March 15, 2022 PAO-02-022-CL-19
Process validation is a requirement of regulatory authorities that involves demonstration of process control. Both branded drug manufacturers filing new drug applications and generic drug companies seeking approval for off-patent products must complete process validation to clearly show that their processes are reproducible and produce batch-to-batch consistent product that meets all specifications set for the starting materials, intermediates, the drug substance, and the final product. Key to this demonstration is the application of the correct and appropriate control strategies across all steps in the overall process for detection of relevant impurities.
Process validation today comprises three phases: process design, process qualification, and continued process verification (CPV). Process design involves side-by-side process and analytical development to establish an optimum process and matching control strategy. Process qualification involves executing a certain number of batches at production scale to show that the process is reproducible and delivers in-spec material.
CPV is the newest aspect of process validation and is performed after the process qualification exercise. The intent is to ensure that the process remains under control by making validation an ongoing activity. As long as a drug product is on the market, the production process used to manufacture it must be assessed on a regular basis to confirm that it remains in a validated state.
There is a great deal of freedom in how to demonstrate that a process is maintained under control. The guidance is designed to allow each manufacturer to implement an optimum system best suited for its products and processes. The drug manufacturer has the final responsibility to perform CPV and must defend the adopted approach during any future regulatory inspection.
In particular, the drug manufacturer must decide what data is needed to demonstrate CPV. The data collected should also enable ongoing process improvement. Smart companies choose data that will support annual product quality reviews as well, which are a separate regulatory expectation. In essence, forward-thinking manufacturers collect a set of data capable to support multiple internal programs while also meeting multiple regulatory requirements.
At Fareva Excella, formal assessments are performed at least annually for products that are produced infrequently. If issues are encountered during a production campaign, an assessment is also performed after the batch run is complete to determine if the issues can impact process validation. For products that are manufactured frequently, assessments are performed after each production campaign.
The need during process validation to demonstrate that processes are reproducible and robust can only be assured if an effective process development approach is taken. Such an approach must take into consideration external variations in raw material quality and address from the outset potential scalability issues across the entire process design space. Leveraging quality-by-design (QbD), it is possible to assess the relevant variables that can influence process quality and consistency and the risk each bears. Information gained through this process can be used to design processes and establish effective control strategies that avoid or at least minimize those risks, leading to a more stable and robust process.
Changes to validated processes can present significant challenges to drug manufacturers. Some changes can be managed within the CPV process, while others require demonstration through comparability studies that the product has not been affected and is still equivalent to the original product produced using the original process.
The first consideration is the ranges for different parameters covered in the validation exercise. If a change in one of these parameters goes outside of the validated range, then additional validation activities are likely warranted. A change in the material of construction for process equipment must also be taken into account. There can be unexpected effects if a process originally performed in stainless steel is then carried out in a Hastelloy reactor or even a glass-lined reactor, and, if this factor was not evaluated during process development, such a change could be significant.
Changes within the supply chain are a third potential issue. For example, if a supplier has two production facilities and uses comparable equipment, the same raw material suppliers, and identical processes to produce a starting material at each facility, it would be a small change if the supplier switched production from one plant to the other, because the impurity profile would be expected to remain the same. It would be a large change, however, if the supplier used different synthetic routes to the raw material at each facility, and additional assessments would need to be performed.
One of the biggest challenges to achieving successful process validation comes during the process development stage. It can sometimes be difficult to find the right balance between doing too much and too little process development. The more process knowledge that is available, the lower the probability that problems will occur during process validation. There has to be a balance, though, or products would never be commercialized. It is essential to determine the level of process development work that is actually needed to ensure that the validation exercise will be successful.
Fareva Excella, in this instance, benefits from the integration of process and analytical development and production activities at one facility. Knowledge about raw material suppliers, equipment materials of construction, vessel geometries, and other parameters are readily available to the process and analytical development experts from the outset of a project. Those constraints help drive the QbD approach and accelerate process development efforts while still ensuring that processes will be robust, reproducible, and validatable at commercial scale. In addition, the production team is kept abreast of the process development efforts as the project progresses. As a result, there is continuous knowledge flow from development through final production, including intermediate scale-up.
In many larger pharmaceutical companies and CDMOs, the development site is located in a separate part of the world far away from the manufacturing facility or facilities. The process development team may not even know initially to which production site the product will ultimately be transferred. A separate technology transfer team manages the process transfer to the production team, which has no knowledge of the development efforts other than provided through documentation. Even if the process is well designed at the beginning, the loss of knowledge flow during such a transfer exercise can lead to real issues during process validation.
In general, the process validation approach is systematic regardless of the process to which it is applied — whether it has three or 10 synthetic steps and whether those steps involve heating, cooling, or pressurization. Difficulty tends to increase when the equipment being used is pushed to its limits, such as a heating or cooling rate at the top of the equipment’s established range.
Reactions run in heterogeneous mixtures may also pose validation challenges, because performance depends on several factors, like heat and mass transfer, as well as adequate mixing. Further on, mixing can vary significantly in small lab- and large commercial-scale equipment. Different mixing conditions can, for instance, result in lower yields, greater by-product formation, or the generation of particles of a size outside the specified range.
The scale and type of mixing is an important factor with impact on validation during scale-up. The performance of a reaction strongly depends on the type of mixing, causing unexpected scale effects if not taken into consideration. The Bourne protocol is used to judge the impact of the mixing type (micro-mixing, mesomixing, and macro-mixing).
Mixing issues can be exacerbated when the heterogeneous mixture includes a complex, special catalyst for which availability may be a problem and quality may be variable. Furthermore, for hydrogenation reactions, additional precautions must be taken to avoid poisoning the catalyst, which halts the reaction.
The job of a CDMO is to adapt a client’s process in an ideal way to the equipment that the CDMO has and to finally produce the drug substance using a validated process. The optimum CDMO has the capabilities to perform almost all needed tasks at one site without the use of numerous external laboratories.
An ideal CDMO partner also has the ability to meet the specific needs of each client. For clients that have their own process validation knowledge, the CDMO must be able to work with the client’s team to establish an appropriate strategy for performing the validation, addressing any issues that might arise, and assessing the results. For virtual pharma customers with little internal process validation resources, the CDMO should have not only development and process validation knowledge, but also onsite regulatory expertise to support the initial product filing.
With respect to process validation itself, trained and knowledgeable personnel — combined with open and transparent communication between development and production teams — is also essential so that as little knowledge as possible is lost during transfer from one to the other.
Similarly, open and transparent communication between the CDMO and client is necessary to ensure that potential problems can be identified early on and preempted and that any issues that do arise can be rapidly resolved. Clear timelines and good project management are also important.
Process validation is a significant endeavor. It starts with development, moves to the first validation batches, and then continues throughout the life cycle of the product. Good project management and transparency with the client are critical for ongoing success.
At Fareva Excella, we have a complete process development unit as well as a development laboratory with access to all of the instruments and methods typically used in the pharmaceutical industry today to establish sound scientific specifications. These groups are located at the same facility as our commercial production area, making it possible to smoothly transfer processes from development to production. Our development colleagues attend the production runs and provide advice and training. Production personnel also follow the development process and provide input as needed. As such, there is excellent communication with no loss of process knowledge.
Furthermore, when a client transfers a process into Fareva Excella, we not only run the process in the development lab as provided, but also explore a wider design space. This approach is important for creating knowledge and understanding about the process and potential events that could lead to deviations — information that should not be discovered during the validation exercise.
Fareva Excella also has the ability to run a wide variety of different analytical methods and therefore can support many different experimental runs in our development labs with the right analytical techniques. In addition, access to such a wide range of methods allows for effective control strategies for many different processes run in the various types of equipment we have in the manufacturing facility. Our analytical scientists are also well-positioned to support the resolution of unexpected issues during the performance of validation batches.
Overall, Fareva Excella has performed more than 100 process validations during the last 30 years. We recognize that developing robust processes from the outset by building broad and fundamental process knowledge minimizes future validation and revalidation work. We also realize that the more substance we add to our process validations, the better we understand our processes. That greater understanding enables us to help our customers extend their product life cycles, because we are positioned to support a product across its entire lifetime. This capability is a critical advantage for our customers.
Juergen Utz is the Director of Project Management API at Excella GmbH & Co. KG. He has 24 years of experience in the pharmaceutical industry. His current main responsibilities cover management of product transfer activities from and to Excella, product change management as well as API process and cleaning validation.