TECHNOLOGY DEVELOPMENT AND TRANSFER

WHO GUIDELINE FOR TECHNOLOGY TRANSFER (TT)

Technology transfer (TT) is a structural guideline which is intended for
quality of the process, products, standardization and cost-effective
productions. This is a systematic process in which knowledge and
experience are gathered and documented during life cycle of products
originated from development, manufacturing, production and marketing
or commercialization and are transferred to an authorized and
accountable organization. TT is a fundamental part of discovery and
development of newer pharmaceutical products and dosage forms.As per
World Health Organization, 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.” In Pharmaceutical industry,
TT is involved in drug discovery, product development, clinical trials
and full-scale commercialization.
DIFFERENT TERMINOLOGIES OF TECHNOLOGY
TRANSFER (TT)
1. Active Pharmaceutical Ingredients (API): Any ingredients or
substances which are used in the manufacturing of a pharmaceutical
formulation and are considered as active ingredient of that dosage forms,
are called as Active Pharmaceutical Ingredients (API).
2. Change Control (CC): Change control can be defined as, “A formal
system by which qualified representatives of appropriate disciplines
review proposed or actual changes that might affect the validated status
of facilities, systems, equipments or processes. The intent is to determine
the need for action that would ensure and document that the system is
maintained in a validated state.” (EU GMP Guidelines, Annexure 15).
3. Control Strategy: The proper sets of control obtained from product
and process understanding to assure the process performance and
product quality which include parameters of products, materials, drug
substances, facilities, equipment availability, standardization process, in
process control, quality of finished goods, etc.
4. Critical Control Point (CCP): Some controls are mandatory in the
pharmaceutical industry to eliminate or to reduce the quality hazards.
CCP is a step at which this control can be applied.
5. Corrective Actions (CA): Corrective actions are taken at CCP while
controlling the quality hazards.
6. Quality Assurance (QA): According to WHO “Quality Assurance” is
a wide-ranging concept covering all matters that individually or
collectively influence the quality of a product. It is the totality of the
arrangements made with the object of ensuring that pharmaceutical
products are of the quality required for their intended use. Quality
assurance therefore incorporates GMP and other factors, including those
outside the scope of this guide such as product design and development.
7. Quality Control (QC): QC is that part of GMP concerned with
sampling, specification, testing, documentation and release procedures
which ensure that the necessary and relevant tests are performed, and the
product is released for use only after ascertaining its quality.
8. Design Qualification (DQ): DQ is a documented verification of the
proposed design of the facilities, systems and equipment that are suitable
for the intended purpose.
9. Installation Qualification (IQ): IQ is an evidence of all key aspects
of the process equipment and ancillary system installation adhere to the
manufacturer’s approved specification.
10. Operational Qualification (OQ): OQ is established by objective
evidence process for the control limits and action levels in product of all
predetermined requirements.
11. Performance Qualification (PQ): PQ is established by verifying a
process, under anticipated condition, consistently produces a product
which meets all predetermined requirements.
12. Drug Master File (DMF): It is detailed information of a specific
facility, process or product which has been submitted to Medicines
Regulatory Authority (MRA) for the incorporation into the application
for the marketing-authorization.
13. Finished Pharmaceutical Product (FPP): A finished
pharmaceutical product will be considered as a product which contains
one or more APIs and has undergone all steps of production,
standardization, packaging, storing and labeling.
14. Technology Transfer: Inter-Company Transfer: The transfer of
technology between sites of different companies is called as
intercompany transfer.
15. Technology Transfer: Intra-Company Transfer: The transfer of
technology between sites of same group of companies is called as
intracompany transfer.
16. Standard Operating Procedure (SOP): It is an authorized written
procedure with detailed instruction for the operation of equipment,
maintenance of equipment, cleaning of equipment, validation of
equipment, environmental control, sampling and analytical procedures.
17. Technology Transfer Report (TTR): A documented report of
technology transfer consists of:
• Procedures
• Acceptance criteria
• Obtained results
• Conclusions
• Deviations, if any
18. Sending Unit (SU) and Receiving Unit (RU): The discipline of any
organization involved in transferring of designated process or method is
called as sending unit (SU) and the organization involved in receiving
the same is mentioned as receiving unit (RU).
GENERAL PRINCIPLES OF TECHNOLOGY TRANSFER (TT)
The basic requirements of TT are:
• Quality Risk Management (QRM)
• Documented approach
• Logical approach
• Skilled and trained staff
• Sending Unit (SU)
• Receiving Unit (RU)
The following general principles are to be followed for the successful
TT:
• The project should attain the quality parameters based on QRM.
• The facilities and equipments available in SU and RU should be
similar.
• The trained and skilled staffs should be available at RU.
• RU should reproduce the documented evidence of transferred product,
process or manufacturing method against the predetermined
specifications of SU.
• Reporting of out of specifications results and errors by the RU to SU.
• The clarity of transfer process should be maintained.
• The legal implications like royalties, intellectual property rights,
conflict of interests should be conveyed prior and during the transfer.
TECHNOLOGY TRANSFER PROTOCOLS
The transfer process should be managed by SU, RU and if required, an
additional agency in which proper directions and approvals are provided.
There should be a proper management plan and formal agreements for
the successful technology transfer.
The following steps should be followed as per the transfer protocol.
• Purpose and objective of the transfer.
• Scope of the transfer.
• Skilled personnel and their responsibilities.
• Comparison of materials, equipments and methods between SU and
RU.
• Documented evidence of each stage of process control and critical
stages.
• The transfer of documents should be achieved satisfactorily.
• Assessment of CCP (critical control points).
• Assessment of experimental process for manufacturing.
• Experimental process assessment for standardization and analysis.
• Information of different batches.
• Process validation.
• Assessment of out of specification or deviated results and change
control.
• Analysis of finished products.
• Documented reports of analysis.
• Retention of reference materials, active ingredients, intermediate
products and finished products.
• Approval of competent authorities or project manager.
QUALITY RISK MANAGEMENT (QRM)
Introduction
In the life-cycle of any pharmaceutical product the quality aspect is very
important. The risk of quality variation in the pharmaceutical product
can be assessed, controlled and communicated by a systematic process
called QRM. It has been mentioned in ICH guideline Q9.
Principle
The basic principle of QRM is the assessment and evaluation of the
associated risks based on scientific knowledge and evidence to maintain
the quality of the product and customer satisfaction.
QRM Process
The process of QRM can be summarized in following different steps
Step (1) QRM initiation:
To initiate the process of QRM the following plan can be followed:
• Types of risk and problem.
• Questions regarding risks.
• Information regarding quality and potential hazards.
• Information of background and raw data.
• Assessment of required resources.
• Specification of time limit.
Step (2) Risk Assessment:
This may include the following:
• Identification of Hazards: Systematic process to identify the risks and
hazards.
• Analysis of Risks: Qualitative and quantitative estimations of hazards.
• Evaluation of Risks: Comparison of identified and analyzed hazards.
Step (3) Risk Control:
The basic purpose of risk control is to reduce or eliminate the risks. It
should be based on the following points:
• The acceptance level of risks.
• Possible steps to reduce or eliminate the risks.
• Balance among benefits, risks and resources.
(a) Reduction of Risks: The level of risk when exceeds the acceptance
criteria, the reduction of risks should be followed. Detection of risks,
risks assessment and the process control can reduce the level of risks.
(b) Acceptance of Risks: It is the decision to accept the risk.
Step (4) Results of QRM and Risk Reviews:
The review of result obtained from the QRM process is a part of quality
management system. Results of QRM process should be documented,
reviewed, inspected, audited and possible change control is suggested.
The unsatisfactory review process will suggest the failure of the
investigation and the process can be started from risk assessment step.
Step (5) Risk Communication:
This is the communication process of the data of risk management
system. The risk management system can be communicated at any step
of risk management process (Risk assessment, control and review
process, mentioned as dotted line). The well documented result of QRM
process should be submitted and communicated (mentioned as solid
line) to the parties. This guideline is very important in pharmaceutical
industry with respect to QRM. The process is applicable for the
pharmaceutical product from manufacturing to inspection process.
INFORMATION REQUIRED FOR TECHNOLOGY TRANSFER
For the technology transfer from research and development section to
production, the RU should be capable of performing and
accommodating the production capacity. The detailed process
development should be transferred. At RU, expert personnel and facility
available at the site are the primary considerations. Development of
protocol by SU and RU jointly for the technology transfer is necessary.
Starting Materials
For the process of successful technology transfer to the production, the
specifications and characteristics of starting materials like API and
excipients should be identical at both the place SU and RU.
Active Pharmaceutical Ingredients (API)
The complete API master file, Drug Master File (DMF) and relevant
auxiliary information of API which are important for the manufacturing
process should be provided by the SU to RU. Some important
information is mentioned below:
• Details of API manufacturer and supplier.
• Detail scheme of synthesis, process outline, raw materials, process
control.
• Details of intermediate products.
• Complete information of API for formulation process. It includes:
- Physicochemical parameters like solubility, partition coefficient
(method of determination).
- Particle size distribution.
- Bulk and tap density with detail method of evaluation.
- Disintegration profile.
- Nature of hygroscopicity.
- Water content.
- Loss on drying.
- Limit of impurities.
• Microbiological factors.
• Environmental factors.
• Pharmacopoeial standards with method of determination.
• Stability studies.
• Storage and handling guidance mentioned in Pharmacopoeias.
Excipients
The excipients used in the process of manufacturing have an important
role in quality of the finished product. The duty of SU is to provide
detail information of excipients to RU. The following information is
some of the examples of detail information:
• Details of manufacturer and supplier.
• Category of excipients.
• Dosage form available.
• Descriptions.
• Solubility.
• For transdermal dosage form:
(a) Lipophilicity, Partition coefficient
(b) Particle size and distribution
(c) Specific gravity
(d) Water content and loss of drying
(e) Dissolution rate with detail process
• For solid dosage form:
(a) Bulk and tap density profile with detail method of evaluation
(b) Compaction properties
(c) Particle size and distribution
(d) Water content and loss of drying
(e) Nature of hygroscopicity
• For semi-solid dosage form:
(a) Melting point
(b) Range of pH
(c) Viscosity
(d) Specific gravity
• For liquid dosage form:
(a) Range of pH
(b) Viscosity
(c) Specific gravity
(d) Water content
• For parenteral formulation:
(a) Range of pH
(b) Viscosity
(c) Specific gravity
(d) Water content
(e) Osmotic pressure
(f) Ionic strength
• For aerosol/inhaled dosage form:
(a) Solubility
(b) Bulk and tap density
(c) Particle size and distribution
(d) Surface area
(e) Water contentProcess Information
Regarding the information of process and testing the following
information should be provided by the SU.
(a) Requirement of facility.
(b) Requirement of equipments.
(c) Requirement of skilled person.
(d) Detail information of raw materials.
(e) Storage guideline and handling of raw materials and finished goods.
(f) Availability of all SOPs.
(g) Manufacturing process.
• Process flow charts
• Process optimization
• Detail master batch records
• Method of addition of raw materials and excipients
• Details of intermediate products
• Reaction conditions
• Environmental factors
(h) Analytical methods
• Standardization process
• Assay procedure
• Finished goods testing
(i) Validation protocols
• Process validation
• Equipment validation
(j) Annual audits and reviews
(k) Change control, critical control point and corrective actions
(l) Quality control and assurance
Finished Products
A finished pharmaceutical product is a final product that has completed
all stages of production and manufacturing. The finished product should
be stored in specific container and proper labeling is mandatory. All the
associated information in well documented manner should be informed
and transferred from SU to RU. The finished product storage and
handling guidelines are to be informed to RU along with the detail
specification and analytical test procedures. The predetermined
specifications should be analyzed and the detail standardization process
should be transferred.
Packaging
Information regarding packaging of finished product should be
transferred to RU. Some
of the important instructions are given below:
• Suitable container
• Proper closure system
• Packing material
• Process of packaging
• Design of packaging
• Proper labeling
• Relevant information mentioned in package and label
The information provided by SU should be analyzed at RU for
packaging either the packaging is suitable, safe, protective and
compatible to the finished product or not. Packaging should be
suggested in such a manner that the final product should not decompose
or affected by the environmental factors. The product should not be
oxidized and should be protected from sunlight. The formation of
undesired substance can make the product spurious and toxic. The
container should not react with the product and the efficacy of the
product should not be altered by any means after packaging.
Documentation
Some of the important documents required in technology transfer are:
• Technology transfer protocol, qualification protocol and report.
• Training protocols and report.
• Standard Operating Procedure (SOP).
• Technology transfer report.
• Analytical methods transfer protocol.
• Validation report (VR).
• Process validation report.
• Cleaning validation protocol and report.
• Validation Master Plan (VMP).
• Master batch record.
For a successful technology transfer, the documents related to facility
available at RU, detail description of manufacturing process, sampling
procedures, approved SOPs for all instruments and process, information
of storage, packaging, cleaning, validations, stability information and
regulatory requirements should be provided by SU to RU before starting
the productions.
Premises
The SU should make available the information regarding the layout and
construction of buildings and services. The air-conditioning system,
ventilation, temperature, humidity and compressed air related
information should be provided to RU before the production. RU should
include the risk management, safety requirements, emergency protocols
and waste management provisions in the list of information.
Equipments
The SU should provide the following to RU regarding equipments:
• List of equipments required.
• Specific model and makers of equipments.
• Manuals and SOPs.
• Set-up, maintenance, calibration and storage protocol.
• IQ, OQ and PQ status.
Qualification and Validation
The qualification and validation protocol should be decided on the basis
of QRM and should be provided by SU to RU in well documented
manner.
Analytical Method Transfer
Analytical methods are used to analyze raw materials, finished products,
packaging materials and cleaning samples. Analytical method transfer
should be performed by providing all the information regarding
analytical testing.
The SU should provide the following information for analytical method
transfer:
• The methods of analysis and testing of raw materials, finished
products.
• Training for analyst and staff.
• Details of equipments used for the testing.
• Testing parameters.
• Experimental principle, design and methods.
• Quality control testing results.
• Validation reports.
After getting all information from the SU, the RU should have some
responsibilities for the successful analytical transfer, some of them are:
• Agreement in acceptance criteria.
• Review of analytical methods.
• Trained and skilled staffs.
• Availability of necessary equipments.
• Documents for recording the analytical results.
• Execution of transfer protocol.
• Proper validation to implement the process.
• Availability of Pharmacopoeias.
WHO has clearly mentioned about the possible experimental designs for
analytical
testing. The tests are:
• Identification test.
• Content uniformity.
• Solubility.
• Assay or percentage purity of the components.
• Dissolution parameter.
• Qualitative and quantitative tests for microbiological assays.
• Limit test for impurities.
• Residues recovery.
The responsibilities from both SU and RU should be performed and
should prepare the report jointly to execute the transfer protocol.
AGENCIES FOR TECHNOLOGY TRANSFER IN INDIA
For the successful TT in India several agencies are working. Some of
them are discussed below.
Asian and Pacific Centre for Transfer of Technology (APCTT)
APCTT is a United Nations Regional Institution that is governed by a
Governing Council consisting of a representative designated by the
Government of India. The agency is under the Economic and Social
Commission for Asia and the Pacific (ESCAP). APCTT was established
in 1977 in Bangalore. The main centre was moved to New Delhi in
1993. APCTT governs TT to and from small and medium-scale
enterprises in Asia and the Pacific. It regulates the development projects
which are funded internationally to provide more strength for TT in Asia
and the Pacific.Technology transfer related areas of APCTT are
institution building, human resources development, studies, business
partnership development.
National Research Development Corporation (NRDC)
NRDC was established in 1953 by Govt. of India with the aim of
promotion, development and commercialization of TT from public
sector to private sector. NRDC is involved in transfer of technologies,
inventions, patents and processes from the national research and
development institutions and universities that are under the
administrative control of the Department of Scientific and Industrial
Research and Ministry of Science and Technology.
Technology Information, Forecasting & Assessment Council
(TIFAC)
TIFAC, an autonomous organization, was established in 1988 under
DST (Department of Science & Technology, Govt. of India). TIFAC is
aimed to promote and support the technology, innovations in selected
areas of national importance. TIFAC concentrates on technology
innovation and development through various sustained programs
between industry and academia. TIFAC released its Vision 2020 under
the leadership of Dr. APJ Abdul Kalam, the former chairman of TIFAC
in 16 technology areas and in 2016. Vision 2035 prepared by TIFAC has
been inaugurated by Hon’ble Prime Minister of India Shri. Narendra
Modi in 12 thematic areas of national priorities and importance in
Mysuru, Karnataka. The 12 thematic areas are:
1. Education
2. Medical Science and Health Care
3. Food and Agriculture
4. Water
5. Energy
6. Environment
7. Habitat
8. Transportation
9. Infrastructure
10. Manufacturing
11. Materials
12. Information and Communication Technologies (ICT).
Biotech Consortium India Limited (BCIL)
BCIL, public limited company, was inaugurated in 1990 under the
Indian Companies Act, 1956. BCIL is promoted by the Department of
Biotechnology (DBT), Ministry of Science and Technology,
Government of India and All India Financial Institutions. BCIL was
aimed for providing the necessary linkages among stakeholders and
business support to facilitate the acceleration of commercialization of
biotechnology. BCIL assists scientists, technologies, research
institutions, universities, first entrepreneurs, the corporate sector,
national and international organizations, central government, various
state governments, banks and financial institutions.
BCIL works in the following aspects:
• Technology transfer
• Project consultancy
• Fund syndication
• Information dissemination
• Manpower training and placement related to biotechnology
Technology Bureau for Small Enterprises (TBSE)
TBSE provides the opportunity to the small enterprises to at the global
level for acquisition of technology or establish business collaboration.
TBSE works under Development Commissioner, Ministry of Micro,
Small and Medium Enterprises (MSME) and it is partially funded by
office of Development Commissioner (DC), Small Scale Industries
(SSI), and Government of India.
The important features of TBSE are:
1. TBSE offers a professionally managed system for technology and
collaboration search.
2. TBSE builds up confidence between partners.
3. TBSE has proper mechanism for arranging technology and finance.
4. TBSE provides a gateway to global technology market through
networking.
5. TBSE takes up project appraisal and preparation of business plan.
Small industrial Development Bank of India (SIDBI)
SIDBI was established on April 2, 1990, through an Act of Parliament,
under the Department of Financial Services, Government of India. It is a
development financial institution in India. The head quarter is situated at
Lucknow, Uttar Pradesh. The purpose of SIBI is to provide refinance
facilities and short term lending to industries, and serves as the principal
financial institution in the Micro, Small and Medium Enterprises
(MSME) sector.
TECHNOLOGY TRANSFER RELATED DOCUMENTS
Confidentiality Agreement
It is also called as non-disclosure agreement (NDA). It is used to protect
the proprietary nature of the technology and retain the confidentiality of
a technology or invention. The drafting of the appropriate clauses can be
essential for the maintenance of the value of the
technology. The need of this agreement is due to the increase in
competition and the new technologies can be exploited. Thus it is
necessary to obtain protection to the continuous innovation process
through confidentiality agreements.
Licensing
The license agreement is generally referred to the licensing of
intellectual property rights such as; patents, trademarks, copyrights, etc.
This agreement has a role on maintaining the confidentiality and secrecy
aspects of the contract.
MoUs
MoU stands for Memorandum of Understanding. It is a negotiated
agreement and contract between the Government and the Management
of the Central Public Sector Enterprise (CPSE). MoUs are used either
when the parties do not imply a legal commitment or where the parties
cannot create a legally enforceable agreement.