Your Questions Answered - Technology Transfer in Sterile Injectables
In April, our sterile injectables experts presented a Technology Transfers in Sterile Injectables webinar. For more insights, take a look at the Q&A as it relates to the three phases of a technology transfer for a sterile injectable project.
General CDMO questions
Is the CDMO selection and qualification process scoped in a way to avoid issues during qualification activities?
During the initial scoping of a project, to minimize issues that may arise during qualification activities, it’s important that the CDMO thoughtfully evaluate the site the product may be transferred to. One should aim to identify any risks early on and work with your CDMO to mitigate them. Manufacturing quality product is a true partnership that requires information exchange. The exchange of product information regarding incompatibilities or sharing that a study hasn’t been done to evaluate incompatibilities helps the CDMO strategize a way to turn required information that is unknown at that moment into helpful data so that both the CDMO and partner can make decisions to reduce process steps/quality/regulatory risks. We also recommend scheduling a due diligence visit, either virtually or on site.
Broad tech transfer questions
Which are the major regulatory compliance requirements that relate to SI tech transfers?
There is a lot to consider for SI products. Incoming QA, manufacturing control, release and stability are key areas to consider. Specifically, for SI products, sterilization processes are an important consideration as the selection of aseptically filled versus terminal sterilization for the product could be challenged by the jurisdiction reviewing the filing. Understanding where the product’s regulatory filings will be submitted will help navigate which guidelines should be followed.
What are the major challenges a CDMO may face in connection with tech transfers to China; how may a CDMO mitigate such risks in planning and execution?
It is important to understand that, even though a receiving site is in China, the site may manufacture product for jurisdictions other than, or in addition to, China. To manufacture products at a site in China for global markets, a CDMO must know its site’s status with respect to the regulatory bodies in jurisdictions applicable to such products, including, for example, what experience the site has in terms of interacting with such regulatory bodies and its inspection history. This information will help to plan the transfer properly.
When the goal of the transfer is to commercialize a product in the Chinese market, the Chinese regulations must be clearly understood, as they are dynamic and distinct. This applies to global products that are transferred into China as well. The regulations appear to be in a constant state of evolution which makes it important to stay on top of them.
How can we further explore the know-how part of the tech transfer process?
Risk assessment can be a good tool to explore the know-how portion of a tech transfer. Working together to walk through the manufacturing process from start to finish helps the receiving site understand the product and helps the sending site/customer understand manufacturing control and other important considerations. This risk assessment discussion may result in more information sharing and could help reduce product and manufacturing risks. Having conversations with the technical experts and counterparts from the sending site will also provide knowledge as to how the product would be manufactured.
Which is the most influential factor that affects the process variability for SI tech transfer and why?
The process robustness, or rather lack thereof, is the most influential factor during a tech transfer. With a robust process, the transfer will be more straightforward but if process controls or methods are less robust then there will be more challenges and even failures.
For a product in development or co-development phase, consider using tools such as Quality by Design (QbD) and Design of Experiments (DoE) to explore the boundaries of the process parameters. For a commercial product, if a process lacks robustness for certain aspects (e.g., testing, compounding, filling, etc.), then it is important to gather as much historical data as possible to fully understand the appropriate controls that need to be put in place.
Failure Modes and Effects Analysis (FMEA) is a useful tool to understand the risk and establish mitigation plans. At the receiving end, ensure the equipment can deliver the controls needed is an important consideration as well.
What is the normal time span that is required to complete all three tech transfer phases?
The time span varies from program to program based on scope. A typical example is one to three months for the scoping phase, one to two months for the planning phase, and, depending on project scope, it could take some time to source the necessary equipment prior to the execution phase.
A tech transfer is only truly done once all applicable regulatory approvals are received and the timelines for the submission and approval process can vary according to jurisdiction.
How is the Failure Modes and Effects Analysis (FMEA) managed throughout the lifecycle of the project?
At the product development phase, the FMEA tool helps identify potential failures in the process and allows an opportunity to take steps to modify the design or add controls in the process. When conducting tech transfers, it is recommended to review the FMEA that was done during the development phase and assess if the updated design and controls are suitable. Also, depending on the gap assessment between the sending unit and receiving unit, an updated FMEA is beneficial to identify additional potential failure modes and determine the mitigation required during the tech transfer project. FMEA is initiated and updated during the initial tech transfer and immediately after an engineering run if mitigation steps were challenged. The FMEA is finalized prior to GMP runs (i.e. clinical or registration) and then is updated again post GMP runs if there were any additional mitigation steps challenged and/or to document the outcome prior to process validation/commercial batches.
Is it possible to connect gap analysis with risk assessment?
Yes, the gap analysis and risk assessment are connected. When a tech transfer occurs, the gaps are identified by comparing the attributes from the sending site and receiving site. The attributes may include equipment, utilities, SOPs, and consumables. When a gap, (i.e., a difference) is identified between the sending site and the receiving site, then there is likely a risk associated with the gap.
Depending on the nature, type of the gap, and the product robustness, the risk can be ranked at low, medium, or high.
There may be different types of risk assessments depending on where the product is in the lifecycle. For this case of linking the gap analysis with risk assessment, the risk being evaluated is to the manufacturing process and potential for success of the tech transfer. There is also a regulatory risk assessment, which is used to understand/agree to mitigations for potential regulatory scrutiny of the application when submitted.
How are the acceptance criteria for the temperature mapping of lyophilization validation made before manufacturing the exhibit/registration batch?
Temperature mapping of lyophilization chambers is executed as part of the initial chamber qualification work, or when shelves are replaced or repaired on the system, which will require re-qualification. Temperature shelf mapping is not usually done for technology transfers and acceptable parameters are tied to equipment capabilities, such as reaching certain temperatures, minimum controllable pressure, and shelf temperatures.
Each product could present differences regarding how the final container will behave even in similar or equivalent chambers. A Kv (heat transfer coefficient) parameter is unique to each vial/chamber combination, which could lead to slightly different outcomes when manufacturing a product in multiple, different chambers.
What are the considerations involved in a risk management plan?
One consideration for a risk management plan is ensuring a CDMO evaluates the process from incoming materials through packaging/distribution. Another is that a CDMO considers product knowledge or other inputs that may impact manufacturing processes. For example, consider how your analytical methods are used to support the manufacturing process. If in-process testing is required, the length of method should be evaluated for impact on efficient manufacturing timelines and solution hold durations. A similar evaluation for final release testing may be needed if [[the client] is] expecting shortened cycle time for batch release. Risk mitigation plans also extend to the regulatory submission/approval as well. Risk based strategies should be well considered and plans to mitigate regulatory scrutiny should be agreed to with the partner ahead of the submission.
What are the factors involved in a mitigation plan in the execution phase and when it is finalized?
There are various factors involved in a mitigation plan; factors may include risk to product quality, likelihood of occurrence, detectability, and the frequency of occurrence. It’s also important to weigh in financial factors if these issues happen frequently and cause manufacturing delays, it may be worth fixing to reduce costs. The main consideration is to make sure the decision is properly documented in the risk assessment.
When is the best moment to start change control process?
The best time to start change control process is during the scope/defining phase as key activities should be captured in change control and put in open state to execute immediately when done with the planning phase. Change control may be broken into development and commercial phases if each are to occur a few years apart.
Action items can be captured during the scoping phase that are critical to milestones and added to the change control to ensure activities are tracked and data/documentation is captured. CDMOs should assemble a team to define action items with representatives from all the areas the project will touch (e.g., manufacturing, engineering, regulatory affairs, batch records, and development support teams, etc.) to account for actions needed to be completed.
Why were elemental impurities not mentioned during the segment of the presentation about transferring to a CDMO?
Elemental impurities are an important risk factor to consider that falls into the ever-changing regulatory landscape. Elemental impurities should be part of an overarching site strategy and built into the program during the scoping/defining phase of a project.
In the engineering run of lyophilization, what are some important technical factors to consider?
From a product perspective, examples of certain important technical factors to consider for a lyophilization engineering run are the vial size, the fill volume, type of formulation (e.g., the percentage content of solids, salts, and sugars), and temperature of glass transition for the formulation considered, all of which will define lyophilization cycle parameters. There may be other factors to consider as well, this is not an all-inclusive list.
From an equipment perspective, important technical factors to consider are the system capacity to control shelf temperatures and pressure around set points. For example, whether the lyophilization cycle requires parameters to be controlled within a very small range, the Kv (heat transfer coefficient) for the specific vial/chamber combination, the proper system capacity to remove water from the product, and if volatile solvents are present in the formulation are key to to understanding the system’s ability to handle such factors.
A water run typically only serves the purpose of evaluating commodities (e.g., vials and stoppers), how well the fill line equipment handles those commodities, and the lyophilizer chamber loader and capper machine operations.