With combined 2009 revenues estimated to be over US$40 billion, monoclonal antibody (MAb) products have become the dominant component of the biopharmaceutical market (1). Continued interest and development of this exciting class of products will drive the overall sales of biopharmaceutical products in the future, making them the fastest growing segment of the overall pharmaceutical market (2). To help companies developing MAb products, BioProcess Technology Consultants recently published a comprehensive report outlining the complex technical, regulatory, and strategic chemistry, manufacturing, and control (CMC) activities necessary to successfully advance new MAbs from discovery to first-in-human clinical trials and the market as quickly and economically as possible (3). As discussed in the report, numerous interconnected tasks must be completed cost effectively and on schedule to enable human clinical testing of a new MAb candidate. Those tasks include construction and testing of production cell lines, development of a suitable manufacturing process and suitable analytical methods to produce and characterize the antibody and ensure safety and desired functionality, and production of good manufacturing practice (GMP) material for use in human clinical trials.

Figure 1 shows a typical timeline for CMC development activities required before filing an investigational new drug (IND) application (3,4). This timeline is based on the assumption that development is carried out in the context of a reasonably well-established platform process for MAb product manufacture and a set of analytical methods for product characterization and quality control (QC) testing. Because these initial CMC activities are on the critical path to an IND filing, it is essential that they be completed as quickly as possible to facilitate the initiation of human clinical trials.

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Figure 1: (Click to enlarge)

Each major group of tasks in Figure 1 is generally performed by distinct functional groups, either within a product development company or outsourced to service providers. All technology developed before the first CGMP manufacturing run — such as the production cell line, analytical methods, and cell culture and purification processes — must be transferred to a manufacturing and product testing site(s). Later in product development, manufacturing processes and analytical methods are often transferred from an initial manufacturing site to facilities that can produce larger batches of product. Whether such transfers occur within a company/facility or between organizations (such as from a company to a service provider), careful planning and management are essential to ensure the knowledge and experience gained during development and early and clinical manufacturing is effectively transferred. That enables the receiving organization or party to quickly and effectively perform the critical elements of transferred methods or processes (5).

Tech Transfer Considerations

For efficient and successful technology transfer, planning should begin at a very early stage and be driven by the target product profile (TPP). A TPP describes a product's intended use and quality targets to ensure that product development begins with the end product in mind and that a final product meeting the objectives of the TPP is delivered to the clinic — and eventually to the market. The purpose of the TPP is “to provide a format for discussions between a sponsor and the FDA” regarding potential label claims and characteristics of a new product. The TPP is a dynamic summary of product characteristics that is subject to revision as a product moves through development (6). Nevertheless, it will help define the critical product characteristics that must be maintained or met during technology transfer, allowing the transfer plan to be clearly delineated and thereby preventing ambiguity between the sending and receiving parties.

A technology transfer plan should outline all transfer activities in detail, including the timing of initiation for each transfer activity, the interdependence of various activities, and the criteria for determining successful technology transfer. Each activity should be defined in sufficient detail so receiving parties can plan accordingly and allocate appropriate resources to successfully complete it within a specified timeframe. For most technology transfer programs — such as transfer of a manufacturing process — a project kick-off meeting should be held before the technology transfer plan is finalized to delineate transfer activities, timelines, and responsible parties for all sub-activities. Both the sending and receiving parties must agree on the plan details.

A technology transfer plan also should outline an appropriate governance structure to oversee all transfer activities and ensure that information is shared appropriately over the course of the transfer process. With a cross-company governance team established early in the project, challenges can be readily addressed or prevented to facilitate the process. This governance team also ensures proper buy-in from both parties for the transfer activities and helps with staff allocation, overseeing the transfer project budget and coordination of related activities.

In addition to the technical details of a process being transferred, the regulatory expectations and responsibilities of both parties also should be clearly defined. This includes identifying what regulatory submissions will be required as a result of the transfer and who will be responsible for preparation of those documents. Regulatory expectations and responsibilities can be outlined in the technology transfer plan, but they also should be concisely captured in a formal quality agreement (also known as a technical agreement) between the two companies in an outsourcing arrangement.

The quality agreement is a legal document that defines the relationship of two or more parties with respect to their quality responsibilities, with the business objective being a service or product supply. In the European Union, such agreements are not only an expectation, but also a regulatory requirement (7,8). In the United States, quality agreements are not required by the FDA, but the agency does expect sponsors and contractors to have a formal quality agreement in place, and inspectors often want to review such agreements during regulatory inspections. The fact that FDA has cited sponsors for violations in their quality agreements with contractors demonstrates the importance of having such agreements and ensuring that they accurately reflect each party's roles and responsibilities (9).

Once the initial prospective planning is complete, the technical portion of a technology transfer begins with assembling a summary of all prior knowledge about the cell line, method, product, or process being transferred. The team identifies critical quality attributes (CQAs) and critical process parameters (CPPs) that define the process and need to be controlled during each production batch.

As the foundation of product knowledge and understanding, CQAs are the critical molecular and biological characteristics for ensuring safety and efficacy of a product. When transferring an early stage product, the CQAs are unlikely to be firmly established yet because both product and process knowledge are minimal. For a broad class of products such as MAbs, however, defining what the product attributes should be can be based on general properties of antibodies and on established safety parameters for all biopharmaceutical products.

Likewise, in early stages of process development, the CPPs most likely to affect the quality attributes of a product are unlikely to be well defined. This can make early stage transfers difficult because no robust data set can be referred to for troubleshooting. However, at this point, the TPP serves as a guide to capture product attributes (e.g., purity and stability) as they emerge. To establish the process under these circumstances, additional work may be necessary to verify that a process has been transferred correctly and to collect the knowledge through design of experiments (DoE) at the receiving site.

If the process being transferred is relatively well understood, then process verification (simply running the process as defined) may be sufficient to establish it at the receiving site. To facilitate process verification, prepare a detailed description of the current process that clearly describes each of the major operational steps being transferred. This process description should generally follow the format of a high-level batch record, but without the details of a complete batch record. Alternatively, development reports that describe the process can be used in lieu of preparing a separate document. In either case, the process description will allow a technology transfer team to review preliminary documents and confirm that all necessary information for each unit operation or process step has been accurately and completely documented.

The existing process is then transferred into a development or pilot laboratory and run as closely as possible to verify that the receiving site can reproduce the process. Results from the process verification run(s) determine how much — if any — process adaptation is required to fit the process to a receiving facility. For early stage transfers, adapting the process to the facility may be more appropriate because a large body of process data will not yet exist. Such process adaptation might involve reducing the elution volume from a chromatography step to allow an existing vessel to hold it. However, for later-stage or commercial transfers, adapting the facility to the process (within reason) is more appropriate because the risk of affecting a CQA/CPP is greater if a process is changed at that point.