Manufacturing Process Transfers in the Pharmaceutical Industry:
A Best Practice Approach

Defining Technology Transfer

According to Annex 7 of the World Health Organization (WHO) guidelines on the transfer of technology in pharmaceutical manufacturing, technology transfer is defined as “a logical procedure that controls the transfer of any process together with its documentation and professional expertise between development and manufacture or between manufacture sites.”¹

There are three main concepts to highlight in this definition:

1. A logical procedure: Every transfer requires a well thought through analysis, which is planned and defined in advance.
2. Documentation: Any evidence of a successful transfer should be properly documented.
3. Professional expertise: As far as possible, all previous experience with the product and/or manufacturing process should be transferred.

A further implied aspect which is not as evident in the definition, is the possibility that the transfer also includes a scale-up to a larger batch size. This is very common during the different stages of the development of a pharmaceutical product and particularly as the drug development moves through to the manufacture of the first commercial-scale batches.

Technology Transfer: Key Considerations

There are a number of activities involved in a tech transfer, including development and manufacturing transfer, the transfer of analytical methods, and necessary skills assessments and training. The planning and management of the transfer is also key—as is the assessment of facilities and equipment, documentation, and, finally, qualification and validation.

All of these transfer activities involve several, if not all, departments within each of the participating companies. It’s important to recognize that the transfer of products from development to manufacture, or to different manufacturing sites, is always a new and time-constrained process, with relatively short deadlines when compared to other phases of the life cycle of a product such as development or production. All this makes it essential that there is a project lead to coordinate the activities and departments involved.

Regulatory Considerations

Any manufacturing process transfer needs analytical support to guide its progress. Similarly, it is also necessary to know the regulatory implications of the transfer activities. Regulatory requirements in the countries of the sending unit (SU), or manufacturing plant transferring the technology, and the receiving unit (RU), or manufacturing plant receiving the tech transfer, and in any countries where the product is intended to be supplied, should be taken into account.

There are no regulatory limitations in case of investigational medicinal products (IMPs), except if there is a change of manufacturer affecting an ongoing clinical trial. Once the pharmaceutical product is granted marketing authorization (MA) and becomes a medicinal product for human use, the MA holder has the responsibility to manufacture, control, and market the drug product according to the conditions and requirements described in the documentation submitted and approved by the Health Authorities. Any change in that documentation has to be evaluated and notified to the Health Authorities according to EU laws and regulations. A product transfer between manufacturing plants is considered a modification in the manufacturing site of the finished product (section B.II.b.1).²

A case-by-case assessment will be required to determine if additional documentation over the requirements of the previous section is necessary. The purpose of the documentation is to prove that, despite the change of manufacturer, the drug product will continue to meet the quality, safety, and efficacy requirements that allowed it to receive the MA. In order to ensure the authorized therapeutic effect, the product must meet the quality specifications, remain stable, and its bioavailability must be equivalent.

Ensuring Successful Process Transfers

In every manufacturing process transfer, there are two key teams. On the one hand, the technical team of the SU, which has the knowledge of the product and process to be transferred (critical steps, critical quality attributes—CQAs—and critical process parameters—CPPs, etc.). On the other hand, the technical team of the RU has knowledge of the available technologies and equipment at the receiving manufacturing plant. The key for a successful transfer lies in the coordination, alignment of goals, and understanding between both teams.

Every manufacturing process that is transferred has an inherent or residual variation and produces a finished product with certain specifications and specific CQAs. The goal of a successful transfer is to ensure that this residual variation is not negatively affected by factors such as the usual changes in materials, equipment, methods, personnel, and environmental conditions. This means that the product is able to maintain the same quality it had in the SU.

The transfer must be based on a risk analysis of each one of the previously described factors, and other less obvious aspects should not be forgotten, such as the HVAC system and containment level. Although less critical, these can occasionally have a relevant influence on the product or can impact the safety conditions for the operators.

A common process transfer plan should start with a protocol written jointly by the SU and RU and should include:

• Objectives, scope, personnel, and responsibilities
• Raw material specifications, including supplier and manufacturer details
• Equipment and facility requirements of the SU
• Detailed manufacturing process from the SU
• Health, safety, and environmental issues
• Critical points (CQAs and CPPs)
• Sampling points
• Acceptance criteria
• Change control and retention samples

Other available documentation, such as process validation and pharmaceutical development reports etc., may also be extremely useful. However, it is recommended to check if they comply with current regulatory requirements at the time of the transfer.

In addition, the raw materials (excipients and packaging material) used may have an impact on the final product. Therefore, an evaluation of the raw materials proposed by the RU should be conducted. The simplest option is to use identical raw material references to those used by the SU. However, this is not always feasible. It’s important to consider what should be done when the available references in the RU are similar but not identical to those used by the SU. From an economic standpoint, it is not desirable to increase the number of references of the basic same raw material in the RU; however, at the same time, it must be ensured that there is no impact on the CQAs of the product. The raw material specifications should be thoroughly reviewed, identifying the differences

and assessing their potential influence on the CQAs of the product, based on a risk analysis. There is always the option to perform confirmatory testing during the transfer.

Defined Process

It’s important to remember that during a manufacturing process transfer there is a quantitative-qualitative formulation, a defined manufacturing process and previously defined CQAs for the finished product that cannot be modified. There are other variable aspects that can be modified or adjusted at the tech transfer stage in order to obtain a product within specifications, such as the correct selection of equipment, the determination of process parameters and its control strategy. Therefore, knowledge of the available technologies and equipment at the RU is critical.

After the selection of materials, facilities, and equipment, it is necessary to assess the training needs of the RU personnel, based on objective criteria of their knowledge of the technology being transferred.

A logical sequence for each of the transfer trials in the RU would be:

• Definition of intermediate output material CQAs and CQAs per manufacturing step (for instance, particle size distribution and density in the granulation step)
• Identification of CPPs and establishment of values for the RU
• Experimental and documented execution of each trial
• Assessment and comparison of intermediate output material CQAs and CQAs per manufacturing step (SU vs. RU)
• Conclusions and next steps

Useful Tools

There are a number of tools that can be very useful during a process transfer, including:

• Ishikawa diagrams: This is a brainstorming tool to identify factors that could potentially impact product quality and to investigate the process to be transferred (materials, process parameters, equipment, etc.).
• Risk analysis: The parameters or factors defined above should be reviewed against the CQAs of the product. The risk level should be established, along with a valid justification of the classification. In a process transfer, the intermediate output material’s CQAs should be defined and may provide a bridge between the analyzed factors and the finished product’s CQAs. For instance, the influence that the density of the granulate has on the blend flow is well known, as is the influence of the latter in the mass variability of a tablet.
• Design of experiments: This is a systematic method to determine the relationship between factors affecting a process and the output of that process. It will also help to establish the residual variation of the transferred process, estimate interactions between factors, and, above all, define and understand the design space of the manufacturing process in the SU.
• Process capacity: Every process has an inherent variability that can be assessed with statistical methods. It is recommended that the transfer teams perform statistical calculations of the number of units that will be manufactured out of specifications in order to confirm the capacity of the process.
• Dimensional analysis: This helps to simplify the study of any single phenomenon, even if it depends on many physical magnitudes, as independent variables. It involves finding adimensional numbers (Reynolds, Froude, Newton, etc.), which describe the process. The value of these numbers remains constant regardless of the scale or place of manufacture and may help to set process parameters in the SU.

Conclusion

In summary, it’s important to keep in mind that each process transfer is unique and it is only performed once. There is no be-all and end-all single process transfer. Every transfer has to be analyzed and planned from scratch, assessing the best way to carry it out, while minimizing risks.

At the end of every transfer, there must be a report describing, among other aspects, the raw materials and equipment used, the detailed manufacturing process, the process parameters, and the control strategy. The transfer is not the end goal per se, but the path to manufacture the pharmaceutical product in a different plant. The aim is to have documented proof that the transferred manufacturing process can be validated and the product can be routinely manufactured at the RU.
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References

1. Annex 7. WHO guidelines on the transfer of technology in pharmaceutical manufacturing
2. Guidelines on the details of the various categories of variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No. 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorizations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures