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Jennifer Markarian is manufacturing editor of Pharmaceutical Technology.
Transferring the manufacturing of a drug from one scale to another or between manufacturing sites presents both technical and business challenges.
A successful transfer of a drug manufacturing process-whether from pilot to commercial scale or from developer to contract manufacturing organization (CMO), for example-requires a thorough understanding of the product, the process, and the equipment by both the sending and receiving site teams. Quality-by-design (QbD) approaches are increasingly used for developing this understanding and for conducting verification of a transfer. As with any project involving multiple teams of people, good communication is crucial.
Alignment and communication
Alignment between the receiving and transferring sites is one of the most significant challenges of a technology transfer. “More than the technology or the knowledge itself, the alignment of systems (for example, information technology and quality systems) and mentality, culture, and approaches to issues between these two main stakeholders are the most important factors for success,” says Mirko Gabriele, technology transfer manager at Patheon’s Ferentino, Italy site and co-leader of the Parenteral Drug Association’s (PDA’s) tech-transfer interest group, which was formed in July 2015. An external technology transfer, which requires aligning two groups from different organizations, is typically the most challenging to coordinate. Gabriele notes that it is crucial to face the issue of alignment head-on at the beginning of a project, as well as to evaluate and quantify alignment of systems throughout the project life by establishing and tracking key performance indicators. Evaluating system alignment is a crucial part of selecting a receiving site, says Gabriele; “If a receiving site is close to the transferring site-same systems, same approach, same mindset-it will be easier to work with them and there will be less risk associated with the project.”
Early communication between the sending and receiving sites at the beginning of a transfer process is crucial. “We prefer to have a face-to-face kickoff meeting at the beginning of a transfer to establish a robust transfer process,” says Stefanie Kortenbreer, deputy head of product transfer for Rottendorf Pharma. A QbD approach involves experts from various parts of the company, including development and production, who perform a risk analysis and determine the critical process parameters (CPPs), for example. “It is better to spend more time in the beginning to avoid changes later,” Kortenbreer explains.
Sharing knowledge is crucial for technology transfer success. “Some can debate that intellectual property protection is needed for transferring site safety and, therefore, the less you share, the more you protect yourself. However, the knowledge of what you are doing is a ‘condition sine qua non’ of technology transfer. You must know what you are doing in order to put in place an appropriate governance of the process,” says Gabriele.
Knowledge about the development of a product and process makes data points more useful. For example, “transfers typically include the appropriate process settings, but it would be useful to know how those parameters were selected and what flexibility might exist,” says Susan J. Schniepp, fellow at Regulatory Compliance Associates. She advocates sharing information about the results and conclusions related to investigations and deviations encountered during product development, because this knowledge can help save time should issues be encountered during the technology transfer activities. “The more knowledge [the receiving site has] about the product going into the validation activities, the smoother the activity will go. Bottom line--sometimes we learn more from our failures than our successes, and this information should be shared during a technology transfer project.”
Process and equipment concerns
Aligning the process equipment and systems is no small feat. Site readiness in a GMP environment is a logistical challenge that requires a significant amount of up-front work, says Bill Randolph, vice-president of technical services at Janssen Supply Chain. This preparation includes identifying and setting up data-processing systems, preparing for documentation requirements, planning cleaning validation for the introduction of new APIs, transferring production and cleaning methods, qualifying manufacturing equipment, and ensuring that laboratory equipment and capacity are prepared. An organized system to coordinate these activities is essential. As part of its supply-chain reliability program, Janssen established a taskforce dedicated to building a technology-transfer checklist. “Developing a tech transfer checklist pre-defines all transfer procedures and identifies functional responsibility and ownership of each operation,” says Randolph. “It clearly documents the protocols for the sending and receiving site and summarizes the description of the manufacturing process, process flow, materials, and equipment of the sending site and proposed manufacturing strategy for the receiving site. Having a system like this in place is important because it outlines the global standard for equipment, including instrumentation and data collection, to reduce development work during transfer. Additionally, identifying equipment-independent process control parameters for tech transfer is helpful when the equipment trains are different.”
Product transfer between manufacturing sites can be particularly difficult if there are differences in equipment, such as size/capacity, material handling, and automation/process controls, notes Randolph. Translating a process to new or alternate equipment requires understanding differences in parameters such as mixing intensity, heat transfer, and airflow.
Performing a gap analysis early in the planning stages can identify any differences in equipment, adds Kortenbreer. “Once the gaps are identified, the design group members, which include experts from various departments, put their knowledge together to identify risks, using risk analysis tools like failure mode and effects analysis (FMEA). The group can decide if engineering batches are needed and how many at what scale, as well as whether a design of experiments (DoE) is needed to verify CPPs.” Rottendorf has found that running an engineering batch, at full scale but prior to the GMP validation runs, is useful in identifying any deviations that were unforeseen in smaller-scale batches. “For example, we found, in one case, that a longer compression time was needed at the full scale. We also discovered that the equipment became warmer because of the longer dwell time and that this temperature change affected compaction. Parameters needed to be adjusted to compensate,” explains Kortenbreer.
When the equipment is unfamiliar to the receiving site, as may be the case with new technologies such as continuous manufacturing, process analytical technology, multi-layer compression, or micro-tablet technology, additional personnel training is required for existing and new employees to ensure that they understand the new operations and can deliver the same level of product quality and reliability, says Randolph.
Older products and processes, on the other hand, might need to be updated. For legacy products, “analytical methods may not meet current regulatory standards, reliability needs, and/or best practices, and may require further development,” comments Randolph.
When scaling up from pilot-plant to commercial scale, challenges “are often technology specific and usually occur when intermediate quality attributes are influenced by process scale or equipment differences (e.g., blending and material handling),” notes Randolph. Solutions employed by Janssen Supply Chain include using process models to assist in establishing process parameter estimates and standardizing equipment if possible. Continuous manufacturing provides benefits for scale-up (see "Continuous Manufacturing Eases Scale Up for Solid Dosage").
Whether processes are new or old, risk-based approaches are commonly used to identify how processing steps and equipment will impact critical quality attributes (CQAs). “Evidence from previous experience, process development, and the literature helps define CPPs to be monitored and validated. Mitigation plans must be put in place where needed. The purpose is to reduce, as much as you can, the risks to the quality, safety, and efficacy of the product,” explains Gabriele. A risk-based approach will also highlight areas of high uncertainty, where additional knowledge is needed, as discussed in PDA’s technical report on technology transfer (1).
Process validation trends
Traditional process validation, which calls for three validation batches, is required by European Union GMPs (2) and is still widely performed globally, even though FDA has moved to continued process verification based on a lifecycle approach and on monitoring CPPs to ensure that a process remains in control (3).
“We have been performing technology transfers based on a QbD approach and have seen increasing requests for this approach over the past two years,” says Marcus Spreen, head of strategic planning at Rottendorf. “We expect to also see more requests for continued process verification in the near future, although most still want three validation batches.” He explains that Rottendorf already tracks CPPs and evaluates them annually, and expects that continued verification will be similar, perhaps with more frequent reporting.
Even apart from government regulation requirements, the industry is changing its view of process validation from a limited evidence of the end result of the development and transfer process to a more holistic view of the “overall chain of events that brings a molecule from the lab to the patient,” adds Gabriele. “The industry is moving from a standard, fixed number of batches to a scientific approach in which data coming from several process stages are evaluated and used to plan, and later on confirm, that a robust, consistent, and safe process has been transferred.” In the approach laid out by FDA’s 2011 process validation guidance (3), the commercial manufacturing process is based on knowledge gained through development and scale-up, and continued process verification ensures that a process remains in a state of control and changes, improvements, additional information from operations, quality, and development are properly taken into consideration, notes Gabriele.
1. PDA, Technology Transfer: Technical Report No. 65 (Bethesda, MD, 2014).
2. EC, Eudralex Vol. 4, EU Guidelines for Good Manufacturing Practice for Medicinal Products, Annex 15: Qualification and Validation (Brussels, Mar. 30, 2015).
3. FDA, Guidance for Industry: Process Validation: General Principles and Practices (Rockville, MD, January 2011).
Article DetailsPharmaceutical Technology
Vol. 40, No. 4
When referring to this article, please cite it as J. Markarian, "Technology Transfer Connections," Pharmaceutical Technology 40 (4) 2016.