The new Process Validation Guidance publication: General Principles & Practices introduces a life cycle approach to process validation. While the guidelines no longer think the use of traditional three-batch 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 life cycle can be monitored with suitable data capture
systems. Which will be be used in product release and simplification of end-product release analysis?
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 a process 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 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 Qualification 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 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 parameters, since the establishment of critical process parameters is one of the mast important pre-requisites for PQ / PV. In general, 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 validation. These are deemed “quality” or “important” parameters”.
Prospective 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 validation.
Recommended in-process controls.
· Data to support upper control limit and lower control limit.
· Validated analytical methods
· References to development studies
· Reference to previous validation, if any
· PQ/PV protocols available prior to execution.
Before reaching the conclusion that a 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 verification testing should include testing under conditions that simulate actual use. Product process qualification 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 will produce a product that meets the pre-determined specifications and quality attributes.
The SOP for Computer Equipment Validation continues to be an extremely popular document. This document leads you through the validation process, from the URS to the final P2Q.
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The Risk and Part 11 Validation Risk Assessment (VRA) protocol is becoming the most important document in the validation train. The VRA reassures the regulators that you have looked at specific equipment functionality and considered the appropriate level of validation that is required. You have also considered various aspects of its use and the implications of any malfunctions. From the results of this exercise the scope of all validation activity can and must be justified. This is a robust and simple to execute document, one that will lead you through the process and deliver a result that can be used as the foundation for your validation activities.
This VRA now includes the assessment table for categorizing and documenting the new 21 CFR Part 11 guidance ruling on what predicate data must be stored in a Part compliant system, along with the new broadsheet to establish your new database of part 11 records. (now mandatory).
Equipment combined IQ/OQ/PQ Protocol.
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. It is interactive, easy to use and
suitable for all mixes of equipment with and without software.
The IQ section establishes documented verification that key aspects of the equipment adhere to approved design intentions and that 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 documentary evidence to demonstrate this. The PQ section gives documented verification that the equipment performance in its normal operating environment is consistently exactly as specified in the URS.