A new chemical with promising therapeutic effects has to be tested in animals and humans for safety and efficacy as a drug. Demand for the chemical, depending upon its potency, at the various stages of development can vary from a few kilos to a few metric tons. Usually, the chemical development group in the research and development organization of the pharmaceutical company has the responsibility for sourcing the chemical (1).
Many pharmaceutical companies rely on their pilot plants as the main suppliers of chemical to meet the demands of the various toxicological and clinical studies. The chemical development group, however, really has three potential sources for developmental supplies: the pilot plant, the manufacturing plant, or custom synthesis (that is, using an external, contract manufacturer). Assuming that safety and quality are not issues, the decision to use one or more of these alternatives usually is based on the relative speed of implementation and cost. Needless to say, at the early phases of product development, the chemical process is not as well developed - so, speed is of utmost importance.
The attractions of custom synthesis
Going to a contract manufacturer may make sense for a variety of reasons: Capacity. While a company's pilot plant may be able to produce the chemical, it may not have adequate capacity to provide all the supplies needed. Often, either due to lack of capacity in existing equipment or the time required to procure new equipment, it is not prudent to try to make the chemical internally.
Coping with change. The chemical supply business in an R&D environment has to deal constantly with unexpected changes in plans and product mix. Even with the best efforts of a proactive planning system, it still may not be possible to satisfy all needs at all times. And, occasionally, it is worthwhile to go to a toll manufacturer so that an internal facility is not taxed to the point that it cannot handle any special requests for additional product.
Speed. A custom manufacturer with special expertise in certain types of organic synthesis or with access to special equipment may be able to make an intermediate faster than one possibly could internally.
Risk reduction. Because R&D invariably involves a very high failure rate, it often is not cost effective to add new equipment and expand current facilities for the rapid production of additional chemical.
Spurring innovation. The mission of a pilot plant in drug development should be to support rapid innovation, as well as to produce chemical; trying to maximize utilization of the facility may impede such efforts. At times, it may be wise to keep the unit idle in anticipation of rapid, but very short notice, production requirements for new products. Development teams also may want to try different experimental designs. Going to a toller can free up pilotplant time for such efforts.
Need for foreign supplies. Pharmaceutical companies sometimes must make supplies in an ex-U.S. facility for early clinical trials in Europe and Japan. If the company does not have a chemical development group or a pilot plant outside of the U.S., it usually uses custom manufacturers to satisfy that need.
Differences from normal sourcing
The Rc*D environment imposes special demands on custom synthesis: Quantity. The amount of a particular chemical required can vary from one kilogram or less to several hundred kilograms, depending upon the stage of development.
Speed. Often, especially at the early stages of drug development, chemical supply is on the critical path. Therefore, the ability to use a custom manufacturer to make the proper quality and quantity of chemical quickly is of utmost importance. Pharmaceutical companies often are willing to pay a premium for speed.
Flexibility. In the early stages of a project, chemical needs keep fluctuating. Pharmaceutical companies usually have a hard time finalizing the number of animals or patients they will be dosing in a study. This can cause tremendous strain between the company and the contract manufacturer. In addition, R&D projects can be dropped or priorities can change, requiring the custom manufacturer to slow down or stop working on a production project. On the other hand, sometimes, the toller may be asked to increase production by several fold.
Duration of contracts. At the R&D stage, companies usually seek short-term contracts for tolling with no long-term commitments. Sourcing long-term supplies, in most companies, is a manufacturing decision. R&D organizations should not make commitments for long-term supply.
Complexity of chemistry. Bulk pharmaceutical processes frequently involve relatively complex chemistries. For the early stages of development, the development teams do not have time to optimize the process or to develop simpler manufacturing routes. The process, in a lot of instances, may not even be well characterized. One, therefore, has to look for contractors with the ability and experience to implement relatively complex organic chemistry.
Status of technology. Often, the level of process development is insufficient. The contractor may have to undertake some process development itself before being able to run the process in its facilities. Tollers with some capabilities in organic process development definitely will have a significant edge over those without such capabilities.
Business issues
Success, of course, depends upon selecting an appropriate, capable contract manufacturer. (For tips on finding the right toller, see the article by Worstell et al. on p. 45.) The strength of the relationship with the custom manufacturer is all important. Familiarity with each other's personnel and systems, especially analytical methods and techniques, is critical to successful technology transfer. We highly recommend that staff from the toller visit the customer's facilities so as to understand its systems and meet its key people. Technical personnel from the custom manufacturer also should be free to call the customer's technical personnel to ask questions. Building trust and good communications is crucial.
Treat the custom manufacturer as a partner rather than as just a supplier. It is in the customer's interests to ensure that the toller does not go out of business or incur undue losses trying to satisfy its requirements. Indeed, the customer should make every effort to develop a relationship based on true partnership this may require a paradigm shift. But, it is important to realize that, for the pharmaceutical company to be successful, the custom manufacturer must be successful, too.
It is better to establish long-term relationships with a few reliable custom manufacturers than shortterm relationships with numerous ones. Communications are enhanced and, thus, time is saved when parties are familiar with each other's systems and personnel. The personal nature of the relationships between the two parties can be sustaining in times of crisis. Likewise, dealing with a few, trusted tollers helps to protect confidentiality; maintaining secrecy could become quite resource-intensive if one deals with a large number of custom manufacturers.
Once a contract is awarded, a project team - consisting of 3-5 key individuals from each company, including one project champion from each - should be formed. This team normally should include an engineer, chemist, analyst, and project manager. All team members must be familiar with the technology. Additional members also may be appointed, based on project-specific needs. Such a team allows better coordination and improved communication between the two companies. To avoid confusion, make sure to define the roles and responsibilities of the project team members and its leaders, and to identify communication channels.
To maximize the success of any project, it is very important to have a decision-making process that allows for the rapid evaluation and resolution of issues as they arise. The staff assigned the responsibility for managing a project on a day-today basis must be empowered to solve technical problems and decisively resolve urgent matters that inevitably occur during a project. This group of people also must be empowered with the authority, albeit limited, to make decisions that impact on a project's budget.
Technical issues
Once a contract manufacturer is chosen, the custom synthesis process involves several steps, as listed in Table 1. Technology transfer probably is the most important step to help ensure the success of the program.
Always remember in technology transfer that every contract manufacturer is unique -- perhaps with a different system for taking a process from the laboratory to the plant, and certainly with different equipment as well as people with different levels of skills and experience than other tollers you may have used.
At the initial stages of the project, the chemical development group should try to provide as much inhouse experience and knowledge as possible so that the custom manufacturer can determine the feasibility of carrying out the project and provide accurate time and cost estimates.
After the contract is agreed upon, a Technology Information Package (TIP) should be supplied to the contract manufacturer. The effectiveness of the technology transfer greatly depends upon the quality of the TIP. Often, if the quality of the TIP is very good, the custom manufacturer is able to successfully complete the job without a lot of faceto-face communication or meetings. This significantly reduces the cost and time of the project. However, the importance of direct dialogue between the two parties should not be downplayed.
The extent to which technology is transferred to a custom manufacturer can vary widely from project to project. The quality of the TIP will reflect the process's stage of development and the internal resources the pharmaceutical company has dedicated to the project. Thus, the TIP could vary widely from a rough, laboratory process description only to a process description and small-scale (5-50 gal) processing information to a process description, small-scale and largescale (200-1,000 gal) processing information with a very detailed, stepby-step operating procedure. The quality of the hazards package also may depend upon the project and its stage of development.
A well-organized TIP that includes chemical, engineering, analytical, and safety data is mandatory for smooth and successful technology transfer. We cannot overemphasize how important it is to capture all the information and observations in this package. After all, many scale-up problems result from inadequate communication between chemists in the laboratory and the engineers in the pilot plant within the same company, let alone separate companies.
The chemists, analysts, and engineers working on the project should compile the TIP. Table 2 lists the suggested contents.
People may have difficulty in finding time to prepare a good package. However, much more time may have to be spent later if a poor package resuits in poor transfer of technology.
Other considerations
Project objectives need to be well defined at the beginning and clearly understood by both parties. These include identification of specific compounds, quantity, purity, timing, specifications, requirements for Good Manufacturing Practice (GMP) and documentation, and the like.
Conducting laboratory experimentation for process familiarization. At Searle, we encourage the custom manufacturer to carry out laboratory experiments with process knowledge we supply. This is very important for process familiarization and technology transfer. Usually, this is done at Searle's expense; we consider it a worthwhile investment to ensure success of the project and continued good relations with the custom manufacturer. Searle also benefits from the study and analysis of the process from another group's perspective. Sometimes, at this stage, new problems with the process are uncovered and the two sides jointly may decide not to proceed with the work. Alternatively, the process can be much improved based on the new information.
Transfer of prior knowledge and experience. It is important to transfer as completely as possible to the custom manufacturer all knowledge derived from past experience with the project, to avoid repeating mistakes at the toller's plant. If the customer currently is making the product in its laboratory, pilot plant, or commercial plant, it is advisable that the toller witness the runs so as to anticipate problems. Similarly, chemists and engineers from the R&D organization should witness laboratory experiments and plant runs at the custom manufacturer until both sides feel comfortable with the implementation of the technology.
Raw materials and reagents. At an early stage of the contract, it is important to define the specifications and sources of the various raw materials and reagents. Often, a preferred option is to have the contractor procure, whenever possible, all required raw materials, reagents, solvents, etc. However, the customer may be actively involved in the purchase of these raw materials if there is a need or advantage to do so. The customer should provide any proprietary intermediates that are required; the contract should specify this, so there is no chance of confusion at a later date.
Quality assurance. Before a commitment to a GMP production campaign at a contractor's facility can be made, staff from the pharmaceutical company's quality assurance department must visit the proposed manufacturing site to conduct a formal QA audit. The results of the audit may be used to determine if the contractor's equipment, manufacturing practices, and staff expertise can meet the company's standards for GMP production. For the sake of establishing long-term relationships, it sometimes is beneficial for the pharmaceutical company to assist the custom manufacturer in developing systems to meet GMP requirements.
Analytical capabilities and reference standards. For all contracts, the customer normally should supply documented analytical methods, as well as samples of all available reference standards. Much of the analytical methodology may involve chromatographic techniques. The reference standards should include raw materials, intermediates, final product, known impurities, suspected impurities, etc. If the contract requires the contractor to use specific analytical methods and conduct inprocess checks, acceptance testing, or release testing, it is important that detailed documentation and samples be made available.
An option worth considering
Custom synthesis can play an important part in supplying chemicals for pharmaceutical R&D. But, this requires pharmaceutical companies to establish good relations with a select group of custom manufacturers around the world. High-quality TIPs and effective technology transfer are essential for success, as is the custom manufacturer taking the time to familiarize itself with the customer's process in its laboratories before undertaking to make the chemical on a large scale.
[Reference]
Literature Cited
[Reference]
1. Basu, P. K., J. Quaadras, R. A. Mack, and A. R Noren, "Achieve the Right Balance in Pharmaceutical Pilot Plants," Chem. Eng. Progress, 94 (2), pp. 67-74 (Feb. 1998).
2. Basu, P. K., J. Quaadras, J. E. Holliman, R. A. Mack, and A. R. Noren, "Pharmaceutical Pilot Plants are Different!," Chem. Eng. Progress, 93 (6), pp. 66-75 (June 1997).
[Author Affiliation]
P. K. BASU is Director, Process Development and Chemical Processing, for Searle Chemical Sciences R&D, a unit of Monsanto, Skokie, IL ((847 982-7733; Fax: (847) 982-7465; E-mail: prabir.k.basu@monsanto.coml. His main responsibility is to provide the chemicals required for the development of new drugs by the company via pilot-plant or contract manufacturing. He received a PhD in chemical engineering from the Univ. of California at Berkeley, and an MBA from Webster Univ. He is a member of AIChE and ACS.
[Author Affiliation]
R. L BUCHMAN is Director, Global Sourcing, for Searle, a unit of Monsanto, Skokie, IL ((847) 581-5862; Fax.: (847 581-6044; E-mail: russell.buchmanimonsanto.com). His main responsibility is to coordinate the contracting of intermediates and active pharmaceutical ingredients for the company. He received a PhD in medicinal chemistry from Purdue Univ.
[Author Affiliation]
A. L CAMPBELL is Vice President, Chemical and Bio-process Sciences, for Searle, a unit of Monsanto, Skokie, IL ((847) 982-7411; Fax: (847) 982-4799; E-mail: arthur.l.campbell@ monsanto.comr. His main responsibility is worldwide drug-substance development to support the registration and manufacture of new drugs. He received a PhD in medicinal chemistry from the Univ. of Kansas, and completed post-doctoral work at Colorado State Univ.
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