The process description is revised to reflect the refinement of the process during this stage. The research technical summary report from Stage II is appended to justify the process and testing changes that have been implemented during this stage. The report references original data and also outlines remaining work that needs to be performed to complete the process and product characterization, as well as additional work identified during this stage.

The end of this stage is reached when the quality assurance department has dispositioned product from the manufacturing batches. Additionally, the appended research technical summary report, the revised process description, and the description of additional work needed to complete the process and product characterization are generated, and the PTP is updated.

Stage IV: Verification The objective of this stage is to verify the choices made during the previous stages and to demonstrate the consistency of the process and the methods used to test the product. The starting point is the development report from Stage III, supplemented with the approved batch records from the pilot manufacturing campaign.

Scale-up studies are performed if the Stage IV manufacturing scale is greater than the Stage III manufacturing scale. These scale-up studies evaluate the relevance of Stage III operating parameters to the larger-scale equipment. Performing at least one engineering batch using draft batch records provides additional assurance that the API manufactured meets its predefined specifications and presents an opportunity to correct deficiencies in equipment performance, manufacturing instructions, or operator training. The results of these studies are described in a scale-up summary report.

Production of verification batches occurs in a controlled environment using appropriate production and control procedures to ensure the quality of the drug substance. Personnel trained in the specific unit operations perform all manufacturing and testing activities, actively assisted by process development personnel as required. Each batch is approved or rejected by quality assurance, applying appropriate GMP concepts.

A stability study of the API and selected intermediates is initiated. The design of the stability study is appropriate for the intended use of the API. Expiration or retest dating is established for product from the verification batches.

At the end of this stage, the process description is revised to reflect the refinement and additional characterization of the process. The process is controlled under critical change control procedures and is not subject to change after the end of Stage IV. The development report is appended to justify the process as it is defined in the process description and describes any additional work needed to begin commercial manufacturing. The report forms the basis for the commercial regulatory applications. The report also identifies unsuccessful approaches to developing the manufacturing process. Additionally, the PTP is updated to reflect any changes that might have been made during this stage.

Diosynth prepares the Project Master Plan (PMP). The PMP describes the general plan for process and cleaning validation for the project. Preparation of the PMP components is the responsibility of the appropriate validation departments and is executed during Stage V.

Stage V: ValidationThe objective of this stage is to demonstrate that the manufacturing process, when executed within the constraints of specified process parameters, yields a product that reliably and reproducibly meets its predetermined acceptance criteria. The PMP is used to direct this demonstration.

The PMP has two components: process validation and cleaning validation. Process validation is performed under protocol during a minimum of three consecutive successful manufacturing batches (validation batches) at commercial-manufacturing scale. Cleaning validation is performed concurrently under protocol for three consecutive manufacturing batches, and it may be continued to monitor the effect of routine production on the suitability of equipment cleaning procedures. Execution of the protocol is typically the responsibility of the operations department.

Each protocol describes the acceptable operating limits of the process and equipment that, if met, ensure that the product will meet its predefined quality attributes. Execution of the process validation protocol demonstrates that the equipment can direct and control the process within the established limits. Execution of the protocol also demonstrates that the process, as performed by operations personnel, yields a product that meets its predetermined specifications. For cleaning validation, execution of the protocol demonstrates that the cleaning methods ensure contamination and carryover are maintained below predetermined acceptable levels.

After the validation protocol has been executed, the respective validation department prepares a validation summary report. This report is reviewed and approved by quality assurance. The operations department assumes responsibility for routine production. Process performance is monitored and additional data are gathered to monitor process trends and to provide data on resin and membrane lifetimes.