Given the financial realities in the pharmaceutical industry today, there is intensifying pressure to decrease time to market and raise productivity, while containing costs for both facilities and R&D staff. These factors, coupled with the FDA’s elimination of the Establishment Li-cense Application (ELA) for biologics conforming to the definition of “well-characterized” products1, are driving rapid expansion in the area of contract manufacture for biologics. All areas of manufacture are available, including preclinical test materials, clinical trial (Phase I-III) supplies and marketed product. The decision to outsource manufacturing services is most effectively driven by a comprehensive strategy within the sponsoring organization for at least the near-term (and preferably, long-term) overall development of the product.
Clearly, adjustments to the strategy will need to be made along the way as more is learned about the properties of the drug (e.g., its pharmacokinetic and pharmacodynamic properties, scalability and yield of the process, as well as regulatory strategies). Many decisions can be made early to facilitate the product development process later. Let us focus on the search for outside manufacturing services in each of the above phases of development and discuss how this search interfaces with other activities necessary in the manufacturing and development of a biopharmaceutical product.
The development stage of a product clearly plays a major role in selecting a contract group for its manufacture. The considerations in the different developmental stages are obviously quite different, especially with regard to regulatory aspects specific to manufacturing.
At the earliest stages of biological product identification and testing, its DNA sequence(s) may or may not be known (in the case of a recombinant protein product). The particular type of protein will dictate the type(s) of expression systems (i.e., mammalian/microbial) that are likely to be successful in producing viable quantities for testing.
For instance, monoclonal antibody production is, at present, limited to mammalian systems (although some recent reports have suggested that it is possible to produce antibodies using yeast expression systems2). Technologies are also currently available to produce fully human antibodies to an antigen of choice using transgenic mice, thus eliminating the need for “humanizing” a murine (mouse-derived) monoclonal antibody. Does the protein have glycosylation that is necessary for its activity?
The sponsor should keep in mind that the expression system chosen will determine to a large degree how much protein will be available for testing. Therefore, careful and thorough screening at this point will pay off later in the manufacturing process (and probably in later clinical manufacturing as well). In addition, some expression systems carry with them licensing fees—another factor that must be considered in the selection process.
All of the above issues must be considered during the selection of a site for production of preclinical material. Other important activities that must be ad-dressed at this stage are robust analytical assay development (addressing how to identify and quantify the amount of protein yielded) and fermentation and downstream recovery development. These all play a key role in outsourcing selection. Obviously, all of the above will be greatly facilitated by in-house expertise at the sponsoring company.
When looking for a contract manufacturer for preclinical material, the sponsor must decide whether to go to a “full-service” provider, i.e. a contract organization that can supply all of the services needed, from molecular biology to fermentation/cell culture development, as well as downstream purification and analytical methods development, or alternately to go to different suppliers for these various activities. While it is obvious that there may be advantages and disadvantages associated with both approaches, some mixture of the two choices could be most effective from both development and cost perspectives. Certainly, there is quite a broad range of choices at this stage of development.
Early Stage Clinical Product (Phase I/II)
The experience gained in preclinical outsourcing should be quite informative in driving the selection process for outsourcing of clinical-grade material to support phase I/II clinical testing. Beginning with human trials in Phase I, product must be produced under current good manufacturing practices (cGMP). This serves to limit the selection of potential contract suppliers considerably, in comparison with the options available to supply material for preclinical testing. Specifically, the contractor must be able to demonstrate compliance with FDA guidelines (or those of another country, depending on where the trials will be conducted) with regard to facilities, raw materials handling and manufacturing control and their associated documentation.
Since the ultimate responsibility for product compliance rests with the sponsor, one of the first steps in the selection process for outsourcing clinical product must be a thorough audit of the facilities and procedures used in the proposed contract site. Someone with intimate knowledge of current FDA guidelines should conduct the audit. In addition, this individual should have prior experience in the area of biomanufacturing.
During the early stage of clinical product development/ manufacturing, the contract manufacturer can play a vital role in assisting the sponsor with all of the activities related to the manufacture of the product. When it comes to selection, it is important to assess the level of expertise in each of the critical areas related to the successful manufacture (and IND filing) for the product.
It is now quite common to find personnel at contract organizations with extensive industry experience. This experience can be invaluable during planning and execution of the project; the staff can also provide advice at key points in the project. Usually, a process coming out of preclinical development needs at least some refinement in order to translate into a fully documented manufacturing process ready for execution under cGMPs. The contract manufacturer should be able to supply experienced guidance in this area.
If the process (or parts thereof) is to be developed by a contracted group, the sponsor must make sure to ask, “Who owns the process?” In other words, are there potential areas in a process that could be claimed by the contractor as inventions and thus are subject to licensing by the sponsor? This becomes an issue if the sponsor decides to move to another contractor. This area must be addressed up front with any potential contract manufacturer.
Late Stage Clinical Material (Phase III)
Production of material for Phase III clinical trials is a much more complex activity than that encountered in the early phases of clinical trials. By this time, the sponsor’s process should be very clearly defined (with, of course, some modifications and optimizations still in the works) and there should be a general idea of how much product will be required both for ongoing and future clinical studies as well as initial market launch. Is the facility under consideration capable of producing enough material using the current process to support not only Phase III trials, but also (very probably) the initial product launch? The level of regulatory scrutiny directed at the product at this stage will be quite high, in view of the fact that the lots produced will be used to support the eventual Biologics License Application (BLA) filing.
The above considerations limit the choices for contract sites in Phase III to a handful and, in some senses, make the job of selection easier. The facility used at this stage for product manufacture should be either already-licensed (that is, already producing marketed product) or licensable since your first marketed product may well be produced here.
The downside of all of this, of course, is that the small number of contract sites that meet the above criteria have become flooded with requests from potential clients, all looking to use outsourcing as a strategy for manufacturing. Since the site of Phase III manufacture will likely be at or near the scale contemplated for commercial launch of the product, discussions should begin early in negotiations regarding the long-term outlook for facility availability, potential expansion and, in general, where the contract manufacturer sees its business going.
Again, the contract site can play a major role in assisting client companies with expertise in a variety of areas, ranging from process scale up to validation issues. It is quite important at this stage to maintain a very close (and effective) working relationship between the sponsor and contract group, since many issues will arise that will require close collaboration. The smoother the relationship is, the more effective the problem solving.
How does one go about effectively looking for information about contract manufacturing and development activities? A number of sources exist for identifying organizations that offer contract manufacturing. For development and manufacture of preclinical material, choices range from university-based programs to full service contract organizations that can go from preclinical material through late-phase clinical trial product and beyond. Increasingly, the internet is becoming a valuable source of information for contract sites. For instance, www.biospace. com (the website of BIO, the Biotechnology Industry Organiza-tion) offers links to organizations offering various contract manufacturing and development services. Detailed information about contract manufacturers can be found by accessing their individual web sites.
The Selection Process
Once the sponsor has made its preliminary selection of a group of contract sites, the next step is to screen them to see which ones fit the criteria most closely. As mentioned above, the number of candidate organizations decreases dramatically as the project moves from preclinical development through clinical trials to marketed product.
The process usually begins with a call to the contract organization to get a better idea of its capabilities in the area of interest. During this initial discussion the sponsor should be prepared to offer some (non-proprietary) information about the product, its development stage and what some of the expectations are. If the fit looks good, the next step is to sign a Confidential Disclosure Agreement (CDA) with the contractor. This will allow the conversation to enter into more detail about the product, the organizations, the expectations for product supply (if appropriate) and the near- and long-term availability of the contract manufacturer’s facility and personnel. These initial discussions can take place by telephone, fax or e-mail and will set the stage for a personal meeting. During these discussions, it is also appropriate to ask for references from past customers; these can be a very good source of information.
Visiting the Site
During the sponsor’s initial visit to the contract site, it is usually possible to get a good sense of the compatibility of the project with the facility and also of the sponsor personnel’s compatibility with the people. During the tour of the facility, representatives from the sponsor can talk with in-house experts in the fields applicable to the project. They can also meet with management and the project coordinator (there should be an individual assigned to handle all of the details associated with the project and to act as contact between the organizations). The sponsor should be prepared to discuss the project in intimate detail in these meetings; this will allow both sides to assess whether the site is appropriate for the project.
If the project involves process development/improvement activities on the part of the contract organization, how will any discoveries arising from this work be handled from the standpoint of intellectual property? These negotiations are better handled up-front than after the fact. Will the project require any specialized equipment that must be purchased and installed (and also validated) prior to manufacturing? The latter point is potentially rate limiting with respect to the overall timing of a project. It may be much easier to go to a site that already has the necessary pieces of equipment than to try to install such equipment elsewhere.
The sponsor must ask the contractor how other projects have been handled and how the two groups will work together to develop successful strategies for technology transfer and trouble-shooting between the organizations. Both sides must work to formulate a plan for decision-making during manufacturing. This usually involves having a representative of the sponsor present during the production process (preferably on the manufacturing floor) to help in critical decision-making. The value of this will depend upon the input of the sponsor to the development and scale up of the manufacturing process itself. Therefore even if the contractor develops the entire process, someone associated directly with the sponsor organization should possess detailed knowledge of the technical fine points and of its strengths and weaknesses.
As stated above, once the choice of manufacturers is narrowed down, a thorough audit of the facilities is in order. This will ensure that the chosen sites are in compliance with cGMP regulations. Remember: the sponsor bears ultimate responsibility for the regulatory compliance of the manufacturing environment and procedures, even when it is carried out at a contract site. Therefore, this critical due diligence should not be overlooked.
The Final Choice
After investing all of the work to explore the possibilities, the list of viable candidates will be short. If all of the indicators are positive at this point, the sponsor must get a clearer idea of the cost of the services. This comparison can be quite interesting since, obviously, there is no fixed formula for determining the cost of contract manufacturing and the associated activities. While this is a complex issue, given all of the above considerations, I can attest that cost for similar services can vary widely. It should be pointed out that the cost of goods at the early (and intermediate) stages of development is unlikely to impress the chief financial officer anyway, so cost should not be the driving force in a sponsor’s decision.
The final choice of the appropriate contract site for a project involves a complex interplay between technical capabilities, regulatory compliance, project management and cost. All of these must be factored into the decision of where to manufacture an important biopharmaceutical product at each stage of development. n
1. In 1996, the FDA eliminated the requirement for establishment licensure for certain biologics, such as recombinant DNA-derived therapeutic products, monoclonal antibodies for in vivo use, synthetic therapeutic peptide products of 40 or fewer amino acids, synthetic plasmid nucleic acid therapeutic products and therapeutic DNA plasmid products. The latter are products that can be extensively characterized from a physicochemical point of view. The FDA excluded blood products, gene therapy viral vectors and therapeutic cells and tissues from the list of potentially well-characterized products.
2. N. Motwani, personal communication, presentation at IBC “Antibody Engineering” meeting, San Diego, CA, December, 1999.