The final laboratory step of this stage is the demonstration of the process at an ~100-L production scale. Draft batch records in Diosynth Biotechnology format document this production. After this demonstration is complete, including testing the product by appropriate analytical methods, a process description is prepared. This document provides a list of raw materials used, the sequence of operations for the process, provisional operating ranges for process parameters, in-process controls, and provisional acceptance criteria for the product. Preliminary stability information on API is generated to support the suitability of the research batch for the intended use. Packaging materials are investigated.

Analytical methods that test product safety, identity, strength, purity, or quality are developed, appropriately evaluated, and used to test product from small-scale and research batches during Stage II. The method evaluations are performed under protocols that are reviewed by the quality department. These methods are used to establish provisional specifications for the product. On a case-by-case basis, Diosynth develops/transfers in methods designed to test the potency of the product. An interim reference material is made available before method evaluation begins.

Raw materials, starting materials, process consumables, and other process aids are specified for the process during this stage. Compendial raw materials are selected unless compelling process reasons exist for the use of non-compendial materials. Raw materials, starting materials, process consumables and other process aids used in this stage and subsequent stages are selected, as applicable, from the standard list of approved raw materials at Diosynth. These materials are procured from the company's approved vendor list. If a necessary material at this stage is available only from a vendor not on the list, that vendor is added to the list when the quality department approves the vendor.

Stage III: Development The objective of this stage is to implement the process developed in Stage II at manufacturing scale. The starting point for this stage is the research summary report.

Evaluation of analytical methods in anticipation of method validation continues during this stage. The method evaluations are performed under protocols that are reviewed by the quality department. Where in-process control and test results dictate manufacturing decisions for the batch, appropriate test methods are developed and evaluated by the same standards used for product release methods. Approved written analytical methods are used for testing product from this stage. Provisional product specifications and a reference standard are established before API manufacturing begins.

Critical attributes of raw materials, API starting materials, process consumables, process intermediates, and other process aids are identified, and appropriate methods are developed to test for these attributes. In some instances, the suitability of a raw material may be determined in small-scale reactions — use testing — rather than by analytical testing alone.

At the end of this stage, development batches of the product are produced. Batch records are prepared by process development staff and reviewed and approved by the appropriate operations and quality assurance personnel. The batch records in this stage are flexible and consistent with assuring the quality of the product. SOPs specific for the process are prepared and approved and staff training is completed. Raw materials and supplies are procured, tested, and released by quality assurance. Testing methods for intermediate release are developed where appropriate.

The effectiveness of cleaning procedures is demonstrated on process equipment. The demonstration includes, at a minimum, swab, visual, and rinse data. These data are generated at the beginning of the manufacturing campaign(s) for this stage and are summarized in the manufacturing campaign summary report. The cleaning procedures are finalized so that the equipment is suitable for production of material for human use. Sterilization cycles and glasswash cleaning cycles are fully qualified prior to use in the manufacture of API for use in humans.