What is a Validation Protocol?
It is a central component of the large interdependent process of drug manufacturing that extends from plant design to the actual manufacturing process. These protocols must be generated and executed in all validation qualification phases of the facility development, maintenance and processes in order to ensure industry regulatory requirements are met. Validation protocols have to be approved and should contain predetermined acceptance criteria prior to execution.
How is this Document Developed?
There are many different qualification models which can be used as long as they have previously been justified to an auditor. These systems are generally based on a pre-established system:
- URS establishes the acceptance criteria for PQ
-FRS establishes the acceptance criteria for OQ
-Eng documents establish the acceptance criteria for IQ
Figure 1: Example of an Overall Validation Approach
The general sequence used for validation is:
-Design Qualification
-Installation Qualification
-Operational Qualification
-Performance Qualification for Facilities
-Performance Qualification for Equipment:
-The validation process for equipment is preceded by a commissioning process. This will include a Factory Acceptance Test which is carried out on vendor's site to ensure the equipment purchased meets the agreed requirements.
-Further testing is then performed once equipment is delivered as part of Site Acceptance Test
-Validation of the process can be carried out using a process validation protocol (post equipment qualification). This often involves successful execution of three consecutive batches in accordance with pre-determined acceptance criteria.
-Cleaning validation is carried out in accordance with a cleaning validation protocol and ensures no product cross contamination or carryover of cleaning agents occurs.
Use of Grouping in a Validation Protocol
Some of the areas mentioned above can be grouped to avoid unnecessary duplication of work. For example, SAT execution documents may be leveraged into OQ document. Furthermore, the IQ and OQ document may be merged into an IOQ document. If this strategy is employed it should be clearly stated in the Validation Master Plan (VMP).
What is the function of this Document?
The general function of each type of validation protocols is provided below. These definitions are in accordance with site Validation Master Plan and applicable regulatory requirements:
-The Design Qualification Protocol documents the source and location of design information to be used in developing the facility.
-The Installation Qualification Protocol ensures equipment is installed in accordance with engineering documentation such as P&IDs. It also includes utility measurements taken at equipment location and a log of calibration data.
-The Operational Qualification Protocol ensures that the equipment does what it is supposed to do. It provides information for testing each individual running aspect of equipment. It also includes SOP verification and alarm/interlock verification.
-Performance qualification ensures that the system meets design criteria and operates according to requirements. This includes things like ensuring all vessels reach adequate temperature profiles in all areas of the SIP vessel as measured by thermocouples.
-The Process Validation Protocol determines whether or not the process produces drugs in consistent and reliable manner. This is generally measured by obtaining three consecutive successful batches in accordance with the protocol. Maximum hold times should also be challenged here.
-The Cleaning Validation Protocol proves through rinse/ swab analysis that there is no cross contamination or carryover. Maximum clean and dirty hold times will be challenged here.
Validation Protocol Maintenance
After the initial qualification is completed, validation is carried out as part of the site validation life cycle. This involves periodic validation and control/assessment in the event of any changes which can make re-validation necessary. The validation life-cycle approach ensures systems continually remain in a validated state.
In a typical large project, validation protocol execution contributes 25% but accounts for more than 60% of the project man-hours. As stated above, the validation protocol is a large proportion of the interdependent manufacturing process and must be generated at all phases. For this reason it makes sense to put extra time, resources and effort into developing high standard protocols. This can prevent complications and spiraling man-hours later in the project.
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