Click here to read part one of this article.

Development

The ultimate goal of the development stage is to characterize and understand which process parameters, materials, and material attributes are important to ensuring that the product will consistently meet the requirements needed for its’ safety and efficacy.

While development activities will vary within each product type and even from product to product, there are some key elements to any product development. First of all, product development should utilize sound and practical scientific methods. While this may seem obvious, often experiments are done poorly lacking appropriate controls and clear documentation. A good understanding of design of experiments, or DOE, provides the foundation for good development work.

Multifactorial experimental designs are particularly useful. Creating the risk documents discussed in the planning stage is particularly important. These risk evaluations not only drive the development process, but also will provide the basis for key decision making and should feed directly into the CMC section for IND’s and ultimately NDA’s or BLA’s.

In addition to the experimentation it’s important to identify and source the materials that will be needed. If it’s preferred to identify and use GMP grade or USP grade materials in the development process this may save time later and should be defined in an SOP. Outputs from the Development stage should include risk documentation, material specifications, a master batch record, initial evaluation of container closure systems, analytical methods, etc.

A stage end review is critical at the end of the development stage. This is because it implements what is known in the device world as a “design freeze”. The design freeze doesn’t mean the product is frozen forever, but it marks the implementation of change control.

During the development process documents may be changed and managed under the document control system with little regard for the impact on the product. But demarking the end of the development stage with a formal stage review puts the product under change control where changes have to be evaluated for their impact.

Production

In our example, we’ve split the ICH’s commercialization stage into Production and Commercialization. The reason for this is that we would like to make clinical material in small scale batches and we’d like to do that in a production environment.

In the ICH version this occurs under development, but in reality it’s better to transfer this to a production or pilot stage, where the product is made under GMP, with various caveats, such as process validation, method validation, packaging system validations, not yet having been completed.

During this stage we are using GMP, we are qualifying equipment and facilities prior to use and we are ultimately going to end up at commercial scale. These materials will be used to support Phase I and II and ultimately Phase III clinical materials. Any changes will be made under change control and changes will be evaluated for their impact to the risk management of the product.

Commercialization

The commercialization stage is the final product is on the market stage. The key factors between this stage and the production stage is process validation has been completed, the regulatory filings have been completed and approved and the product is under full GMPs and all supporting validation is in place. We are now at a stage where we are monitoring in-process and final product control parameters and looking for intra and inter lot variability.

In our example cell-based product, we are monitoring cell viability and concentration at key manufacturing points as well as other process parameters which may include agitation rates, metabolic measurements (O2 consumption or CO2 output), protein markers, degradation products, etc.

Obsoletion

Obsoletion of the product is the exit strategy. As previously mentioned it’s how and when we stop manufacturing, and how we phase out the various aspects of monitoring the process, such as product complaints, discontinuing or wrapping up ongoing stability studies, planning out the destruction of reserve samples and records.

Technology Transfer

You might have noticed, we skipped over the technology transfer stage defined in the ICH standards. This is intentional as this is another error in the ICH. Technology transfer is not a stage per say but a process which is implemented whenever technology is transferred from one group to another. It’s a method and process for transferring all of the known design information. Most typically the technology transfer occurs between development and production stages as the product and process moves from a development department to the manufacturing department.

However, the technology transfer may occur at other times as well. For example, in our depiction here of PLM it may also occur between a pilot plant during the production stage and the full-scale manufacturing plant at the commercialization stage. It also may occur anytime during either of those stages if we transferred the process to a CMO (Contract Manufacturing Organization). Or if we setup a second manufacturing plant to increase the capacity a technology transfer would again occur between the original plant and the second plant.

Documentation

Lastly, being in quality we have to discuss documentation. Another gap in all the ICH documentation is now that we have all this documentation of the stage end reviews, the risk assessments, the experimentation and validation activities how do we keep track of it all? In the device world we refer to the Design History File, or DHF. The same concept applies to pharmaceutical and biotechnology products. As part of the development activities, we initiate a product history file or design history file (we might refer to it as a PHF, or a DHF).

If we printed out all the documentation at any given time and put it in a big binder that would be the PHF. However, since our body of knowledge is constantly growing and various documents in it may be being revised, the best practice is to create a PHF index (or PHFi). This is simply a list of each PLM stage and the document titles in each one in an organized manner.

This allows anyone to review the PHFi and look for the information in an organized manner and allows for us to provide this in an audit, so what we did and how we did it and the reasons we did it or there for the world to see.

The Takeaway

I hope this brief discussion of the product lifecycle management process has been useful. It really is a good way to realize product. I’ve realized over the past few years that this concept is not very well understood, and even less so in the biotechnology and pharmaceutical space.

More often than not quality gets stuck on single line cross-out corrections and whether or not documents are in a fire-resistant cabinet, and those are important things, but recent 483’s and warning letters indicate, FDA and other regulating agencies are becoming less focused on these details and more and more on how we make the decisions we do and document the process of realizing product over its’ entire lifecycle, how we validate the processes and methods and how we analyzed the risks associated with the product.

A good SOP with clear direction and distinction of the various product stages will go a long way in providing this evidence.