2004N-0181 - Critical Path Initiative; Establishment of Docket
FDA Comment Number : EC38
Submitter : Dr. Herbert Bresler Date & Time: 08/02/2004 07:08:08
Organization : Battelle
Other Organization
Category :
Issue Areas/Comments
Comment Issues
4. For each problem identified, if a solution would facilitate the development of drugs, biologics, and/or devices for a particular disease or categories of disease, please indicate which diseases would be affected?
Any disease for which cell-based products are under development, particularly autologous products and those produced in small batches.
5. Nature of the Solution. For each problem identified, please describe the evaluation tool that would solve the problem and the work necessary to create and implement the tool/solution. For example, would a solution come from scientific research to
Creation of superior manufacturing systems for cell-based products requires application of systems and manufacturing engineering alongside biology and medicine. New industry standards for best practices in manufacturing systems should be established. Resources (internal and external to FDA) and appropriate FDA guidance could both be provided to assist companies developing cell-based products. Solutions are being developed, but refinement and improvement of these approaches will almost certainly be required. Additionally, while cell-based product manufacturing must be customized to meet the specific needs of each cell-based product, certain principles and best practices can be applied broadly to ensure quality and proper documentation.
One innovative approach to assist the process of creating better manufacturing systems for tissue engineered and cell therapy products is being developed at Battelle. The approach is summarized very briefly here. Space limitations do not permit a full description. More detailed information can be obtained from Battelle, and can also be found in the May 2004 issue of Cell & Gene Therapy (Williamsburg Bioprocessing Foundation).
Development of better manufacturing systems (and their constituent ?devices?) for cell-based products involves the merger of fundamental biologic processes with engineering design. This mixture of technologies and differing approaches to development, presents a substantial challenge and a high probability of failure if the development team does not understand and appreciate the nuances of both. Furthermore, cell therapy and tissue engineering companies typically do not possess the diversity of required to execute the full range of product development processes necessary to conceive and implement a viable commercial-scale manufacturing process.
Much can be learned from the process of designing medical devices. When designing manufacturing systems, it is important to maintain the same flow of activities in a sequence from identification of the user needs through to the final product and detailed manufacturing system design. It is accepted best-practice in medical devices that the elements of engineering design are generally completed in order beginning with user needs and a well-developed product concept. Requirements are then derived from the product concept and user needs. Specifications are developed from requirements, and finally, system architecture (?devices?) is created to meet the specifications.
The first step toward translating a laboratory-based cell manufacturing process into a true commercial-scale system involves an engineering process-flow analysis of the existing manufacturing process. This map clearly defines the various steps of the process and their interrelationship. The map is derived by detailing the steps in the original SOPs as well as observing the manufacturing processes as actually conducted. Manufacturing is mapped in its entirety, including operations outside the traditional manufacturing environment.
In the second step of the mapping exercise, an engineering segmentation analysis is performed. The engineering segmentation analysis begins by dividing the process into functionally discrete process steps. These process steps are differentiated by changes in container, procedure, temperature, environment, reagents, etc. Activities associated with the various steps are captured, as are the core requirements for successful product manufacturing (quality measures).
After the process steps have been mapped, the engineering segmentation analysis aids in revising process steps, altering vessels, and combining vessels and steps. Design and implementation of a new manufacturing system is driven from the engineering analysis. A natural outcome of this process is a SOP that supports commercial-scale manufacturing.
Throughout, efforts to increase the speed and efficiency of the process must not jeopardize the desired biologic results.
6. For each solution identified, please indicate which could be accomplished quickly, in less than 24 months, and which require a long-term approach?
Establishment of critical requirements for manufacturing systems and agreement on best practices could likely be accomplished within 24 months. Incorporation of best practices into guidance documents and acquisition of staff to support new approaches to cell-based product development could be accomplished in that same timeframe, but would more probably be conducted over a longer period as best practices evolve based on experience. While significant progress could be made in 24 months, education of the cell therapy and tissue engineering communities would necessitate a continuing effort.
7. For each problem identified, what role should FDA play and what role should be played by others?
FDA could provide a key educational role. The Agency should also convene discussions on best practices to gather all relevant points of view. Even though the fields of cell therapy and tissue engineering are currently dominated by academic research, industry participation will be very important to find solutions that are relevant for industrial-scale production of these products.

Additionally, the FDA can provide advice, in the form of written documents as well as providing a wide diversity of expertise among its reviewers and advisors.

8. What factors should guide FDA in setting priorities among the hurdles and solutions identified?
FDA should focus attention on those hurdles that, if adequately addressed, would be most likely to yield the greatest increase in licensure of new products. Improved manufacturing preparedness for cell-based therapy companies is an area that would be expected to significantly speed development of these products. This is a critical time for the cell-therapy and tissue engineering industry, when many products are in clinical trials and will need manufacturing assistance to get through the enormous challenges of scale-up. Specific guidance from the FDA on best practices and appropriate, acceptable manufacturing improvement would help these companies as they seek to build on their early clinical successes.
2. Please rank each hurdle identified in Question 1, above, in priority order according to which hurdles create the most severe product development problems.
Manufacturing preparedness and adequate product characterization are the two most critical regulatory hurdles for cell-based therapy companies. They are highly interrelated. Standardized approaches to address these two issues, and tools to measure compliance in each, will be vital to the success of these products.
3. For each problem identified, please indicate the type of drug, biologic, or device to which the hurdle applies.
These comments address issues common to many cell-based products under development, particularly autologous products and those produced in small batches for which traditional pharmaceutical production methods are unsatisfactory.
1. Hurdle Identification. Please describe the product development issue, the nature of the evaluation tool that is out-of-date or absent, how this problem hinders product development, and how a solution would improve the product development process.
These comments address issues common to many cell-based products under development, particularly autologous products and those produced in small batches.

Companies developing cell-based therapies all begin, by the nature of their academic origins, as research companies. They are inclined toward ?process? development. The cell processing techniques employed are inexpensive and flexible. This is entirely appropriate, and even necessary, at an early stage of a company?s development. However, a consistent problem is that companies cling inappropriately to their old manufacturing processes as they advance through clinical trials. The flexibility of labor-intensive, manual processing becomes an obstacle to satisfying business needs and the necessary regulatory requirements. It is extremely difficult, and very expensive, to adequately validate and document all manufacturing operations when relying heavily on manual manipulations. Furthermore, companies often fail to adequately consider the entire manufacturing processes as a system, taking into account all aspects of manufacture, including those steps that take place outside the traditional laboratory environment (for example, harvest of starting material by a surgeon).

Using off-the-shelf laboratory tools to manufacture cell-based products is appealing to companies because they think it exactly replicates the academic legacy process (using pipettes, flasks and other off-the-shelf ?devices? and components). This provides the company a false sense that their process can be performed consistently with these tools. The same flexibility a pipette provides becomes its downfall when trying to validate that a specific step in a manufacturing process is done reliably, and exactly the same way every time, time after time, in a manufacturing setting. One cannot validate (in the true sense) and document that a technician will deliver precisely the volume specified in an SOP every time, when the tool they use allows for many other possible outcomes.

Cell-based product success is critically dependent on manufacturing success. Manufacturing must be improved over the course of cell-based product development to allow for the success of early clinical trials to be translated into products. Manufacturing must change to allow for better control and documentation, while simultaneously enabling scale-up.

New tools for manufacture of cell-based products need to be developed that will control the process, allow for easier validation and provide a basis for better documentation. These tools will have to be customized for each cell-based product because each cell-based product manufacturing process is unique. However, companies distrust changes in their manufacturing processes for fear that those changes will adversely affect the product. Consequently, companies that cling to their legacy manufacturing processes struggle to advance their cell-based products into late phase clinical trials and onto the market. This continued reliance on manual approaches to cell-based product manufacturing is also partly due to the lack of expertise in systems and manufacturing engineering in cell-based product companies. Many companies stall or fail during the scale up phase of their product development.

Legacy processes inappropriately impose specifications and processing "devices" on a manufacturing system. For example, specifying a pipette to move fluid from point A to point B imposes a "device" architecture (the pipette) on the fluid transfer. Using a pipette may not only be unnecessary, but as pointed out above, it may be undesirable, and even detrimental, to a scalable process.

A rigorous but flexible method to approach manufacturing improvement for cell-based products would be a great help. It would allow companies to approach scale-up and satisfaction of regulatory requirements simultaneously. For these reasons, it would also help speed product development.

GENERAL
GENERAL
The Critical Path Document is a seminal publication. It concisely presented the issues related to the causes and possible solutions to the relative lack of new products entering the market. It points out that showing the milestones along the critical path may not provide sufficient guidance for companies to get from one milestone to the next.
Among the companies that struggle to find their way along this path, companies developing cell-based products perhaps have the greatest struggle, mostly due to the fact that the industry is still in its infancy and the methods for characterization, manufacture and delivery of cell-based products have not yet been perfected. Cell-based products currently represent the best hope for treatment for diseases that either have no effective treatment,
or for which treatments are sorely inadequate. Providing those companies with new tools and methodologies to approach their large-scale manufacturing needs will greatly facilitate the development of these promising new products.