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The objective of the feasibility stage is to determine whether the proposed biotechnological process can be executed.
The fundamental goal of technology transfer is to implement a process in a different place, whether from preclinical to cGMP manufacturing, between two sites, or from one company to another. The reasons to transfer a process include considerations of capacity, scale, facility availability and compliance, and production economics.
Technology transfer is always challenging, even in organizations with years of experience in cGMP manufacturing, and if care is not taken to ensure meticulous planning and execution, it can be wrought with unpleasant and costly surprises. Further, a thorough understanding of the manufacturing requirements throughout the development pathway — from research, through clinical development, to commercial manufacturing — is fundamental to successful biopharmaceutical drug commercialization. Diosynth Biotechnology is dedicated to delivering products and services with the highest level of quality. It is with that in mind that the company developed standards in the form of a Standard Operating Procedure (SOP)1 to clearly define all requirements from early process development through commercial manufacturing of recombinant proteins. Diosynth has implemented this product development process SOP to help ensure that a customer's product enters the company's system at the most appropriate stage.
The process is divided into five stages that serve as guidelines to streamline process transfer and development. It is a uniform approach to cGMP manufacturing and quality operations that ensures seamless production within and between the manufacturing sites in Research Triangle Park, North Carolina and Oss, The Netherlands. This approach also helps Diosynth Biotechnology and its customers in evaluating, developing, and executing high-quality, efficient manufacturing processes by ensuring that the most appropriate program and development stage is assigned to each product. This not only saves up-front time but also helps avoid the costlier delays in redevelopment later in the clinical trajectory.
While every project is unique, a formalized approach to process development allows rapid progress during preclinical and early clinical testing. To ensure that each program and product enters Diosynth's system at the optimal stage, process development and technical services specialists initially evaluate the process fundamentals, regardless of whether the product is in preclinical development or approved for the commercial market. If the process and analytical methods are robust, transfer to cGMP manufacturing areas can occur rapidly, though process and method refinement are often requested by the customer or are required to fit the customer's process into the company's facility and equipment. By gaining familiarity with the molecule and the process, process development scientists are well prepared to support further refinement and development during the development trajectory, including support of validation through small-scale modeling and experimentation.
The product development process is divided into five stages.
The objective of this stage is to determine whether the proposed biotechnological process can be executed.
Marketing and sales (M&S) is typically the first department to be in contact with a potential sponsor concerning a proposed program. The M&S representative records information presented by the potential sponsor and presents it to the Diosynth Biotechnology Global Portfolio Review Board. This group reviews the information and determines whether the proposed program conforms to the company business model. If this group approves the program, the process development, operations and quality/regulatory departments review the information and comments on the technical feasibility of the work proposed. A resource estimate and timeline are provided. The process development staff also evaluates, with environmental, health and safety personnel, the effect of the potential program on human safety and the environment.
During development of the Statement of Work (SOW), Diosynth forms a project team. Representatives from the quality, process development, and operations technical management departments and a program manager comprise the project team. The purpose of the project team is to ensure that the program is executed according to the SOW. The project team assembles the appropriate resources to execute the program on an as-needed basis as the program proceeds through the development process.
The objective of this stage is to generate a prototype manufacturing process at a laboratory scale. The starting point for research is a cell line that produces the molecule of interest.
The duration of effort in this stage depends on the extent and suitability of a sponsor's previous work. However, each process transferred to or developed at Diosynth Biotechnology is confirmed first at an ~10-L production (fermentation or cell culture) scale in the process development laboratory. During this confirmation, significant process parameters are identified and provisional operating ranges are established or confirmed.
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.
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.
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.
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.
The rationale for each unit operation is expanded to include the quantitative description of the specific impurities removed or generated by the process. Additional methods are developed and evaluated for testing API and intermediates. Characterization of product and process-related impurities are completed during this stage.
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.
The 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.
During routine commercial manufacturing, critical parameters are monitored and trended to ensure that the process is still operating in a valid manner. Reprocessing or rework is allowed at this stage if such processes are being validated under protocol or if such processes have already been validated. Reprocessing or rework requires approval of the sponsor.
Implementation of this procedure for process development and transfer enables Diosynth and its customers to use a common language to manage expectations for contracted work.
Diosynth Standard Operating Procedure SOP#80GN1327: Evaluation, Development and Execution of Manufacturing Processes at Diosynth RTP