
This section will briefly discuss the determination of critical process validation parameters, since the establishment of these critical process parameters is one of the most important requirements for successful process validation. The primary objective of each unit operation is identified as it relates to the critical quality characteristics of the product. Acceptance criteria are defined for the critical quality characteristics based on the allowable variation in the process step, relevant to its location in the process. That is, steps become more important as the process moves closer to the bulk drug substance and drug product since there are fewer opportunities to improve product quality.
A risk assessment, based on the margin between the normal operating range (NOR) and the proven acceptable range (PAR), should be performed to evaluate the likelihood that a parameter will cause batch failure. If the parameter is deemed to have a high likelihood to cause hatch failure and it is a difficult parameter to control, it is deemed critical. In other words, the normal operating range is close to the proven acceptable range. If the risk is low because the proven acceptable range is relatively large and the parameter is easily controlled, the parameter is still of interest, hut it does not need to be evaluated during process validation. These are deemed “quality” or “important” parameters”.
Prospective process validation involves manufacturing, sampling, and testing validation batches according to a pre-approved test protocol Validation batches are not released until all batches specified in the protocol have been manufactured, all tests have been executed, all results have been reviewed, deviations addressed, all acceptance criteria are met, test reports have been written and approved and all change requests have been closed. The system owner must justify any exception to the above conditions and the justifications must he reviewed and approved by QA.
The following is a checklist of knowledge that must be available prior to starting PQ and/or PV:
· Critical Characteristics & associated limits must be established
· Critical parameters & associated limits must be established
· Rationale for non-critical process parameters
· Process description and process drawings
· Equipment and materials requirements
· Proposed hatch records and standard operating procedures
Initialization of cleaning process validation.
Recommended in-process validation of controls.
· Data to support upper control limit and lower control limit.
· Validated analytical methods
· References to development studies
· Reference to previous process validation, if any
· PQ/PV protocols available prior to execution.
Before reaching the conclusion that process validation has been successfully completed, it is necessary to demonstrate that the specified process has not adversely affected the finished product. Where possible, product process validation, verification testing should include testing under conditions that simulate actual use. Product process validation testing should be conducted using product manufactured from the same type of production equipment, methods and procedures that will be used for routine production. Otherwise, the qualified product may not be representative of production units and cannot be used as evidence that the manufacturing process validation will produce a product that meets the pre-determined specifications and quality attributes.
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Equipment combined IQ/OQ/PQ Protocol. $159.00
This combination protocol has been produced in response to several
hundred reader suggestions we received in our ‘Suggestions Section’. It
has been carefully designed to make it the preferred choice for Process
and Laboratory stand alone equipment and associated standard operating procedures. The associated Validation Master Plan is interactive, easy to use and
suitable for all mixes of equipment with and without software.
The IQ section establishes documented verification that all validation Online executables are catered for and that key aspects of the equipment adhere to approved design intentions and the recommendations of the manufacturer have been suitably considered. The OQ section establishes that there is documented verification that the installed system functions as specified and that there is sufficient documented process validation executables to demonstrate this. The PQ section develops documented evidence that all the requirements specified in your corporate validation 4U manual have been verified as operating consistently and exactly as specified in the URS.
The Process Validation or Qualification is the culmination of the validation process. The protocol is used in conjunction with the SOP for the process, to run three batches through the process being qualified and verify that the process consistently produces product to within the process specified tolerances. The results of the process must be recorded and reviewed with a view to ensuring that the deviances (within permitted tolerances) that exist are random and not a trend that could lead to out of specification produce being produced.
This Validation 4U, Risk & Requirements Plan (VrrP) is one document designed specifically to replace three. The contents of the three original documents were completely revised and edited into a more compact and interactive format. This new format will make a significant difference to the man hours required to produce and execute these standard operating practice process validation executables. There will also be a very noticeable reduction in the time required for the reviewing and approving tasks. This new document titled the VrrP replaces the VP, VRA & URS and now compliments our equally new 4Q Protocol, which integrates the DQ/IQ/OQ/PQ into one document.
This is an essential step forward for companies seeking to reduce validation 4U costs whilst remaining compliant with their Corporate Validation Manual.
4Q Equipment Validation 4U Protocol (4Q-Equip) has been designed specifically to replace four standard protocols. By taking the contents of the four protocol and carefully weaving them into one notably easy to use protocol, we have made a significant advance in the task of streamlining process validation Online executables documentation and associated standard operating procedures, by reducing protocol numbers by close to 75%. The new bang up to date 4Q protocol replaces the DQ, IQ, OQ & PQ and now compliments our equally new VrrP Protocol. By integrating the old style DQ/IQ/OQ/PQ into one 4Q document there will be enormous savings in man hours in the authoring, reviewing, updating and approving tasks.
For everyone's convenience, the Corporate Validation 4U Manual template is written in written in word.