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.
A research technical summary report is prepared at the end of this stage. The report describes the experimental justification
for the process description, with references to original data, and a preliminary rationale for each unit operation and analytical
methodology used. The report also outlines additional work that needs to be performed to complete the process and product
characterization and contains a process flow diagram. Additionally, a Process Transfer Package (PTP) is generated which consists
of the following five components: a detailed process description (DPD), process flow diagram (PFD), bill of materials (BOM),
equipment list (EQL) and sampling plan (SP). The PTP fully defines a process as it is to be manufactured under cGMP conditions
at a specified scale at Diosynth Biotechnology facilities. It is a lifecycle document that fully describes scale-dependent
and scale-independent process parameters.
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.