Addressing Challenges in Sterile Manufacturing
Biopharma Companies Seeking a CDMO Partner Need to Consider a Broad Range of Capabilities
With a market value of $62 billion in 2016, the contract development and manufacturing organization (CDMO) industry has a compound annual growth rate (CAGR) of 6-7 %, according to the study by EY “Consolidation of the CDMO industry: opportunities for current players and new entrants”. This CAGR is slightly higher than the CAGR of 5-6 % seen by the pharmaceutical sector as a whole.
Early clinical development of new products requires in-depth expertise. For example, large biotech molecules such as monoclonal antibodies and proteins are extremely sensitive, with high costs and limited availability of bulk material. Small molecules such as peptides are frequently poorly soluble, posing additional challenges from the process and analytical perspectives. In addition, the first GMP batch of clinical material has often not yet been manufactured at an industrial plant.
Formulation and Development
The work performed in the development laboratory is critical to ensure the success of a suitable formulation and development of a scalable process in an industrial facility. Examples of approaches used include the design of experiments (DOE) concept and risk management tools such as failure modes and effects analysis (FMEA). These may be applied even in the earliest clinical phases, with the goal of avoiding challenges at later stages, when the product is on the critical path to the clinic.
In addition, advanced technological tools may help improve product knowledge. For example, micro-flow imaging and other particle measuring techniques for detecting aggregates in solution can be very useful in aiding the formulation development of biopharmaceuticals; and cryomicroscopy and statistical models are helpful for the development of a lyophilization cycle.
The review of process parameters in each critical step at laboratory scale is key to managing risk during scale-up; it is vital to be able to work with very limited quantities of expensive APIs within a tight timeline.
In the analytical field, investigational skills are required when unexpected results occur, the causes of which can vary widely, for example unknown chromatographic peaks may be due to chromatographic conditions not being optimized, or to the presence of contaminants – the source of which can require a great deal of effort to pin down.
For early stage clinical trials, the analytical methods require a lower level of validation compared to the ICH requirements. However the “understanding” of the reliability of such methods is critical to ensure the reliability of analytical results, in particular when they are indicative of stability.
During early development, stability data at different temperatures generated by non-GMP lab-scale batches are needed to predict the behavior of the product. This is typically carried out at least three months before scale-up and confirmed with the data generated by the first GMP batch.
Compliance with Regulatory Requirements
Regulatory requirements for sterile manufacturing are becoming more stringent, with challenging expectations from a technology point of view. In a recent development, the European Commission issued a long-awaited draft of Annex 1 Manufacture of Sterile Medicinal Products on December 20, 2017. The revision is aimed at adding clarity, incorporating the principles of quality risk management (QRM) to enable inclusion of new technologies and processes, while ensuring that microbial, particulate and pyrogen contamination associated with microbes is prevented in the final medicinal product.
Compliance with these new requirements also facilitates a “fast track” approval from regulatory bodies, during a pre-approval inspection in particular, for products that have orphan indications or for which there is a currently unmet need.
Under these regulations, there is an expectation that the product will be fully characterized and evaluated at critical process steps. Data may come from freeze-thaw studies (where required), the establishment of a formulation design space, and additional process parameters such as holding times, process materials compatibility studies, mixing, agitation, filtration and filling. Another key element is the robustness of the lyophilization cycle. Having this information helps to guarantee high quality and deep product knowledge by the time the registration and validation stages are reached.
Scale-up and Technology Transfer
The success of scale-up and technology transfer are key indicators of a CDMO’s ability to develop and manufacture a product on time, meeting client expectations from both technical and quality standpoints. It is important to be able to tackle unexpected challenges during the development cycle of a sterile drug, such as lack of stability, generation of aggregates, or failure to meet product specifications.
Equipment in sterile facilities is also becoming increasingly automated, with greater use of restricted access barrier systems (RABS) or isolators, as well as automatic loading and unloading systems for lyophilizers, which increase sterility assurance effectiveness and minimize the risks of human contamination. CDMOs face increasing pressure to offer best-in-class technology to meet client and regulatory expectations, while retaining flexibility and pricing in line with market rates.
Operational Excellence and Skilled Workforce
Operational excellence is essential, enabling continuous improvement and helping to develop ‘best-in-class’ site cultures. Visual Management, Kaizen, Gemba walks and Value Stream Maps are among the tools that will help the CDMO to be ever-more efficient in responding to market requests.
A focus on developing a skilled workforce is also essential in this environment, particularly when science is equally as important as the ability to be a proactive communicator and a leader. These skills are needed to optimize speed and resolve issues on the client’s behalf and, equally critical, to help with retention. The role of the manager to develop such talent through coaching and feedback is a clear goal.
In conclusion, a CDMO’s people are its most important asset as it works to develop the high performance organization required to meet these various requirements. Flexibility, teamwork and passion should be in a CDMO’s DNA – originating from individuals who are natural problem solvers and can think ‘outside the box’ in resolving product development challenges. Critical skills include the ability to apply technical and scientific expertise to drive the development of robust processes, particularly for large molecules that require lyophilization, or complex poorly soluble formulations for scale-up.
Biopharma companies seeking a CDMO partner should consider a broad range of capabilities in addition to cost, with reliability topping the list, followed by flexibility and expertise in troubleshooting. This partnership can work towards a shared mission of providing patients with timely access to needed therapies that are produced ‘right first time.’