The updated Guidance for Industry on Process Validation: 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
Could the way forward be by considering process validation as a continuing activity that constantly verifies the process compliance?
Could this be achieved by continuous
monitoring of process critical parameters by the use of suitable data capture
systems and of the subsequent use of this data in product release and thus
minimizing use of end-product release analysis?
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 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.
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Why does something as simple as a spreadsheet figure in so many regulatory citations? Good question; and at times a difficult one to answer. When you ask a group of compliance personnel the same question you will be informed that Excel cannot be validated because it does not seal the original copy (of the spreadsheet), allows the original to be modified and has an audit trail that can be disabled. All true, but none of these problems interfere with your ability to validate that the spreadsheet is fit for purpose. They only preclude you from using the spread sheet as a compliant repository for any data that has to be store in compliance with 21 CFR Part 11.
If the spreadsheet is signed off and dated by the user, their supervisor and QA, it becomes regulatory acceptable data stored in hardcopy, and Part 11 does not apply.
After numerous requests for this, we have launched our brand new SOP for Spreadsheet Creation to cover these and other known target points that the regulators consistently hone into as soon as they find that spreadsheets are being used. Use this Spreadsheet Creation SOP to ensure that you create spreadsheets that are validatable. Then use our spreadsheet validation pack to validate them.
SOP for Spreadsheet Creation. -- $125.00
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. 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.
SOP Equipment Validation.
Purchase your copy now at Special Price of $22.00.
Validation Risk Assessment (Issue11.) -- $125.00
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).
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.
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.