Transfer of soft capsule products between 2 CMOs: best practices
The transfer of softgel capsule manufacturing between contract manufacturing organizations (CMOs) is a complex process that is often underestimated.
There may be various reasons why a company would need to transfer the manufacturing of softgel capsules from one facility to another. For example, capacity constraints at the current manufacturing site can necessitate a move to a CMO with greater production capabilities to meet growing market demands. Moreover, quality issues, such as deviations in product specifications or lapses in Good Manufacturing Practices (GMP), may prompt a transfer to a facility with a more robust quality management system. Lastly, commercial considerations, like cost savings through outsourcing to a specialized CMO, can also be a key factor. In many cases, a transfer of a softgel product is a complex process that often has the characteristics of new product development.
In this article, we explore the primary challenges that arise during softgel capsule transfers between CMOs and examine the strategies and best practices used to overcome them. We also deep-dive into the regulatory considerations that must be navigated to ensure compliance and product safety throughout the transfer process.
Why are there differences in manufacturing processes?
Softgel capsules are commonly produced by CMOs, each of which may adhere to slightly different standards and processes, particularly in processes like encapsulation, manufacture of gel mass, and drying. These differences can significantly impact the transfer process.
For instance, the batch sizes and processing conditions for gelatin mass (temperature, mixing speed, and duration) are standardized at each facility based on the available equipment and likely very limited adjustments are possible. Moreover, each CMO uses a particular design for encapsulation tooling. Thus, even if tooling for the same nominal capsule size is used, the applicable ribbon thickness and capsule shell weight may be different across various manufacturers, effectively leading to a different product composition.
The drying process is typically also standardized at each manufacturing facility and is determined by the equipment (i.e. trays or tumblers) and the applicable room conditions (relative humidity and temperature).
As such, a process that works seamlessly in one facility requires significant adjustments in another due to differences in equipment and standardized processes.
The expertise and data gap challenge
A common challenge in transferring softgel capsules from one CMO to another is the gap in expertise and data. The product owner or customer often does not possess deep technical knowledge about the softgel product, and the original manufacturing facility typically is not willing to cooperate during such transfers, as it leads to a loss of revenue. This lack of expertise can lead to incomplete or imprecise data being provided to the new manufacturer. For example, if the original manufacturing process or product composition is not provided in sufficient detail, the new CMO will face difficulties in replicating the product accurately.
IP considerations for transfers of softgel capsules to a new CMO
Before transfer to a new CMO is initiated, the product owner should conduct a thorough freedom-to-operate (FTO) analysis of contractual and intellectual property aspects. Sometimes, CDMOs that have developed the soft capsule product as a fee-for-service project, use their own background IP (e.g. gel mass manufacture) that may not even be shared with the product owner and may be submitted to authorities by the CDMO directly using a drug master file (DMF).
In other cases, the company may have all data related to the background IP of the CDMO, but is not allowed to provide it to third parties. This effectively limits the possibility of a 1:1 transfer to a new facility, as the facility needs to reverse-engineer the product to some extent without any data. In practice matching the product composition exactly is impossible, and changes to the drug product composition are inevitable.
How is a transfer of a soft capsule to a new CMO conducted?
Practically, each transfer of a softgel product often resembles the development of a new product. The new CDMO must engage in extensive development work to adapt the transferred product to its standard processes and equipment. This often involves the following steps:
Freedom-to-operate analysis: as described above, this step involves assessing contractual obligations and intellectual property rights to identify any potential constraints.
Review of relevant dossier sections by the CMO, identification of transfer scope and potential changes.
Characterization of the current product, at least for physical parameters: This involves a thorough assessment of the softgel capsule's dimensions, weight, and other critical quality attributes to establish a baseline for comparison during the transfer process.
Depending on the degree of required changes and available information, the transfer of manufacture may entail a limited scope (e.g. manufacture of a technical transfer batch for familiarization and confirmation of changes)followed by process validation and stability studies. However, it can also have the characteristics of a full development program, especially in case some background IP of the original CMO cannot be disclosed, e.g. on shell formulation.
Depending on the product classification, clinical studies may be required to establish the new manufacturer as comparable to the original CMO.
Update of CTD file - this is typically done by the product owner based on source data provided by the new CMO.
Common changes to the dossier of soft capsules during transfers
The transfer of softgel production also involves navigating complex regulatory landscapes, often in various countries where the product is registered. Regulatory agencies require detailed documentation of manufacturing processes, and any changes in the production site can trigger the need for additional stability studies, validation processes, and possibly even clinical trials to ensure that the transferred product meets all safety and efficacy standards.
The typical changes required during the transfer of softgel capsules depend on the scope of the transfer and often impact the entire Module 3. The following CTD sections likely will need to be adjusted to accommodate a new manufacturing facility for a softgel product:
3.2.P.1: Description and composition of the drug product: likely due to changes in shell weight and calculated dry capsule weight
3.2.P.3.1 - Manufacturers: something missing here
3.2.P.3.2. Batch formula: in case different batch sizes of fill mass or gelatin mass are applied at the new facility
3.2.P.3.3- Manufacturing process and controls: Typically at least minor adaptations may be required (e.g. gel mass manufacturing process and/or drying process), as well as further adaptations may be needed depending on each product. Moreover, adaptation of IPC tests and frequency may be required during transfer.
3.2.P.4. Excipients:- in some cases, the suppliers of excipients are changed to adapt to qualified suppliers at the new facility. In such cases, changes to this section may be needed in case of differences in specification or especially in case new gelatin suppliers are introduced.
3.2.P.5.1 Specification of the drug product: During the transfer, the product specification may need to be adjusted, even so slightly (e.g. in case of different capsule mass).
3.2.P.5.2 and P.5.3. Analytical procedures: in case of differences in testing methods between the two facilities, information on the methods and their validation has to be provided
3.2.P.5.4 - Batch analyses: CoAs of DP batches produced by the receiving unit have to be supplied
3.2.P.6. - Reference standards: in case the analytical methods are transferred too, this section may need to be updated.
3.2.P.7. - Container closure system: while the primary packaging of the finished product typically is not changed during transfers, the primary bulk packaging material may be adapted to the new CMO’s standard, and in this case, this section has to be updated as well.
3.2.P.8. - Stability data: the stability data of DP batches produced at the new CMO must be provided.
What are the best practices for the transfer of soft capsule products between 2 CMOs?
To mitigate the challenges during product transfer, we recommend keeping in mind these best practices:
Build product know-how: Ensure that sufficient know-how is available at the product owner beyond the documentation in the dossier to allow the realistic definition of critical process parameters and material attributes and efficient information exchange.
IP ownership: If possible, the development should be performed at a CDMO which allows for full IP ownership of the product by the customer rather than relying on the license of the CDMO’s background IP.
Regulatory strategy: Involve DRA from the onset and have a clear view of the potentially required data in support of the anticipated changes.
Need support with transferring your softgel from one CDMO to another? Our team is here to help. We offer:
+ We provide independent expertise and a hands-on approach
+ We perform technical gap analysis and FTO analysis for transfer
+ We help identify strong and competent partners for commercial production
+ We support you during the RfP process and COGs benchmarking
+ As independent softgel experts, we make sure that the critical product data is available and manage the entire transfer process from one CMO to another