Navigating Regulatory Guidelines For Effective Tech Transfer

By Bilel Khedir and Dalenda Bouslah, Opalia Recordati

The WHO defines technology transfer as a “logical procedure that controls the transfer of a process with its documentation and professional expertise between development and manufacturing sites or between manufacturing sites.”¹

From the FDA perspective, the technology transfer is “the process of transferring skills, knowledge, technologies, and manufacturing methods among governments and universities — and other institutions — to make sure that a wider range of users has access to scientific and technological developments. These users can, in turn, develop and use the technology to create new products, processes, applications, materials or services.”²

The phases of a technology transfer project are:³ project initiation, project planning, project execution, and project review and close-out.

According to ICH Q10, the knowledge transferred is the basis for manufacturing process, control strategy, process validation approach, and ongoing continual improvement.⁴ However, the knowledge transferred can be divided into two categories: documented and undocumented knowledge. The second kind of knowledge is crucial for technology transfer success. Examples of undocumented knowledge include test frequencies of in-process controls or stress relaxation for tablets.⁵

In this article, we will discuss some important aspects of a technology transfer project.

1. The Project Team

In the WHO guideline, the project team members are required to have “necessary qualifications and experience.” Thus, the transfer team (TT) should include members from many disciplines to allow for the representation of different perspectives.⁵

A TT team can include, for example:

• Project manager
• QC member
• QA member
• Process engineer or production (production specialist)
• Pharmaceutical development specialist

2. The Project Management Plan

The WHO states in its guideline on TT that “There should be a project management plan which identifies and controls all the necessary activities identified at the start of the undertaking.”¹ The same guideline describes an important document, which in my opinion is key to determining the success of the TT: The Technology Transfer Protocol. The TTP should include:³

• Objective
• Scope
• Key personnel and their responsibilities
• Parallel comparisons of materials, methods, and equipment
• The transfer stages with documentation that each critical stage has been satisfactorily accomplished before the next commences
• Identification of critical control points
• Experimental design and acceptance criteria for analytical methods
• Information on trial production batches, qualification batches, and process validation
• Change control for any process deviations encountered
• Assessment of the end product
• Arrangements for retaining samples of active ingredients, intermediates, and finished products and information on reference samples where applicable
• Conclusion, including signed-off approval by the project manager

3. Gap Analysis

The WHO defines a gap analysis in its draft guideline 2021 as “the identification of the critical elements of a process which are available at the SU [sending unit] but are missing in the RU [receiving unit] with the objective to assess which gaps have potential impacts on the process or the method and to mitigate those gaps, as appropriate.”³

The gap analysis allows the RU to identify the actions necessary to reproduce the process being transferred. Many pharmaceutical professionals assume that the RU should have identical capabilities as the SU (equipment and premises, for example). However, the RU is not required to have identical capabilities (e.g., equipment), but should have similar capabilities that allow a successful transfer. This is clearly stated in the WHO guideline of 2011¹: “The capabilities of the SU and at the RU should be similar, but not necessarily identical, and facilities and equipment should operate according to similar operating principles.”

The same perspective is also maintained in the WHO draft guideline of 2021: “ The technology transfer project should fulfill the following general principles and requirements. There should be[…] similar capabilities between the SU and RU, including but not limited to, facilities and equipment.”² In the case of equipment, the WHO provides in its guidelines the points to consider when conducting a comparison:

WHO 2011 Guideline:¹

• Minimum and maximum capacities
• Material of construction
• Critical operating principles
• Critical equipment components
• Critical quality attributes
• Range of intended use

WHO 2021 Guideline:³

• Working principles
• Capacities
• Make and models
• Minimum and maximum capacities
• Material of construction of contact surfaces
• Critical operating principles
• Components
• Range of intended use

For the equipment, one guideline can be extremely helpful in the comparison: The FDA SUPAC Manufacturing Equipment Addendum. The TT team can use this guideline to demonstrate they have similar manufacturing equipment.

Once the gap analysis is accomplished, the RU will be able to decide whether to acquire new equipment or adapt the equipment it has. Decisions to adapt the process or equipment must be justified and scientifically sound, and this is generally determined through a risk analysis conducted by the RU TT team.

4. Risk Assessment

The risk assessment is a key step in the technology transfer. In fact, changes during the tech transfer may occur. The risk assessment can include many parameters (critical process parameters, manufacturing equipment, etc.). To demonstrate that the process is under control, the team must undertake a detailed documented risk analysis. The main objective of the risk analysis, in general, is to look for the areas where the risk is high and intensify the controls there.

The risk assessment is generally done using a failure modes and effects analysis (FMEA) tool, but there are novel approaches that integrate fault tree analysis (FTA) and FMEA to exploit advantages of both methods and minimize the drawbacks of each method when used alone.⁶ The risk assessment will be divided into two phases:

• Phase 1: Identification of failure modes through FTA.
• Phase 2: Assessment of criticality using FMEA, where only the most critical failure modes will be selected.

Phase 1 and Phase 2 analyses will both be performed in a recursive way at three levels: system, component, and function:

• The system is the technology transfer project as a whole.
• The functions associated with the system are manufacturing process transfer and analytical methods transfer.
• The components may be, for example, aspects of the manufacturing function, such as mixing, granulation, tabletting, coating, and packaging. Components of analytical methods transfer include analytical validation (partial or complete) and comparative testing.

Performing the risk assessment using a combination of FMEA and FTA is well explained in References 6 and 7.

Examples of areas where risk analysis would be very useful are in stability and in manufacturing process and equipment. 

Stability

Stability data should be generated in principle from drug product made at the RU. On the other hand, in order to generate sufficient stability data, companies must spend time and money, and that might be an obstacle. However, with a science-based risk analysis, the tech transfer team may alleviate the work that needs to be done in this area. In fact, complex dosage forms are defined by the FDA as drug products that have complex release mechanisms, delivery systems, and manufacturing processes that are likely to be affected by the site transfer. Thus, if the applicant manages to demonstrate that the drug product transferred presents minor risk (e.g., an immediate release solid oral dosage form with high solubility), they can claim a site transfer without stability data at the RU (data will be submitted in the annual report).

The ISPE guideline for technology transfer proposes a risk-based classification of dosage forms that can be very helpful in elaborating a risk analysis.

Manufacturing Process and Equipment

The RU may be obliged to adapt the process or the equipment to its capabilities. In this kind of situation, the RU tech transfer team must conduct a risk analysis based on scientific data to demonstrate that the changes did not affect the quality of the product.

The specific tests and the amount and the type of data required to back up the risk analysis can be determined by referring to the SUPAC Guidelines of the FDA.⁸ The first step is to define precisely the type of changes made in terms of process and/or type of equipment. The second step is to determine the level (level 1, 2, or 3, defined by the FDA) of the changes made according to the specific FDA Scale-up and Post-Approval Changes (SUPAC) guidances for immediate release, modified release, or semisolid drug products, as well as the SUPAC Manufacturing Equipment Addendum. Once the TT team has successfully defined the level of changes made, they will be able to decide which tests and documentation are needed according to SUPAC guidelines and include all the data used in the risk analysis.

Conclusion

Among the indicators of success of a technology transfer project as defined by the WHO, there are “full mastery of technology transferred,” “achievement of agreed quality standard,” and “more affordable price (more access to medicines).”⁹ That being said, differences in the regulatory standards in the countries of the RU and SU may pose a significant barrier for technology transfer projects. Effective patient-centric and science-based communication between drug manufacturers and local regulatory authorities helps to achieve the ultimate goal of technology transfer, which is, in my opinion, easier access to quality drugs in emerging countries.

Acknowledgment:

The authors would like to thank Mohamed Rouahi, regulatory affairs manager at Opalia Recordati, for his input and insights.

References

1. World Health Organization (WHO), 2011, WHO guidelines on transfer of technology in pharmaceutical manufacturing. Link: https://extranet.who.int/pqweb/sites/default/files/documents/TRS_961_Annex7_2011.pdf#:~:text
   =1.5%20Transfer%20of%20technology%20requires,development%2C%20production%20and%20
   quality %20control.
2. US Food and Drug Administration, (2021, October 18), FDA Technology Transfer https://www.fda.gov/about-fda/doing-business-fda/fda-technology-transfer
3. World Health Organization (WHO), 2021, WHO guidelines on the transfer of technology in pharmaceutical manufacturing (Draft working document for comments). Link: https://cdn.who.int/media/docs/default-source/essential-medicines/norms-and-standards/qas20-869-transfer-of-technology.pdf
4. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human guideline Q10 on pharmaceutical quality system - Step 5, 2008 [cited 2023 May] LINK https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human_en.pdf
5. A successful concept for Technology transfer in drug manufacturing, GMP-Verlag Peither AG. Link: https://www.gmp-publishing.com/media/pdf/a3/32/de/Reading_Sample-Successful_Concept_for_Technology_Transfer_in_Drug_Manufacturing.pdf
6. Peeters, J. F. W., Basten, R. J., & Tinga, T. (2018). Improving failure analysis efficiency by combining FTA and FMEA in a recursive manner. Reliability engineering & system safety, 172, 36-44.
7. Shafiee, M., Enjema, E., & Kolios, A. (2019). An integrated FTA-FMEA model for risk analysis of engineering systems: a case study of subsea blowout preventers. Applied Sciences, 9(6), 1192.
8. International Society of Pharmaceutical Engineering. (2003). Technology Transfer Good Practice Guide
9. Moon, S (2011) Pharmaceutical Production and Related Technology Transfer. World Health Organization. Link: https://apps.who.int/iris/handle/10665/44713

About The Authors:

Bilel Khedir works for Opalia Recordati as a pharmaceutical development project manager and quality assurance specialist. He is also a pharmacist and MSc student in drug development. His expertise includes conducting preformulation studies and formulation of drug products, analytical methods validation, in vitro bioequivalence studies, and writing new drug products’ marketing authorization dossiers (CTD format). In his previous role at Opalia as quality assurance pharmacist, he oversaw cleaning validation, including routine cleaning and disinfection activities, and executed continuous improvement strategies. You can reach him at khedir.b@opaliarecordati.com.

Dalenda Bouslah is quality management manager at Opalia Recordati. She joined the company after earning her B.Sc. in biology and has built a deep knowledge in various quality assurance fields, including supplier qualification, change control, process validation and cleaning validation, CAPA, and (recently) data integrity.