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Sheryl Henderson is the director of Plant Network Strategy Implementation at Pfizer Inc.
Steven McWethy is the senior manager of the fermentation plant at Pfizer's Kalamazoo, Michigan, site.
Keith Dixon is the director of bioprocess development at Pfizer.
The authors describe the critical aspects of an ideal fermentation services provider.
The need for good manufacturing practices (GMP) fermentation is likely to increase during the next several years—at a time when many pharmaceutical businesses are rationalizing and sometimes downsizing their core manufacturing operations, resulting in what many believe will be a growing need to identify outsourced fermentation sources to augment their own supply chains. Seeking additional outsourcing strategies while working to ensure quality for their end products, manufacturers are increasingly challenged when sourcing such specialized functions as large-scale fermentation.
GMP fermentation today is a complex process that requires a large investment in expertise, equipment, process, and quality control, and very few companies in the industry currently have or choose to invest in developing those resources in-house. A deep understanding of quality systems, strain development, process development, scale-up, isolation, and purification can help ensure pharmaceutical firms make the right decisions in large-scale fermentation outsourcing and help companies make the right choices for their supply-chain requirements.
Make or buy?
The fermentation of microorganisms is the basis for the production of a wide range of products such as antibiotics, hormones, and specialized proteins, thereby making fermentation an important process for related commercial products. Fermentation is frequently the preferred production method, particularly with therapeutic proteins or chemical compounds requiring a multistep synthetic process offering the optimal economic route and allowing firms to shorten their production process and time to market. Because of the importance of fermentation in the industry, it figures prominently in a company's overall decision regarding which processes and functions it must outsource.
With GMP fermentation, quality is built into the entire process, as opposed to simply testing for product quality at the end of the process. Fermentation achieved in this manner is expensive to implement—a key factor to consider. A pharmaceutical business or its fermentation services provider must maintain the facilities, procedures, and controls needed to ensure that the manufacturing, packaging, and handling of the product is conducted in a way that meets the requirements of regulatory agencies regarding safety, product identity, quality, and purity characteristics. Essentially, for a specialized function such as GMP fermentation, the "make" decision is simply not an option for most companies, and they must outsource this key process.
Figure 1 (ALL IMAGES ARE COURTESY OF PFIZER INC.)
Fortunately, selecting an outside provider offloads a number of procedures and controls related to the fermentation process, including raw material qualification, master and batch production records, change control procedures, deviation investigations, fermentation sterilization validation, downstream process validation, cleaning validation, equipment qualification, expiration testing, and stability testing.
Perhaps the biggest factor that drives pharmaceutical manufacturers toward the "buy" decision for fermentation is cost. The capital investment for a properly equipped current good manufacturing practices (CGMP) fermentation facility, including manufacturing equipment and utilities, is significant and often runs into the high tens of millions of dollars. In addition, the provision and training of a technical staff (manufacturing, technical support, quality assurance and quality control, engineering, maintenance and utilities, etc.) further adds to the investment required. By outsourcing to a company that already has the staff and facilities in place, customers can significantly accelerate their timeline and minimize overall investment. Quite often, outsourcing to a specialized provider of custom fermentation services is the lower cost option, a key driver in swaying executive management in a time of tight cost controls.
Once the outsourcing path is chosen, the supplier selection process requires a series of key considerations for making the right contracting decisions regarding large-scale fermentation.
Fermentation process experience
Although it sounds like an obvious factor, GMP fermentation experience is extremely important but easy to overlook. Several factors should be taken into consideration to determine whether a prospective supplier is equipped to handle fermentation services.
Fermentation process development begins with strain selection and optimization, media development, process development, and scale-up to maximize productivity. Downstream processing can use various technologies for extracting, concentrating, and purifying the product from a dilute fermentation broth. Any provider of custom fermentation services must be proficient in these aspects.
Figure 2 (ALL IMAGES ARE COURTESY OF PFIZER INC.)
Flexibility in the types of microbial systems with which a contract manufacturer can work is important because it ensures a broad base of staff knowledge and expertise across a wider spectrum of microorganisms. When looking through product literature or otherwise evaluating contract capabilities, the following capabilities are typical: microbial cells (bacterial and fungal), microbial enzymes, recombinant organisms, enzymatic bioconversions, and secondary metabolites.
A company should also rate a prospective partner on fermentation downstream processing. A well-rounded capabilities portfolio includes various technologies for extraction and purification. A fermentation services provider should be able to easily handle soluble and insoluble products in the fermentation broth using technologies such as centrifugation, ion exchange, large-scale distillation, nanofiltration, large-scale crystallization, filtration, and drying.
Process development and ongoing production support are additional tools a contractor should have at its customers' disposal. Troubleshooting and process optimization (to reduce costs and improve processes) are two important examples. Operating a biological process such as fermentation is a great deal more complex than operating a chemical synthesis process, largely because there are many more variables to consider and control. For example, the media components used in fermentation are essentially agricultural products like soy, corn flour, natural cereals, fats, and oils, and other materials that can literally vary from crop to crop, harvest to harvest, and year to year. The fermentation services contract manufacturer must manage these natural changes on a day-to-day basis, taking them fully in stride and adjusting its process accordingly.
Beyond initial outlays for any specialized equipment required, a contractor should sustain an aggressive maintenance program that includes annual or periodic calibrations of sensitive instruments. When evaluating a provider, ask to see its maintenance schedule or other proof that equipment is adequately cared for and updated as required.
The team running all this technology is equally as important. Initial and ongoing training in all aspects of fermentation is essential and includes operator, laboratory analyst, and specialized support-staff training. All personnel should have required curricula for their fermentation-related assignments. Training is not limited to providers of fermentation services, it is an integral part of GMP, and the complexity of fermentation processes underscores its importance when potential partners are evaluated.
Another important contract manufacturing criterion, and is by no means restricted to fermentation services, is technical development and regulatory support. A potential provider should understand its customer's drug products, markets, and business needs. Ideally, the provider will maintain an experienced team of professionals that provides a continuous surveillance of global regulatory and CGMP requirements, and writes and maintains worldwide registration documents. Typically, such a customer support team will handle the technical package, quality agreements, customer audits and inquiries, technical facilitation, investigation support and supply team feedback, among other responsibilities. If the fermentation provider can't point to a standing team capable of helping manage these details, think twice before engaging with them. Fermentation operations are complex and can easily consume the customer's time if a contractor isn't willing or able to offer such a range of technical and regulatory value-added services.
Systems for quality control remain one of the most important and effective bulwarks for protecting the supply chain and ensuring patient health and safety. This is true especially in biologically based production. As such, quality must be very high on the list of the criteria for selecting a provider of fermentation services.
When searching for a contract manufacturer, don't expect the company to have identical standards. However, it must have a comparable and compatible set of standards that ensures high-quality products using fully compliant operations. Today, no manufacturer can take the chance of using contract suppliers that do not have the quality and compliance systems already in place or whose track record meets only the minimal levels of performance. The service provider must clearly demonstrate quality and compliance in its fermentation offering. One question to ask is whether the supplier's quality and compliance records in fermentation services are among the best in the industry. If not, don't consider engaging with them; the downside potential for the supply chain is simply not worth the risk.
When evaluating quality systems, look carefully at the laboratory facilities and trained quality analysts and quality assurance personnel. Do these elements operate under CGMP conditions, ensuring that even routine updates are made on an ongoing basis for quality reasons?
A company should also know whether a service provider has a standing quality assurance group that is responsible for ensuring written procedures are followed so that all components, product containers, closures, in-process materials, and finished materials conform to appropriate standards of identity, strength, quality, and purity. Request to see samples of written procedures that cover sampling, identification, storage, handling, testing, and documentation of test results. Auxiliary or support activities such as training, calibration, maintenance, stability evaluations, and audits must also be described in written procedures.
Trained personnel (according to a formalized certification program) should be the ones performing all laboratory testing, which is conducted according to current written, validated, and approved procedures. The use of validated analytical procedures ensures the accuracy, precision, specificity, sensitivity, ruggedness, and reproducibility of test results. The GMP computer systems in the supplier's laboratory operations should be validated. Record checking systems provide the necessary verification that the appropriate tests, procedures, and calculations are used and performed correctly and that the transcription of data is performed accurately. In a service provider's quality assurance process, every item essential to the analysis of the material or product must be checked; look for such assurances when conducting a supplier capabilities evaluation.
Technology transfer and scale-up
Typically when a company has made a decision to outsource a large-scale fermentation process, it has developed the process at the laboratory- or pilot-scale, and the contract manufacturer works with the company during the technology transfer stage to first transfer the process at the same scale and then optimize the process in the contract manufacturer's facility. Sometimes, however, the relationship starts at the preclinical or early clinical materials stage. In such cases, it's worth identifying a contract supplier that can offer extensive pilot-scale facilities and commercial-scale facilities.
Once underway, the technology transfer experience becomes one of the most important in the relationship, so vetting a contract manufacturer on this point in advance is recommended. A supplier must have the technical resources in place to receive technology from a customer and implement successful scale-up and commercial supply in a timely manner. Evaluate its track record and its ability to demonstrate success in this key area. Technology transfer includes a number of challenging steps, including transferring process knowledge, analytical methods, raw material specifications, equipment requirements, and so forth. So a pharmaceutical firm should look for a strong technical team that can successfully implement every step. A contract manufacturer's staff should be able to quickly learn how to operate the process themselves.
There is a great deal that can go wrong when lab- or pilot-scale quantities of material are scaled-up. Scale-up can include various hurdles, and key alterations may need to be made in the process. A contract manufacturer must demonstrate clearly the capabilities of its project management approach. Without experienced support resources on-hand during this difficult period, successful technology transfer, scale-up, and implementation will not be possible.
Ensuring the "supply" in supply chain
A final point to consider: none of the above points, from process expertise to scale-up, means anything without the assurance of supply. A successful fermentation services provider must prove it has the capacity and robust business systems (e.g., raw material supply, production planning) to provide reliable supply for a customer, both in terms of quantity of material and timing of deliveries.
Important questions to ask well in advance are: Does the supplier have the available capacity for the fermentation requirements for the foreseeable future? Are its packaging, shipping, logistics, and customer service infrastructure and procedures adequate to guarantee your supply requirements on a regional, national, or global basis?
Large-scale GMP fermentation is a complicated undertaking and requires more than just a token commitment by a contract manufacturer. It requires a commitment to excellence at each stage of the manufacturing and supply process, a substantial investment in fermentation expertise and infrastructure, and a series of best practices across the broad spectrum of contract manufacturing support services.
The investment in expertise, equipment, process, and quality control can be daunting; certainly enough so that many companies are driven to seek outside supply for fermentation. By carefully defining project requirements, evaluating prospective suppliers on objective criteria for fermentation specifically and contract manufacturing overall, and being willing to walk away if there isn't a fit, a pharmaceutical company can rest assured it is taking the most rigorous steps possible to identify an important partner in its product supply chain.
Sheryl Henderson is the director of Plant Network Strategy Implementation at Pfizer Inc., tel. 269.833.5667, fax 269.833.9106, firstname.lastname@example.orgSteven McWethy is the senior manager of the fermentation plant at Pfizer's Kalamazoo, Michigan, site. Keith Dixon is the director of bioprocess development at Pfizer.
*To whom all correspondence should be addressed.