Success with Tech Transfer
Mastering the art of moving to a CMO
By Mike Power
Contract manufacturing covers a wide landscape, from development to clinical supplies, Active Product Ingredients (APIs) to medical device components, and intermediate and final product manufacturing. So what does it take to be a successful contract manufacturer? In a nutshell, a mature and well defined technical transfer process. This article examines well-established strategies for technical transfer for contract manufacturing organizations (CMOs) and their clients.
As more and more life sciences companies look to expand their development, clinical, and manufacturing competencies through the use of CMOs, CMOs are rapidly becoming more involved in biologics development, clinical trial activities, and in some cases are handling the manufacturing of all of their life sciences clients’ intermediates and final products. Why the shift?
Life sciences companies recognize that CMOs can be truly global companies offering a variety of specialized skills and services as well as experience in dealing with local regulatory and compliance issues. CMOs in China, India, Brazil, and many European countries are leading the way in providing contract services for the life science industry. And since a CMO’s own success is determined by the success it brings to the companies it serves — increased revenue, improved efficiency and financial profitability — life sciences companies also know that CMOs have a vested interest in helping them to succeed.
The CMO’s Role in Technical Transfer
When a life sciences company engages a CMO, the CMO is customarily asked to demonstrate its ability to provide details associated with the science and technology related to the manufacture of the client’s products. In response, CMOs provide facility tours, present certifications and validations of their facility assets and equipment, and describe the training and skills of their personnel and management. However, few CMOs ever talk about their ability to manage the technical transfer of the client’s product and process definitions into the contract manufacturer’s facilities and supporting systems. Without a clear process for technical transfer, CMOs and life sciences companies alike leave themselves open to errors.
Figure 1 is a diagram that illustrates how technical transfer is initiated within a development-to-manufacturing product cycle. The underlying premise of this diagram is an emerging philosophy by the U.S., European, and Asia/Pac regulatory agencies called Quality by Design (QbD).
|Figure 1: Quality by Design Approach
Many large life science companies have struggled with difficult and time-consuming technical transfer cycles. Generally, the CMO is expected to provide quick and efficient technical transfer. So how is technical transfer effectively managed? What are considerations that streamline the technical transfer process and reduce errors associated with the process? The answer is a disciplined approach to the overall process.
Technical transfer to contract manufacturing may occur anytime within the product lifecycle. It may occur in product development, the manufacturing of clinical trial materials and scale-up for manufacturing or in the transfer of legacy systems to CMOs late in the product cycle. A Key to good, clean technical transfer is the implementation of a product and process repository or knowledge space. Within QbD is a suggestion for a centralized database with product and process information. As the product moves through its lifecycle, the centralized database is updated to contain the most current definitions for product and process, plus all of the previous definitions as history. It is from this repository that all technical transfer details and information should be derived. The product and process repository then becomes the authoritative source for information about the product and its process.
The Common Language of Technical Transfer
Technical transfer must involve a foundation of common language and understanding. This language and understanding comes in multiple sets of definitions:
- The product is a compilation of definitions describing the components needed for creation. These definitions may be drawings for medical device components, molecular diagrams for pharmaceutical and biologics products. The definition will usually be in the form of bills identifying the components of the product. Bills of material, electrical components, and intermediates may be categorized as product definitions.
- The product will have a defined process or processes required for manufacturing, packaging, labeling and shipment. These definitions may take the form of process flows, workflows, or ISA-S88 recipe structures. ISA-S88 is a structured method for sequentially diagramming a batch process, recipe or definition. The original concept for ISA-S88 was developed by a global association know as WBF (World Batch Forum) in 1995 and has become an industry standard for process definitions.
- The process definitions include bills of materials, equipment and process values that shape the process. These include bills of critical parameters as identified and set by development product process design of experiments, bills of process variables that bind the process, bills of instructions that define and sequence the process, and a bill of quality that defines test methods, and quality parameters that define and limit the process.
To increase efficiency and to reduce translation errors during technical transfer, product and process definitions should, according to QbD recommendations, share a common underlying form. At the last WBF meeting, an emerging concept of product and process definitions was discussed. The definitions were based on the underlying foundation of XML (eXtensible Markup Language) and BatchML, a derivative of XML. The next European WBF meeting in November 2008 includes a session to expand on the concept of a structured process definition in BatchML that may be either printed and included as a paper set of instructions — a batch record — or electronically interfaced to XML MES, CMS and DCS systems.
Having product and process definitions based on XML greatly enhances life sciences companies’ ability to methodically technically transfer the definitions to a CMO without errors. This means the transfer process can be completed in days instead of weeks or months. The common product definitions, defined in bills, enable product details to be interfaced to MRP (manufacturing resource planning) applications. Interfacing to MRP reduces errors generally seen in product technical transfer. Most contract manufacturers and most pharmaceutical and biologics manufacturers manually enter the bills in their MRP and/or manufacturing execution systems (MES).
XML-based definitions may be efficiently stored and maintained in the newly emerging XML databases. XML is a facilitator in achieving the overall QbD approach for a common product/process ‘knowledge space.’
Common Sense Success Factors for Technical Transfer
Since the goal for successful technical transfer is to completely and accurately transfer product and process definitions from the client to the CMO; another strategy for increasing technical transfer success is to have the development scientist work ‘hand-in-hand’ with the CMO manufacturing authority. Some CMOs have sophisticated systems and processes in place to enhance technical transfer; thus programmatic interfacing and definition transfer may be completed. However, for those contract manufacturers with reduced levels of process sophistication and applications, the QbD approach may not be achievable. In this instance, the development scientist and CMO manufacturing authority will interchange product and process using paper-based forms or spreadsheets.
The risk involved in entering product and process definitions from manual forms or spreadsheets is partially mitigated if the development scientist assists in the technical transfer process. As soon as a decision is made to use a CMO, it is appropriate to begin involving the development scientist in the technical transfer process. Some companies will pair a development scientist with a CMO manufacturing authority early in the development cycle.
|Figure 2: Graphical Approach to Process Authoring
If the client is moving a legacy product to a CMO, involving a client manufacturing engineer, a client development scientist and a CMO manufacturing authority in the technical transfer process will greatly reduce the errors and time required to complete the transfer. For legacy products, real value is achieved in creating new product and process definitions that apply the principles of common bills for products — a common structure for the process definitions (ISA-S88) — and rendering the full set of definitions in XML.
One Fortune 10 life sciences company recently completed a pilot where structured product and process definitions were generated to facilitate technical transfer between its manufacturing plants and selected contract manufacturers. Using the structured definitions based on ISA-S88 and XML, the company saw a dramatic reduction in the time in takes to complete technical transfer from 12 to 20 weeks to a range of two to three weeks.
Process Validation To Enhance Technical Transfer Success
Another factor in the success of technical transfer from a client to the contract manufacturer is the selection of a CMO that has demonstrated a process validation capability for the specific category of processes to be transferred. It is common for a development scientist to create a process in the lab that is difficult — sometimes impossible — to scale or transfer to manufacturing. If a contract manufacturer is used, it is possible the equipment and supporting systems and applications may not align well to the process design. Once the process is received by the CMO, it is imperative that a complete validation plan and protocol be written and executed by the CMO to document and validate that the process has been properly transferred and understood. Also, it is good practice to involve a client development scientist, and a client manufacturing authority in the validation plan, protocol and final report of the protocol execution. The same comprehensive approach is required in process validation as in technical transfer to manufacturing within the client site.
For those instances where legacy products are being transferred to a contract manufacturer, the product and process are thoroughly known by the client, so the client will have existing process validation protocols. These process validations will require updates to reflect the contract manufacturing equipment and process resource. The updated protocols will need to be reviewed by the client, and executed at the contract manufacturer’s site to document the understanding of the process by the contract manufacturing authority. For technical transfer of either newly developed products and processes, or legacy products and processes, the completion of process validation documents the overall accuracy of the product and process transfer.
Recently, a global Fortune 15 pharmaceutical manufacturer transferred a legacy product from a plant scheduled for closure to a contract manufacturer. The product and process definition was mature, and the client looked for a manufacturer with similar equipment and validated processes to their facilities. A clear set of product and process definitions was transferred to the CMO with good collaboration between the client manufacturing subject matter expert and the CMO manufacturing engineer. Once the technical transfer process was initiated, an ‘at scale’ process validation was completed, reviewed and approved. The CMO began to manufacture the product at scale based on the successful validation runs. The time from technical transfer to production run was 11 days. The result of the quick start-up was ‘zero impact’ on the client’s supply chain, illustrating that technical transfer of a product and process to a CMO, when done correctly, can become a strategic and financial advantage for both the CMO and the client.
Legal Considerations in Technical Transfer
There are of course legal considerations when dealing with the technical transfer of a product to a contract manufacturer, as compared to the technical transfer of a product to a client manufacturing site. For the CMO, there will be contracts outlining specific deliverables, requirements, adherence to mandated regulations, metrics and the enforcement of the contract terms. These may seem like minor details, but keep in mind that the CMO's contract serves as the legally binding ‘process’ between the client and the CMO. The business impact and client risk can be partially mitigated by the contract, and partially mitigated by the process validation of the technical transferred process.
Metrics To Evaluate Technical Transfer Success
After the transfer process is complete, how do the CMO and the client best evaluate the effectiveness of the transfer? The solution is to have measurable goals with metrics shared by both parties. Technically, the metrics for understanding the effectiveness for technical transfer of a process to a contract manufacturer are very similar to transferring a product and process to a client's internal manufacturing site. These metrics include:
- Days-to-market (after the transfer).
- Deviations encountered in the first week, first month, first six months and in first year.
- Number of deviations where a process intervention occurred
- Number of deviations involving changes to process bill structures or process parameters.
- Cost per unit.
- Number of product complaints.
- Days on Hand (DOH) awaiting disposition.
- Total cost of Quality.
Some clients round out this list with customer service metrics to provide a clear picture of the overall process on the new product supply chain.
Evaluating Success Beyond Standard Metrics
In addition to standard metrics, the success of a technical transfer of product and process to a CMO also depends on how well the transfer process worked. Following are some indicators of success:
- There is a full understanding of the product and process definitions as delivered to the CMO during technical transfer. A single source of the truth from which the product and process knowledge is derived. If the details for product and process definitions are transferred to a CMO in a haphazard and unorganized manner, the resulting product and processes transfer will most likely be unorganized leading to errors, rework, extensive transfer cycles and poor quality. Base the details for the transfer on standards such as: bills of “x”, ISA-S88, and underlying structures of XML or BatchML.
- There is open, clear, and detailed communication and interaction of the client development or manufacturing authorities with the CMO manufacturing authority, greatly reducing the risk of a bad technical transfer. Remember, a key factor for success of the transfer is not in how sophisticated the systems and applications are for technical transfer, but how successfully the client and CMO communicate during the transfer process.
- The process validation ensures proper technical transfer and documents the success and understanding of the transferred process from the client to the CMO.
- There is a fair, measurable and unambiguous contract between the client and CMO.
Success in technical transfer benefits both the CMO and the client. When done well, the manufacturing of a product can be scaled quickly and efficiently. When done poorly, both the client and CMO endure longer lead times to market, and increased costs resulting from re-work, and re-engineering due to bad understanding of the process.