Scale-up and Tech Transfer: From Development Lab Studies to Commercial Production

A technology transfer is the moving of a product and process knowledge between development and manufacturing and within or between manufacturing sites to achieve project realization. Key reasons why pharma and biotech companies undertake technology transfers is to ensure an adequate supply for the patient and that there is a backup strategy for production, which is necessary to manage risk in place. Additionally, there may be a lack of appropriate resources/capacity for process optimization, commercial production, secondary packaging, and/or supply chain management. A technology transfer is also necessary for scale-up projects to achieve better efficiency for manufacturing due to the need for a larger batch size (e.g., when transferring from clinical to commercial manufacturing for product launch).

Due to its complexity, every tech transfer has a high risk and involves strict regulatory requirements and adherence to detail. If attention is not paid to the details, the implications of a poor transfer can have serious and lasting consequences. Therefore, expertise and strong project management are essential.

The necessities of a successful technology transfer

The transfer of an aseptic manufacturing process involves numerous development steps and challenges, especially because multiple partners and sites are usually involved. These include the sending unit (defined as the involved disciplines within the organization where a designated product, process, or method is expected to be transferred from) and the receiving unit (the disciplines where a designated product, process, or method is expected to be transferred and executed).

From a regulatory perspective, a technology transfer of an aseptic commercial product from one cleanroom to another may not differ much in regard to time and effort compared to the initial development and design of the manufacturing process. The scope of such a transfer is, therefore, determined by multivariable aspects, including filing strategies, special arrangements with authorities, and the commitment to accepting potential operational and methodical changes enabling the achievement of state-of-the-art processes.

Managing high process complexity

The stakes are high, and the processes involved are complex with possible unforeseen challenges. A good starting point is the creation of a dedicated team with the necessary skill sets and know-how in addressing multiple areas of the process. The team should include experts from development, production, quality assurance, regulatory affairs, quality control, and qualification/validation. They are responsible for facilitating and executing the process and coordination with the technology transfer/project leader. Roles and responsibilities for all team members involved must be agreed upon, and a system that ensures adequate communication and feedback of information, including a confidential agreement between parties, must be established.

The inception of any process transfer is the process validation approach (Figure 1), which is based on the US Food and Drug Administration’s (FDA’s) Guidance for Industry: Process Validation: General Principles and Practice (1). Its purpose is to always achieve a robust and reproducible manufacturing process with consistent quality at the receiving site. The following sections are the major project steps of a tech transfer.

Process development. A successful transfer includes an initial comprehensive process development based on appropriate relevant documentation and on the application of holistic risk management, according to International Council for Harmonisation (ICH) Q8 (R2) Pharmaceutical Development guideline (2). The assessment of potential gaps in the planned at-scale manufacturing process and derivation of recommended development lab studies will assist in identifying and evaluating any differences between the transfer sites. Additionally, the assessment of generated data leading to proposed operating ranges also helps to identify any critical process parameters that must be controlled to meet critical quality attributes (CQAs) during process design.

Process design. The knowledge gained through the development of the drug product and the experiences of scale-up activities determines the manufacturing process to verify that the process delivers consistent quality for the product. This is achieved by implementing a control strategy at the receiving site for identifying and controlling sources of variability in materials and processes. To develop the most suitable process, technical batches and initial good manufacturing practice batches are designed and supervised, defined ranges of operating parameters are verified through assessment of the potential impact on quality attributes, and obtained data of process robustness are evaluated and assessed. Finally, a risk assessment is performed to determine the impact of process parameters on quality attributes.

Process performance qualification. During this stage, the process design is evaluated to determine if it is capable of a reproducible commercial manufacturing approach. Revisiting the process design data, the related risk assessment, and the critical assessment of defined process parameters that support the guiding process performance qualification (PPQ) strategy are necessary. In addition, PPQ batches are supervised, and the data are assessed against pre-defined acceptance criteria. The coordination of change control as a required step prior to the first commercial batch is also key.

Continued process verification. This final step ensures the process remains in a state of control during routine commercial production for market supply. The basis is the establishment of an ongoing programme to collect and analyze product and process data that relate to product quality. With the handover of the qualified process to the responsible production and quality units for commercial manufacturing, the technology transfer is completed.

Overall, strong experience is required in multiple areas, including an intimate knowledge of the nature of the API as well as the attributes and formulation that result from events that may arise during stability testing. In addition, knowledge of filing strategies is essential because some countries have specific requirements for commercialization that can influence the scope of process qualification strategies, such as bracketing strategies, batch sizes, holding times, etc. Regulatory constraints can also influence the change in a production environment. Furthermore, the exchange of processes—including equipment and facilities, cleaning and sterilizing procedures, input parameters, and in-process controls—within or between production sites must be assessed, and the documentation of the transfer with all its contracts, protocols, reports, and instructions must be completed. In-process and release specifications of the product must be adhered to and be comparable with the design space (i.e., the tolerance levels for specific parameters that still guarantee product quality).

Overcoming technology transfers challenges

As noted, there are many challenges to a successful technology transfer. The following examples help to illustrate difficult situations encountered by a contract development manufacturing organization (CDMO) and how they were successfully resolved.

In the first example, based on a paper-based gap analysis (Table I), both the cleanroom processes were analyzed for differences in manufacturing steps and the equipment (e.g., format and preparation of primary packaging materials) (Vetter, unpublished data). One major change was foreseen for the primary packaging materials because the drug product went from a vial to a glass barrel. In this case, washing and siliconization of the glass barrels, the siliconization level/distribution, and ejection forces were analyzed prior to entering the filling line. The two main differences that had to be evaluated were siliconization distribution over the glass surface and content/functionality testing by determination of break loose and gliding forces interaction. Additionally, stability tests for a drug product solution with the silicon oil level—in contrast to a vial without silicon—were carried out. By using specific analytical methods, such as ultra-thin layer explorer and Fourier-transform infrared spectroscopy, the distribution was assessed to fulfil the requirements in combination with the measured break loose and gliding forces to maintain the functionality of the product produced with the new cleanroom process. Additionally, hold-up volume determination and a new design for expellable volume were carried out to fulfil the new requirements of the transition from vial to glass barrel. Because this change of primary packaging material had regulatory consequences, new stability and compatibility studies had to be submitted and adapted.

In the second example, following the relevant attributes derived from the drug product profile—including appearance, particular matter, impurity, and sterility—potential risks around the compounding process, filtration processes, and filling technology using conventional pump systems were identified (Vetter, unpublished data). While this is not unusual given that a larger amount of API is necessary to manufacture more batches, larger compounding equipment was needed in this instance. As such, lab trials were undertaken to support the selection of the appropriate operational parameters for compounding and succeeding filtration processes.

Besides the change in volume, there was also a need to analyze pumping parameters because greater volume and implemented changes created the need for adaptions of fill setup within the cleanroom with regards to equipment dimensions, filter sizing, and fluid dynamics as well as the impact of used transfer medium nitrogen on the filling characteristics of the drug product. As a precaution, the filling operation took place under nitrogen pressure to minimize any potential interaction with oxygen. The degree of oxygen sensitivity in the headspace of syringes is, in most cases, not known and thus not defined as a specification. To maintain the current level of oxygen, the vacuum stoppering technique was additionally used in the cleanroom to reduce the air bubble size to the smallest possible as a second measure of control. Therefore, additional engineering runs were required to evaluate optimal dimensions of fill tubing, fill equipment like break tanks, and fill needles to adjust to an increased line speed because the new fill line had faster filling compared to the donor fill line. Due to this new fluid dynamic of the drug product solution, it was necessary to optimize the filtration rate of the inline sterile filter as well as the transfer force, nitrogen overpressure, in the cleanroom. In the end, an optimized line setup, filling equipment, as well as a filter unit combined with driving force were established to carry out a robust and controlled process. Although engineering runs have the disadvantage of additional cost and time as well as higher consumption of material, their benefits are many and include gaining a greater process understanding and performance while simultaneously training personnel, operations that take place in cleanroom conditions, the demonstration of product comparability, the verification of CQAs, etc. Further, the risk mitigation efforts can be demonstrated, and any issue or manufacturing instruction can be improved.

The third example involved the filling process where the drug product solution had challenging fluid characteristics (Vetter, unpublished data). The goal was to determine a suitable pump system available in the receiving cleanroom. The criteria were to achieve the highest possible accuracy, establish a controlled process, and fulfil critical product quality attributes like appearance, particulate matter, impurity, and expellable volume. In this case, two pump systems with a rotary piston pump as well as a diaphragm pump (Figure 2) were identified to be precise enough for filling assured by supporting product quality data. In the end, the choice was made to use the rotary piston pump due to the timing perspective. Of course, these results were transferred and verified by additional engineering runs at-scale production.

Are you working with the right people?

Due to its complexity and high risk, companies often rely on the expertise of a qualified CDMO that has considerable know-how in process development and the technology to support a tech transfer/scale-up process to product launch. The experience and data gained in previous tech transfer projects can also help reduce timelines.

Tech transfer is only successful when the receiving unit can reproduce the transferred product, process, or method against a predefined set of specifications as agreed with the sending unit of the drug. Thus, a project is ultimately dependent on the skill and performance of the individuals assigned to the project as well as on the experience of the transferring team. The experience of the receiving unit is also important in terms of the drug product, primary packaging, and process and components since the initial gap analysis is paper based. Further documentation is a key element of tech transfer, ensuring consistent and controlled procedures for tech transfer and running the process. Clear documentation should provide assurance of process and product knowledge.

Every transfer must result in as little change as possible to use the existing data and simplify the regulatory approval process. Only then can the handover of qualified processes to responsible production units for commercial manufacturing take place, and the technical lead of potential life cycle projects can be initiated for commercial products.

References

1. FDA, Guidance for Industry, Process Validation: General Principles and Practices (CDER, CBER, January 2011).
2. EMA, ICH Guideline Q8 (R2) on Pharmaceutical Development (June 2014).

About the author

Doris Rottenbusch is the team manager for technology and process transfer at Vetter Pharma Fertigung GmbH & Co KG.

Article details

Pharmaceutical Technology Europe
Vol. 34, No. 11
November 2022
Pages: 18–21

Citation

When referring to this article, please cite it as D. Rottenbusch, “Scale-up and Tech Transfer: From Development Lab Studies to Commercial Production,” Pharmaceutical Technology Europe 34 (11) 2022.