Technology Transfer in Healthcare, Pharmaceuticals, and the Medical Device Sector

 

Anna Ivanova, Associate, BRACE Law Firm ©

March 24, 2023

 

Technology transfer means the process of disseminating and practically applying scientific and technical knowledge during its transfer between different organizations. Technology transfer is a relatively new concept in Russia.

Issues of technology transfer in healthcare are particularly relevant, specifically regarding medicinal product manufacturing technologies, as the number of high-tech solutions in the healthcare sphere is constantly growing. Furthermore, the development of technology transfer is being carried out both within Russia and at the international level, particularly within the EAEU. This article examines the main features of the legal regulation of technology transfer in healthcare, pharmaceuticals, and the medical device sector in Russia and the EAEU.

In global practice, the following types of technology transfer are common:

• Mastering a new technology at an enterprise following in-house research and development (R&D) to obtain new products;
• Manufacturing products under licenses and contracts;
• Performance of development and implementation of innovations by scientific organizations;
• Development of innovative infrastructure — a network of innovation centers, science and technology parks, and other innovation complexes engaged in the development, production, and sale of innovations.

To study technology transfer mechanisms, it is important to understand the relationship and distinction between two key concepts of the innovation process: "commercialization" and "technology transfer". Commercialization can be attributed to the characteristics of the transfer conditions when technology transfer is carried out on a paid basis. The rule of technology transfer is that both parties derive benefit on a mutually advantageous basis. The difference between "transfer" and "commercialization" of technologies can be briefly formulated as follows: commercialization of a technology implies the mandatory receipt of profit and is not necessarily connected with the involvement of third parties (except for the source of the technology and the end user), whereas technology transfer implies the transfer of technology to another party for its industrial mastery, but is not necessarily connected with the extraction of profit by either the transferring or receiving party. Thus, technology transfer should be viewed as one aspect of the innovation process, during which an innovation travels from an idea to a specific product, technology, or service and their practical use. The efficiency of the innovation process, namely the output of high-tech products, is linked to the transfer of new knowledge from one entity to another [1].

According to the Interstate Program of Innovation Cooperation of the CIS Member States for the period up to 2020, approved by the Decision of the Council of Heads of Government of the CIS in St. Petersburg on October 18, 2011, technology transfer is the process of transferring research and development results and knowledge for any use. The goals of the transfer may be the commercial use of these results (in the production of goods and services, attracting additional resources for further research and development, etc.), as well as non-commercial use (search for new research directions, dissemination and exchange of knowledge, etc.) [2].

Legal Regulation of Technology Transfer in Russia

Currently, Russia lacks a single legal act regulating technology transfer. This is due to the fact that Russian healthcare and pharmaceuticals are aimed at integration with the EAEU market. Consequently, in Russia, it is customary to be guided by EAEU legal acts in the sphere of technology transfer.

Thus, by Order of the Ministry of Health of Russia No. 40 dated February 28, 2022, the Center for Transfer of Medical Technologies was created, the functions of which include:

• Assisting persons carrying out scientific and/or scientific-technical activities, as well as federal executive bodies ensuring the development and implementation of scientific research programs in the sphere of health protection, in identifying and providing legal protection for the results of intellectual activity obtained during applied scientific research in the interests of medicine and healthcare;
• Forming recommendations regarding preclinical studies and clinical trials of medicinal products, technical tests and clinical trials of medical devices, and research aimed at ensuring a sufficient level of evidence for methods and means of prevention, diagnosis, treatment, and rehabilitation, based on draft topics of applied scientific research and topics of applied scientific research upon submission by the coordination center for research and development in the field of medical science;
• Consulting on issues of implementing developed medicinal products, medical devices, methods and means of prevention, diagnosis, treatment, and rehabilitation, and materials intended for manufacturing medical devices based on individual patient orders (hereinafter, "development results"), and expanding their application taking into account current regulatory enactments;
• Assisting in the commercialization of development results, including creating and maintaining lists of promising developments and their results, and manufacturers of medical and pharmaceutical products;
• Preparing proposals on mechanisms for financial support of early-phase clinical trials of medicinal products, the rights to which belong to budgetary or autonomous state institutions, based on venture investment principles.

Decree of the Government of Russia No. 916 dated July 16, 2021, approved the Rules for providing grants from the federal budget in the form of subsidies to support the creation and development of technology transfer centers carrying out the commercialization of intellectual activity results of scientific organizations and higher education organizations. According to the Rules, grants are provided based on the results of a competition conducted by the Ministry of Science and Higher Education of the Russian Federation. Grants are provided for a 4-year period.

The result of providing the grant is the achievement of target indicator values for the technology transfer center's activities and characteristic values in the current financial year, as envisaged by the technology transfer center's program, through the grant recipient's performance of measures envisaged by the technology transfer center's program.

The grant is provided for the financial support of the grant recipient's costs associated with the creation and development of the technology transfer center, including the following expenditure areas:

• Expenses for the remuneration of technology transfer center employees;
• Expenses for ensuring measures for the legal protection of intellectual activity results (expenses for patent search, patent strategies, patent promotion, and other measures necessary to ensure legal protection of intellectual activity results);
• Payments related to ensuring access to collective electronic platforms for the commercialization of intellectual activity results and other information resources (digital platforms) necessary for implementing the technology transfer center's program;
• Expenses for the acquisition of equipment and components necessary for implementing the technology transfer center's program;
• Expenses for the acquisition of software and other intangible assets;
• Transportation and travel expenses of technology transfer center employees, as well as other persons involved in the implementation of the technology transfer center's program under civil law contracts;
• Expenses for informing about the activities of the technology transfer center, including expenses for participation in exhibitions, production and placement of advertising, information materials, and other measures to popularize the center's activities (not more than 3% of the grant amount in the relevant financial year);
• Expenses related to professional retraining and advanced training of technology transfer center employees;
• Expenses for consulting services aimed at achieving the goal of the grant provision;
• Expenses for the development of additional professional programs in the field of intellectual property and technology transfer and the implementation of said programs using e-learning and distance learning technologies.

Currently, GOST R 58048-2017 "National Standard of the Russian Federation. Technology Transfer. Methodological Guidelines for Assessing the Level of Technology Maturity" has been adopted in Russia. According to Article 26 of Federal Law No. 162-FZ dated June 29, 2015 "On Standardization in the Russian Federation," documents of the national standardization system are applied on a voluntary basis in the same manner and to an equal extent regardless of the country and/or place of origin of the products (goods, works, services). However, the application of a national standard is mandatory for the manufacturer and/or executor in the event of a public declaration of product compliance with the national standard, including if the national standard designation is used in labeling, operational or other documentation, and/or product labeling with the national standardization system mark.

The specified standard describes the methodology for assessing the maturity of technologies and systems using them through appropriate readiness levels (TRL - Technology Readiness Levels). The readiness level concept is used to assess the current state of newly developed or acquired technologies and components of complex technical systems. Based on readiness levels, decisions are made regarding the possibility and feasibility of transferring specific technologies and further continuing R&D. According to Clause 4.5 of this GOST, various enabling systems are required at all stages of the lifecycle of the target technology and/or system development. Each enabling system has its own lifecycle. Each lifecycle of an enabling system is synchronized with the lifecycle of the target system. If the system under consideration does not yet exist, requirements for the enabling system are determined at the conception stage of the target system (or later, if time permits). In this case, each enabling system can be represented as a target system, which, in turn, may have its own enabling systems. In the practice of assessing the development of technologies and systems, as well as enabling systems, the concept of maturity is used, characterizing their progress along the lifecycle — from conception to application. Assessment of achieving a particular maturity is carried out using scales, the so-called readiness levels. Appendix "B" to the GOST contains typical scales used to assess the readiness level. For example, technology readiness levels include such scales as:

• An idea for solving a specific physical or technical problem has been formulated, and its theoretical and/or experimental substantiation has been produced.
• A technological concept and/or application of possible concepts for prospective objects has been formulated.
• Analytical and experimental confirmations of the most critical functional capabilities and/or characteristics of the selected concept have been provided.
• Components and/or mock-ups have been verified in laboratory conditions.
• Components and/or subsystem mock-ups have been tested in conditions close to real ones. Key technological components are integrated with suitable other ("supporting") elements, and the technology has been tested in simulated conditions.
• A model or prototype of the system/subsystem has been demonstrated in conditions close to real ones. The system/subsystem prototype contains all parts of the devices being developed.
• A system prototype has passed demonstration in operational conditions.
• A regular system has been created and certified (qualified) through tests and demonstrations.
• The operation of the real system has been demonstrated in real operational conditions.

Similar scales in the national standard are provided for assessing the readiness level of manufacturing.

Additionally, Order of the Ministry of Labor of Russia No. 577n dated September 7, 2020, approved the professional standard "Specialist in Intellectual Property Management and Technology Transfer". The main goal of such a specialist's professional activity is ensuring the transfer of intellectual activity results and means of individualization from an organization to another person, including their commercialization. Functional duties include: assessing the value of rights to intellectual activity results created or acquired during the implementation of innovative projects for subsequent use and/or technology transfer, organizing and supporting transactions during technology transfer.

Effectively, the aforementioned legal norms regulate certain features of technology transfer. However, there is no legislative consolidation of the procedure for concluding technology transfer agreements between pharmaceutical companies.

Based on the foregoing, one can agree with the opinion that technology transfer is considered implemented when a "transfer agreement" is signed between the parties, which can take main forms represented by:

• License agreement;
• Technical cooperation agreement;
• Joint venture agreement;
• Production agreement;
• Commercial agreement with technical assistance.

However, it should be considered that in the case of medicinal products, technology transfer must also take into account aspects of quality, safety, and efficacy of the medicinal product, compliance with which is a prerequisite for their production and sale as products. These issues require special study of the characteristics of medicinal products and parameters of technological processes of their development and production, which are affected during the technology transfer process and influence the quality of the final product. Moreover, these aspects act as an object of regulation by the state and are set forth in regional and international guidelines on Good Manufacturing Practice (GMP) and quality control of medicinal products [3].

Nevertheless, the legal regulation of technology transfer in Russia through the introduction of relevant legal norms is effectively just developing. This is due to the fact that technology transfer requires not only legal developments but also the joint work of doctors, heads of medical universities, the scientific community, etc.

Below, we examine the fundamentals of legal regulation of technology transfer in healthcare within the framework of the EAEU.

Technology Transfer in Medicinal Product Manufacturing in the EAEU

According to Decision of the Board of the Eurasian Economic Commission No. 150 dated October 25, 2022, "On Amending the Pharmacopoeia of the Eurasian Economic Union", terms such as the following are introduced:

• Technology Transfer – a documented process aimed at the transfer, implementation, and adaptation of knowledge, scientific research results, new technologies, and developments, carried out from developers to manufacturers, as well as within or between production sites for the production of finished products in accordance with their intended use. Said knowledge constitutes the basis of the manufacturing process, control strategy, approach to the validation process, and continuous improvement.
• Analytical Method Transfer (AMT) – a documented process aimed at the transfer, implementation, and assessment of the suitability of analytical methods for quality control purposes at the receiving party.

Thus, compared to Russian legislation, EAEU legislation contains more detailed definitions of terminology related to technology transfer.

The Board of the Eurasian Economic Commission approved Recommendation No. 11 dated June 8, 2021, "On the Guideline on the Transfer of Technologies and/or Analytical Methods in the Manufacture of Medicinal Products" (hereinafter, the "Guideline"). This Guideline was developed taking into account EAEU GMP requirements. The purpose of the transfer is to transfer information about the medicinal product, its manufacturing process, and quality control of the medicinal product or its manufacturing process within one production site or between production sites, including during the transfer of pharmaceutical development to production, for the release of commercial batches of the medicinal product, as well as the transfer of analytical methods from a production site to an accredited testing laboratory. Based on this information, the manufacturing process parameters, the quality control strategy for the medicinal product and its manufacturing process, the approach to manufacturing process validation, and its continuous improvement are determined. Transfer envisages the transfer of any process together with relevant documentation and professional expert knowledge from the sending unit to the receiving unit.

Main stages of transfer:

• Planning, organization, management;
• Determination of transfer success criteria;
• Formation of the project group (team);
• Consolidation of knowledge, gap analysis;
• Identification of key skills and personnel training (if necessary);
• Conducting risk analysis and assessment;
• Development of a transfer protocol;
• Qualification of production premises, equipment, engineering systems (if necessary);
• Transfer of analytical methods within the framework of technology transfer or as an independent process (if necessary);
• Production of pilot and/or engineering batches;
• Process validation, cleaning validation;
• Documentation of results and assessment of transfer effectiveness based on achieving established success criteria.

The Guideline notes that not all specified transfer stages are applicable to every type of transfer. Manufacturers may select those stages applicable to the procedure being carried out.

The main participants in the transfer are the Sending Unit (SU) and the Receiving Unit (RU). If necessary, a coordinating (managing) party is additionally defined, which may be an independent entity (process administrator).

Transfer may occur in the following cases:

• A new medicinal product is transferred from the development site to pilot production or directly to the production site;
• A medicinal product is transferred from one production area to another within one production site or from one production site to other production sites of the same manufacturer;
• A medicinal product is transferred between production sites of different manufacturers, including within the framework of interstate transfer;
• An analytical method is transferred from a manufacturer to an accredited testing laboratory.

For a successful transfer, the following requirements must be met:

• All quality aspects regarding the production of medicinal products must be controlled during the transfer;
• The transfer must be based on quality risk management principles;
• The capabilities of the sending and receiving units must be similar, but not necessarily identical, and premises and equipment must be operated in accordance with identical operating principles;
• A comprehensive gap analysis between the sending and receiving units must include an assessment of technical risks and potential discrepancies with regulatory document requirements;
• The personnel of the receiving unit must be properly prepared, qualified, and trained at the site of the sending and/or receiving unit, in accordance with the transfer plan;
• Throughout the entire transfer procedure, regulatory requirements of the authorized bodies of the states where the sending and receiving units are located, as well as authorized bodies of third countries to which the medicinal product is planned to be supplied, should be taken into account and interpreted uniformly;
• Effective transfer of processes, skills, and knowledge about the medicinal product should be conducted.

The Guideline contains a separate chapter regulating transfer planning, according to which the sending and receiving units should conclude formal agreements defining the responsibilities of the parties prior to the start of the transfer, at all its stages, and after the completion of the transfer.

The transfer plan and the transfer agreement may be executed as separate documents or as a single document.

Depending on the complexity of the transfer project, the transfer plan may contain the following sections:

• Purpose of the transfer;
• Scope (boundaries and/or object of transfer) of transfer application, transfer completion point, and/or its stages;
• Responsibilities of the parties;
• Volume and timeframe of the transfer;
• Justification for the volume of re-validation (if necessary);
• Assessment and justification for the selection of analytical methods (for analytical method transfer);
• Procedure for conducting personnel trainings, assessment of results;
• Transfer success criteria;
• List of documentation transferred during the transfer (information on the transfer object and relevant documents: specifications for raw materials and supplies, validation reports, production documents, etc.);
• Limitations, quality risks;
• Resources and budget (information on deadlines, resources, and budget).

Depending on the complexity of the transfer project, the transfer agreement may additionally include the following sections:

• Condition on joint execution of the transfer protocol in accordance with the specified transfer stages;
• Procedure for approving changes, deviations from the transfer plan;
• Procedure for documenting actions, document storage;
• Conditions for transfer and storage of samples for transfer;
• Procedure for conducting audits and inspections;
• Other sections (if necessary).

Unlike the transfer plan, the transfer agreement defines strategic intentions and the general framework of the transfer, including requirements for interaction on quality issues.

Chapter 5 of the Guideline contains criteria for assessing transfer success.

The following criteria may be used to determine transfer success:

• Confirmed ability of the receiving unit to reproduce the medicinal product in routine mode;
• Availability of specifications (for release and end of shelf life) for the transferred medicinal product corresponding to the specifications of the registration dossier (for registered medicinal products);
• Availability of a complete set of developed documentation necessary for the transfer (standard operating procedures for production processes, control, equipment cleaning, technological documents (master formula, manufacturing instructions, packaging instructions), test methods, batch production records, plans, protocols, reports, and related records of actions taken or conclusions made);
• Compliance of the receiving unit's technical means (premises, equipment, engineering systems) with requirements established by the sending unit;
• Availability of documented confirmation of abilities, skills, and knowledge among the receiving unit's personnel and the ability to demonstrate these abilities, skills, and knowledge to members of the sending unit's transfer project group (team);
• Timely completion of all transfer stages;
• Successful validation of the technological process and/or analytical methods applied by the receiving unit;
• Compliance with the planned budget;
• Other suitable criteria.

Particular importance is given to personnel accompanying the transfer. Members of the transfer project group (team) must have the necessary qualifications and experience in managing specific aspects of the transfer within their area of responsibility.

The role and responsibility of each member of the transfer project group (team) must be defined in the transfer agreement before the start of the transfer and communicated to the executors.

The sending and receiving units jointly implement personnel training programs that may be required due to the specifics of the transferred medicinal product, technology, and/or analytical methods (e.g., training in analytical methods or equipment use) and conduct an assessment of training results.

It is established that the sending unit must provide the receiving unit with all necessary documentation regarding the medicinal product, technologies, or analytical methods in accordance with the transfer plan and/or transfer agreement.

Specifications and corresponding functional characteristics of starting materials (active pharmaceutical ingredients, starting raw materials for active pharmaceutical ingredients, excipients, intermediate products, bulk products) used by the receiving unit must be equivalent to the specifications and characteristics of starting materials used by the sending unit.

Also, the sending unit must provide the receiving unit with the open part of the Active Pharmaceutical Ingredient Master File (if available) or equivalent information, as well as other necessary information on the active pharmaceutical ingredient, including the closed part of the Active Pharmaceutical Ingredient Master File relevant to the production of the medicinal product.

It is noted that excipients have a direct impact on the quality of the finished product; therefore, requirements for their quality and functional characteristics must be transferred to the receiving unit.

Furthermore, the sending unit provides a detailed characterization of the finished product, including information on its qualitative and quantitative composition, physical description, information on the production method, quality control during the production process (in-process control), control methods and specifications, packaging components and packaging configurations, as well as information on safety and handling conditions for the finished product.

Processes affecting the parameters and course of the technological process or the quality of the medicinal product must be defined, characterized, and documented. The receiving unit, based on information received from the sending unit, analyzes its technical capabilities for the production and packaging of medicinal products.

The sending unit provides the receiving unit with information on the layout, construction, and finishing of premises, information on engineering systems (heating, ventilation, and air conditioning systems, temperature, relative humidity, water supply, power supply, and compressed air systems) that may influence products, processes, or methods.

The sending unit provides the receiving unit with a list of equipment indicating types and models of equipment included in the processes of production, filling, packaging, and/or quality control of transferred products, as well as documents on equipment qualification and validation.

The receiving unit, in turn, verifies the information submitted by the sending unit.

After the parties agree on the transfer agreement or plan, a protocol is developed.

In general, documentation formed within the framework of a transfer project varies depending on the type of transfer, the type of transferred medicinal product, and the capabilities and requirements of the receiving unit.

Documentation of transfer results is carried out in the form of a report, which must contain:

• Transfer scope;
• Success criteria;
• Critical process parameters, critical quality attributes defined by the sending and receiving units, which should be presented in table form;
• Execution of the technology transfer protocol, review of all transfer stages;
• Deviations from the transfer protocol, as well as corresponding actions aimed at their elimination.

Samples of said documentation are provided in the appendices to the Guideline.

Thus, the Guideline most fully and thoroughly discloses the features of implementing technology transfer in EAEU member states. We believe that the adoption of new legal acts regarding the regulation of technology transfer issues in healthcare will be carried out precisely at the EAEU level, due to the development of market integration of EAEU member states. Below, we examine some practical features associated with technology transfer.

Practical Issues of Technology Transfer in Healthcare

Due to the fact that the adoption of legal acts regulating technology transfer in healthcare is a relatively recent phenomenon, both for Russian reality and within the EAEU, there is a lack of a large volume of law enforcement practice. Nevertheless, based on adopted legal acts, it follows that technology transfer requires a comprehensive approach, and a number of practical questions may arise during its implementation.

For example, during technology transfer, just as with the release of an original drug, it is important to comprehensively assess the task and available capacities. In the practice of technology transfer in the sphere of drug enrichment, difficulties often arise due to differences in equipment: for example, different machines are installed at enterprises, making it technically impossible to fulfill certain requirements for secondary packaging or leaflet folding. In this case, the manufacturer, together with the contractor, has to find ways to solve this problem [4].

Some pharmaceutical specialists highlight problems during technology transfer at individual stages and within specific technological processes. For example, it is noted that: "Applying coatings to tablet cores is the final stage of the technological process, not subject to further correction. Technology transfer at the film coating stage is a complex process that may be accompanied by a number of problems having a negative impact on product quality. Technology transfer can be considered successful when a product of proper quality, corresponding to all indicators of normative documentation / quality specification, is consistently obtained. This may require significant changes to coating parameters, the coating preparation process, the process of preparing personnel/equipment for work, and if necessary, working with suppliers / replacing suppliers, as well as changing parameters at the previous stage of the technological process – tableting. If any defect occurs, it is necessary to identify the causes and take measures to eliminate them" [5].

Also, using the medicinal product "Aranoza" as an example, it is noted that the transfer of manufacturing technology required conducting:

• Analysis and risk assessment of individual transfer stages;
• Scaling up the technological process;
• Validation of technological process stages;
• Validation and transfer of analytical quality control methods.

The following were considered as criteria for the success of manufacturing technology transfer:

• Obtaining a medicinal product corresponding to specification requirements (for release and end of shelf life) corresponding to the registration dossier specifications;
• Successful validation of the technological process and analytical methods by the receiving unit;
• Confirmed ability of the receiving unit to reproduce the medicinal product, technological process, or analytical method in routine mode in accordance with a specific set of specifications agreed with the sending unit.

Technology transfer was carried out to a specially organized section for the production of preparations containing highly toxic substances (cytostatics) [6].

Furthermore, some specialists note that: "Timely staffing of technological transfer at the proper level is of key importance for the effectiveness of transfer and implementation of new technologies. Expert survey results showed that currently, the existing personnel training system in higher education organizations is unable to fully satisfy the needs of manufacturing organizations, as specialists who will be engaged in the biopharmaceutical production transfer process need additional training at the enterprise in addition to training in the field of transferred technologies within the framework of a specific transfer project" [7].

Thus, in the lifecycle of a medicinal product, technology transfer takes place at any stage. Practical knowledge about the process is transferred; technology from the laboratory to pilot production; from one production unit to another (with changes in types of main and auxiliary equipment within one organization); from customer to executor or, conversely, between different organizations, etc. [8].

This article has examined the main features of the legal regulation of technology transfer in healthcare, considering certain practical features and problems associated with technology transfer in the pharmaceutical industry. In general, it is important to note that the development of technology transfer in the field of medicinal products, medical devices, and treatment methods is of particular importance both in the interests of healthcare development at the state level and in the interests of every patient.

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References

[1] Transfer of technologies when creating production of a medicinal product. V.V. Beregovykh, O.R. Spitsky // "Vestnik RAMS". 2013. No. 12.

[2] Interstate Program of Innovation Cooperation of the CIS Member States for the period up to 2020, approved by the Decision of the Council of Heads of Government of the CIS in St. Petersburg on October 18, 2011.

[3] Methodological aspects of technology transfer of vital and essential medicinal products. A.A. Dykhanov // "Modern Medicine". No. 2(2). 2016.

[4] Transfer of technologies for production and packaging of medicines: collaboration with a printing supplier as a path to success. Pharmprom. December 28, 2022.

[5] Problems of applying film coatings during technology transfer. A. V. Strelkova, E. V. Flisyuk // "Development and Registration of Medicinal Products". 2022. No. 4.

[6] Theoretical and experimental bases for creating medicinal products for the treatment of neuroendocrine tumors. Z.S. Shprakh. Dissertation for the degree of Doctor of Pharmaceutical Sciences. Moscow. 2021. P. 89.

[7] Substantiation of approaches to improving staffing of technological transfer using the example of biopharmaceutical production. K.O. Sidorov. Dissertation for the degree of Candidate of Pharmaceutical Sciences. St. Petersburg. 2022. P. 121.

[8] Technology transfer in the pharmaceutical industry. M.A. Belova. Materials of the II International Scientific and Practical Conference "Modern Problems of the Domestic Medico-Biological and Pharmaceutical Industry. Development of Innovative and Personnel Potential of the Penza Region". Penza. November 9-10, 2012.