Appropriate transfer of manufacturing technologies (technology transfer) is important to upgrade drug quality as designed during research and development (R&D). Hence, technology transfer (TT) is essential during manufacturing activities. It assures that stable quality is transferred between contract giver and contract acceptor during manufacturing process.
To assure the drug quality, it is important to take note of 5 Ws and 1 H in the process of technology transfer. Here 5 Ws stand for what (what technology), when (at what point of time), why (for what all reasons), where (the place) and (by) whom (who transferred), while H stands for how (how did he/she transfer the technology). One has to share this knowledge and information to stake holders, who are related to drug manufacturing.
What is TT?
In the pharmaceutical industry, "technology transfer" refers to the processes that are needed for successful progress of drug discovery - from clinical trials to full-scale commercialisation - or it is the process by which a developer of technology makes the technology available to commercial partner, who would in turn exploit the technology.
There may be several reasons for a developer of the technology to consider making the technology available to another person to exploit, instead of exploiting the technology himself/herself. Some of the reasons are:
■ To form alliances with partners that can progress the development of the technology to take it to market: The developer of the technology might have the resources to take the technology to particular state of development, such as up to animal studies and toxicology studies, but may not have the resources to take the technology through its clinical and regulatory phases. Hence the developer collaborates with another organisation to take it through these phases and into the market.
■ To form alliances with partners with manufacturing capability: The developer of the technology may have taken the technology to a particular stage of development so that it is nearly ready to be marketed, but dose not have the clean room manufacturing capability or resources to manufacture the product. Therefore, the developer partners with another organisation that has the required capability.
■ To form alliances with partners with marketing and distribution capability: The developer of the technology may have fully developed the technology and even have obtained regulatory approvals and product registrations for the product to be sold, but it lacks the marketing and distribution channels. To give it a marking capability, he/she may collaborate with another organisation that doses have the marketing capability.
■ For exploitation in a different field of application: The developer of the technology might be capable of exploiting the technology in the field of diagnostic applications and may grant exploitation right to commercial partner for the exploitation of therapeutics applications. By transferring the technology for the use in another field of application to another person, the developer of the technology creates another income stream from the exploitation that takes place in the other field.
■ No commercial capability: The developer of the technology may be research institute of a university, which doses not have the capability to exploit commercially at all and need to collaborate with another organisation that does have that capability.
Technology transfer by way of collaboration is a common feature in the pharmaceutical industry.
Importance of technology transfer
There are certain things to be taken care of while transferring a technology. First of all, one need to elucidate necessary information to transfer technology from R&D to actual manufacturing by sorting out various information obtained during R&D. Besides, he/she needs to elucidate necessary information to transfer technology of existing products between various manufacturing places and exemplify specific procedures and points of concern for different types of technology transfer to facilitate smooth technology transfer.
All these apply to the technology transfer through R&D and production of drug (chemically synthesized drug substances and drug products) and the technology transfer related to post-marketing changes in manufacturing places.
TT process
The quality of design will be almost completed in phase II clinical study. To realise the quality of design, various standards and tests for manufacturing will be established in the process of reviewing factory production and phase III study. The quality of design will be verified in various validation studies and will be upgraded when the actual production starts. Technology transfer consists of action taken in these flows of development to realise the quality as designed during the manufacture.
Even if the production starts, there is no barrier for effecting the technology transfer. For instance, technology transfer could be implemented during research, development and production phases.
Research phase
Quality design:
For drug products, the quality design corresponds to so called pharmaceuticals design-to-design properties and functions such as elimination of adverse reactions, improvement of efficacy, assurance of stability during distribution and adding usefulness based on various data. The data may be chemical and physical properties, efficacy and safety and stability obtained form preclinical studies. For drug substance, the quality design is to determine starting materials and their reaction paths, and basic specification of the drug.
Development phase
Research for factory production:
To manufacture drugs with qualities as designed, it is required to establish appropriate quality control and manufacturing methods, after detecting variability factors to secure stable quality in the scale-up validation. The scale-up validation is performed to realise factory production of drug designed on the basis of result from small-scale experiments.
Consistency between quality & specification:
When product specification is established on the basis of the quality of a product, it is required to verify whether the specification adequately specifies the product quality. In short, the consistency between quality and specification is to ensure the products specification. When the quality is predetermined in the quality design, it is assured as the manufacture quality and the product in turn satisfies the quality of design.
Assurance of consistency through development & manufacturing :
To make products, which were developed earlier, the quality of design should be reproducible as the quality of product (assurance of consistency). For this purpose, the transferring party in charge of development should fully understand what kind of technical information is required by the transferred party in charge of manufacturing and should establish an appropriate evaluation method to determine whether a drug to be manufactured would meet the quality of design.
TT from R&D to production:
Transfer of the technical information is necessary to realise manufacturing formula established in the actual production facility. Technical information to be transferred should be compiled as R&D report.
Production phase
Validation & production:
Production is implemented after various validation studies verify that it is able to stably produce a product based on transferred manufacturing formula. While the manufacturing facility that accepts technology is responsible for validation, the research and development department, which transfers the technology, should take responsibility for validation such as performance qualification, cleaning validation and process validation unique to subject drugs.
Feed back from production & TT of marketed products: Technical information of developed products is obtained from data of a limited amount of batches. Hence, various standards have been established from the limited data, and quality evaluation method established in development phase is not always sufficient for factory production. Therefore, it is highly desired to feed back and accumulate technical information obtained from repeated production, if necessary. In addition, it is important to appropriately modify various standards established before based on this information and execute accountability and responsibility for design and manufacturing.
Technology transfer documentation
Technology transfer documentation is generally interpreted as documents indicating contents of technology transfer for transferring and transferred parties. The raw data of the documents should be prepared and compiled accordingly. It should be always readily available and traceable. For successful technology transfer, task assignments and responsibilities should be clarified, and acceptance criteria for the completion of technology transfer concerning individual technology to be transferred should be established.
Quality assurance department should establish conformation process for all kinds of technology transfer documentation, apart from checking and approving the documentation.
Organisation for TT:
One of the most significant elements for successful technology transfer is closed communication between transferring and transferred parties. Therefore, organization for technology transfer should be established comprising both party members. Besides, roles, scope of responsibilities of each party should be clarified and adequate communication and feedback of information should be ensured. It is desirable that this organisation complies with GMP.
R&D report: To realise quality assurance at all stages - from drug development to manufacturing and transfer to manufacturing - transfer of technical documents concerning product development or corresponding documents should be considered.
The research and development report (development report) is a file of technical development, and the research and development department is in charge of its documentation. This report is an important file to indicate rationale behind the quality design of drug substances and drug specifications and test methods.
The development report requires inspection before the approval. Although the development report is not a prerequisite for the application approval, it can be used at the pre-approval inspection as a valid document for the quality design of new drug. In addition, this report can be used as a raw data in case of post-marketing technology transfer.
The development report should contain information such as:
■ Historical data of pharmaceutical development of new drug substances and drug products at stages from early development phase to final application of approval.
■ Raw materials and components.
■ Synthetic route.
■ Rationale behind dosage form and formula designs and design of manufacturing methods.
■ Rational and change histories of important processes and control parameters.
■ Quality profiles of manufacturing batches (including stability data).
■ Specifications and test methods of drug substances, intermediates, drug products, raw materials and components and their rationale (validity of specification range of important tests such as contents, impurities and dissolution, rational for selection of test methods, reagents and columns and traceability of raw data of those information).
Product specification file: The product specification is to compile information, enabling manufacturing of a product and define specification, manufacturing and evaluations method of the product and its quality. The transferring party is responsible for documenting the file. The product specification file should be reviewed at regular intervals and incorporate various information obtained once the production of a product has started. It should also be revised as appropriate. For new products, the development report can be used as a part of product specification file.
Technology transfer plan: The technology transfer plan describes items and contents of technology to be transferred and detailed procedures of individual transfer and transfer schedule, apart from establishing judgment criteria for the completion of transfer. The transferring party should prepare the plan before the implementation of transfer and reach an agreement on its contents with the transferred party.
Technology transfer report: It is to report the completion of technology transfer after data of action taken according to the technology plan is evaluated and the data is confirmed pursuant to the predetermined judgment criteria. Both transferring and transferred parties can document the technology transfer report; however, they should reach an agreement on its contents.
Verification results of technology transfer: After the completion of technology transfer and before the start of manufacturing of the product, the transferring party should verify appropriate methods such as product testing and audit to ensure that the product manufactured after the technology transfer meets the predetermined quality. He/she should also maintain records of the results.
In pharmaceutical industry technology transfer means action to transfer information and technologies necessary to realise quality of design of drugs during manufacturing. Appropriate technology transfer is important to upgrade the quality of design and ensure stable and high quality of the product. The technology transfer does not mean one-time actions taken by the transferring party toward the transferred party, but means continuous information exchange between the both parties to maintain the quality of product manufacturing.
(The author is with Alkem Labs Ltd, Baddi, India)