Introduction

According to the Competence Centre on Technology Transfer of the European Commission:

“Technology transfer (TT) refers to the process of conveying results stemming from scientific and technological research to the marketplace and to wider society, along with associated skills and procedures, and is as such an intrinsic part of the technological innovation process.” 

 
^{Image 1: the stages of a generic Technology Transfer process} 
This generic definition covers all industries and doesn’t convey the progressive discovery stages of pharmaceuticals. Still, knowledge is a crucial concept for having a TT.

All pharma companies, of course, always had a formal or informal process to transfer their productions from R&D to pilot scale and industrial scale manufacturing. Still, for a long time, there was no clear regulatory driver. An ISPE Good Engineering guide, published in 2003, kicked off the conversation for a more formal and visible TT process  , and in 2008 the International Council for Harmonisation (ICH) was the first regulator to mention TT formally:
“The goal of technology transfer activities is to transfer product and process knowledge between development and manufacturing, and within or between manufacturing sites to achieve product realisation. This knowledge forms the basis for the manufacturing process, control strategy, process validation and ongoing continual improvement” (ICH Q10, section 3.1.2) .

Current Regulation

In 2011, the WHO Technical Report 961 Annex 7 turned the spotlight on TT, defining it 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”. It is a systematic procedure that is followed in order to pass the documented knowledge and experience gained during development and or commercialization to an appropriate, responsible, and authorized party. Technology transfer embodies both the transfer of documentation and the demonstrated ability of the receiving unit (RU) to effectively perform the critical elements of the transferred technology to the satisfaction of all parties and any applicable regulatory bodies.
After this high-profile endorsement, TT became a focus point of all regulatory audits!

There are various practical implications associated with the above. Still, in practice, pharma companies now need to define TTs and identify when a TT is required as part of their change control procedures. The TT collects and collates several documents, such as regulatory files, specifications, analytical methods, analytical method validation reports, bill of materials, process validation reports, and manufacturing procedures. The procedure should therefore determine the specific list of documents and activities required in each case. This can be tricky as concurrent changes (scale-up, technology switch, packaging change) must be managed as part of the TT activities, and similar grey areas can be problematic. TT documentation will be often and thoroughly audited, and poor TT documentation can significantly slow down time to market and increase cost, for example. On the one hand, there is a temptation to go over the top with documentation and, on the other hand, a risk of not documenting enough, hence the need to accurately specify the documents required.

Product Lifecycle and Tech Transfer

During the lifecycle of a pharmaceutical product, there can be several TTs.

After the pre-clinical studies, when phase 1 of clinical studies is initiated, a small amount of that molecule is required for safety studies, and this is often produced by an independent company specialised in this kind of supply. This, of course, requires a TT. Decisions made at this stage may have a long-term impact on the future of that product. Similarly, in phase 2 of the clinical studies, another amount of product will be required, still in small quantity in general terms, but at a higher volume than another organisation with another TT may better address.

When phase 3 of the clinical trials is often initiated, the “asset” is transferred to another organisation, better suited for finalising the more extensive clinical study. The TT that enables that is often critical for the product's long-term success. Of course, in phase 3, the volumes and dose form refinement of the clinical trial material are at another scale (for example, in pilot plants), requiring another organisation to deal with it and another TT.

It is not uncommon that the transfer of a new product from R&D / clinical trials organisations to a full-scale manufacturing site is initiated 3 to 5 years before the expected completion of phase 3 clinical studies to allow for the construction and validation of a dedicated facility for the new product introduction and production of initial stability batches. This TT will allow the product to finally reach the patient if the phase 3 clinical trial is successful and the product can be launched.

Sometime after the launch, the required volumes of that product will become more predictable, and they will be (typically) at a different level compared to the initial early-stage assessment, probably driving another TT for having a capacity adjustment.

The product will become generic a few years later, likely requiring another TT.

Several years later, when perhaps new products better addressing the same condition will be launched, the production will probably have a capacity reduction as part of the end of the lifecycle of the product. This will drive another TT.

Finally, the product will be discontinued or may be maintained only for a few patients in the world who have shown adverse reactions to alternative medication. Even at this final stage, a duty of care drives ongoing stability on the stockpiled material. Some organisations or parts of organisations are focused on the tail of the product lifecycle, which will prompt another TT.

^{Image 2: flow chart showing an example of the lifecycle of a medicinal product, with each stage potentially needing a Tech Transfer}

Practical Considerations and Examples

While it is undeniable that the spike of attention for TT after 2011 was due to the new regulatory requirements, arguably, the TT should be incorporated into the core business process of all pharmaceutical companies, as it makes business sense. It focuses on the risks and on the knowledge required to manage them. It enables collaboration and involvement (organisational alignment). It is a legacy for the future (by managing the knowledge to deliver more efficient product evolution in the future, for example).

The common issue is that current regulations don’t provide much further detail beyond the mentioned definitions and principles for a process that can have massive variations depending on the specific applications. In some way, the regulatory authorities are recognising the level of complexity and variety, but they infer: “Do it as you want, as long as you do it right!” The experience from multiple regulatory audits from multiple auditors worldwide indicates that the focus isn’t on the specific detail about how the TT has been executed but on how the knowledge has been managed within the particular context.

Ultimately, the one obvious thing is that we deal with two organisations (the Sending Unit and the Receiving Unit) that will have, in general, some similarities and some differences in their manufacturing capabilities, equipment, procedures, and training, and the TT is there to bridge those differences and allow the Receiving Unit to produce the same product and have the same positive impact on the patient that the Sending Unit has. The clear indications from the Regulators are that the guideline to overcome the discontinuity is the know-how: this is ultimately what TTs are about.

 
^{Image 3: basic principles of Technology Transfer} 

For example, suppose we want to do a TT from an early-stage discovery R&D organisation that discovered a promising molecule (Sending Unit) to a Contract Manufacturing Organisation (CMO) that will produce the material for clinical trials (Receiving Unit). In that case, the TT actions should focus on legal aspects / IP, characterisation, analytical methods, dosing options, and safety aspects, which are critical at this stage of development, and not on yield, cycle time, unit cost, artwork, packaging matrices, cost of disposing of unused product, that at this stage of development are not a priority.

A TT between a late-stage R&D department of a big company that is waiting for some phase 3 trial results (Sending Unit) and a manufacturing site in the same company that will execute the new product introduction to the market (Receiving Unit) will be driven by very different priorities, such as regulatory aspects, analytical methods, time to market, manufacturing scale flexibility, packaging and labelling definition, safety aspects, contingency funding, but aspects like unit cost, yield, cost of disposing of validation batches will not be that prominent in the bigger picture. Of course, while the general drive to benefit the patient will be the same as in the previous case, the action list will prioritise different activities.

The R&D department of a generics manufacturing company developing a product for the “six months exclusivity”  (Sending Unit) doing a TT to a manufacturing site of the same company that will manufacture that product (Receiving Unit) will address the actions that ensure good planning, regulatory, efficiency, cost, documentation, packaging definition, scale definition. In contrast, the cost of disposing of trial batches of material will probably not be a priority.

In the case of a big pharma manufacturing site willing to outsource a well-established generic production (Sending Unit) to a CMO manufacturing site that will manufacture that product (Receiving Unit), there will probably be lots of workaround site audits, commercial and legal, continuity of supply, yield, efficiency, analytical methods, labeling and artwork, logistics, process validation, being able to release for sale as much process validation material as possible, suppliers and perhaps not so much around IP, manufacturing scale flexibility, dosing options.

A TT between the R&D department of a branded generics manufacturer (Sending Unit) that developed a variation of an existing product line and a manufacturing site of the same company already producing the same range and planning to incorporate the variations (Receiving Unit) will probably be about marketing and speed to market, labeling, and artwork transition control, efficient process validation, manufacturing scale flexibility, continuity of supply, being able to release for sale as much process validation material as possible, logistics, regulatory, rather than commercial, IP, site audit.

Let's consider the TT between one area of a manufacturing site with a product of high technical complexity (Sending Unit) and another area of the same manufacturing site, planning to manufacture the same product at different scales or different technologies (Receiving Unit). The action list will deal preferentially with regulatory, validation risk assessment and contingency planning, continuity of supply, and implicit knowledge transfer, and there will probably be no activity on analytical method validation, IP, labeling, artwork, or site audit.

The table below shows typical priorities for Tech Transfer at different stages of the product lifecycle.

Product Lifecycle Stage	Legal / IP aspects	Cost of trial batch	Cost of product	Packaging / Artwork	Speed
Pre-clinical	High focus	Practically irrelevant	Irrelevant	No focus	Relevant
Clinical	Very high focus	Practically irrelevant	Irrelevant	Basic requirements only	Critical
Pilot Plant	Very high focus	Nice to have	Practically irrelevant	No focus	Critical
Launch	Very high focus	Nice to have	Nice to have	High focus	Critical
Capacity Adjustment	Not critical for internal transfers	Important	Important	Not critical for internal transfers	Depends on market demand
Generic Transfer	Critical for the “six months exclusivity”, then less critical	Very important	Critical	Very high focus	Critical for the “six months exclusivity”, then less critical
Capacity Reduction	Lower focus	Important	Nice to have	Not critical for internal transfers	Nice to have
Legacy	Lower focus	Irrelevant	Irrelevant	Focus on basics only	Lower focus

In practice, depending on the specific circumstance, the same action may be critical, nice to have, or completely irrelevant. Aspects that can significantly impact a TT are typically linked to transfer scope, inherent complexity, project changes, stage in the product lifecycle, maturity of process technology, maturity of receiving site, cultural distance, and contractual arrangements.

Different Approaches

Another relevant aspect that can significantly differentiate TT activities is the different procedural approaches to TT in different companies. There are, in fact, two diametrically opposite approaches to TT execution:

1. Procedure driven: the procedure calls for a fixed list of documents to be produced for all TTs within a specific organisation; the procedure will be reviewed and updated periodically;
2. Risk-based: “suitable” Subject Matter Experts (SMEs) get together, assess the risks and, depending on the specific risk profile, generate and drive appropriate activities to manage all risks.

Neither approach is perfect, and, in reality, TT is usually a compromise between them.

The procedure-driven approach is generally more suited to relatively low-experienced executing teams/organisations with somewhat repeatable activities, engaging with skilled professionals to draft TT procedures. It requires an excellent process drafted by highly trained professionals. Still, it is resource heavy as some actions on the list will address risks irrelevant to the specific project, especially if the kind of projects varies significantly. Moreover, when the procedure fails, usually new actions are added to the procedure as CAPA, making it more and more resource demanding. This approach often struggles to address implicit knowledge requirements.

The risk-based approach is resource efficient, aligning resources with risks and allowing faster delivery within the risk management frame. However, it requires an outstanding and streetwise SME team, effectively covering all relevant aspects of the project; otherwise, it can generate disasters. It also requires continued focus from the SMEs at all stages (risk assessments are “live” documents). Generally, this approach fits mature organisations with a high emphasis on delivery times and costs, comfortable with assessing and taking risks.

Case Studies

The following are some examples of how TTs can go very wrong due to issues that the TT overlooked at the time.

A few decades ago, when microcrystalline cellulose (MCC) had recently been introduced to the market, it was discovered that an API with delicate stability in the air could be stabilised by co-formulating with MCC. At the time, only one MCC made and particle size was available on the market, so the development chemist put in his lab book and paperwork the product's commercial name instead of the chemical name. The particle size wasn’t very fitting for the API size, but there