Manufacturing & process solutions: learning along the way
Castle Creek Biosciences discuss their lessons learned in establishing an in-house cGMP manufacturing facility with the capability to produce clinical and potentially commercial supply of cell and gene therapies.
With the rise of precision medicine over the last decade, including many cell and gene therapies, companies need to manufacture potential treatments in a reliable and reproducible way while ensuring safety and efficacy for patients. There are several unique challenges in the development of cell and gene therapies and a range of factors to consider, such as administration methods, vector type, therapeutic approach (e.g. in vivo or ex vivo), target indication and size of eligible patient populations. The nuances of cell and gene therapy production require specific expertise and skills; for many companies this means outsourcing manufacturing capabilities to third parties, including contract development and manufacturing organisations (CDMOs).
Nevertheless, there are a select few cell and gene therapy companies that have learned to overcome the inherent challenges and have developed in-house current good manufacturing practice (cGMP) manufacturing capabilities. As a result, they have realised the benefits of having an in-house facility. For example, companies can manage many aspects of manufacturing, quality control, logistics, and supply chain and have oversight of processes and timelines at different stages of production. There is less risk of wait times for technology transfer or product delays compared to using a CDMO or outside vendor. If an in-house facility is established early enough in the drug development process, companies can also control manufacturing and delivery of products for clinical trials as well as, ultimately, commercial supply, pending market approval. Another advantage of in-house manufacturing is that it employs a highly skilled and dedicated staff who have a vested interest in the patient communities they serve. Also, these employees take ownership of their roles and responsibilities to consistently perform the many precision-based techniques required for producing cell and gene therapies.
At Castle Creek, our cGMP facility benefits from the validated systems and processes previously implemented at the site for manufacture of a prior FDA-approved autologous cell therapy. But that does not mean the path to building an in-house facility for manufacturing our proprietary autologous celland gene therapies wasn’t challenging, particularly because there was no precedent-setting approach to create the operation. Following are five key strategies that we learned along the way that other cell and gene therapy companies might consider.
1. Be forward-looking and thorough, with no shortcuts
When building an in-house manufacturing operation, ideally, companies should design the facility to allow for future expansion of its pipeline and add the technology, processes, and systems to support it. Manufacturing processes for most cell and gene therapies are lengthy, complex, and may be difficult to expand as production needs increase. In just one example, the manufacture of genetically-modified fibroblast cells for an autologous gene therapy requires a process that must be replicated in individualised batches for each patient.
To meet quality control (QC) and demand at every stage, production may require customised technologies and innovations in manufacturing techniques. Companies should always be thorough in assessment of needs, not take any shortcuts, and invest in advanced technologies that are critical to developing clinical and commercial-ready products. Accepting sub-optimal technologies or any under-developed processes that are not productive for scale up at the commercial level would not be a prudent investment in time or resources.
2. Compliance is essential
cGMP compliance is a critical requirement in developing personalised therapies. Cell and gene therapy companies must focus on implementation of quality management systems to ensure cGMP-compliant processes and methods, and advanced laboratory equipment and technologies play a central role in these efforts. It is especially important to focus on compliance as production transitions from research to clinical to commercial stages. The transition from a development and pre-clinical environment to an organisation that fully bears the compliance mindset requires strong leadership, discipline, and a keen eye for detail. Compliance is not just a bolt-on set of procedures – it is a behaviour and a way of life.
3. Be inspection-ready
As companies are focused on manufacturing safe and effective cell and gene therapies, whether for clinical trials or commercial supply, keep in mind that maintaining a safe and compliant operation is imperative at all times. Processes and systems should be used and managed daily, including consistent and timely preparation and assembly of key documents and records, making them readily accessible, keeping all files current, and having risk monitoring systems in place.
In addition, maintenance of a facility’s physical space and equipment should always be a priority to ensure a safe, functional, and compliant working environment. Constant attention is essential to keep the people, plant, and processes in an inspection-ready mode. There should be no need to scramble to prepare for an audit or inspection –once you attain a high level of readiness, it’s all about staying there.
4. Be collaborative, and accountable
Another key factor in successfully establishing an in-house manufacturing facility is fostering a positive and collaborative corporate culture, which starts with strong company management who lead by example. Management must also be able to recognise their team’s skill sets and put the right people in positions to succeed as well as support them along the way. Team members, from executive leaders to managers to employees at all levels, are encouraged to collaborate and hold each other accountable, including when addressing any issues or concerns.
5. Recognise key inflection points
During the product lifecycle, companies will experience key inflection points when important decisions must be made that may determine their success. For example, companies may need to decide when the time is right to move from manual to electronic systems in terms of documentation or logistics. Assessing, prioritising, and investing in upgrades to operations is an ongoing process. When appropriate, companies may consider striking a balance between working with an outside vendor and conducting work internally.
The major challenges in building an in-house manufacturing facility for cell and gene therapies are determining the appropriate timing to do so and acquiring funding to make it happen. Companies must prepare for every stage of drug development and continually assess processes, equipment and logistics and determine if and when upgrades are necessary. In these efforts, the overall and long-term goal continues to be to bring safe and effective therapies to patients in need.