TECHNOLOGY DEVELOPMENT AND TRANSFER INDUSTRIAL PHARMACY ll
BP702TT
B.PHARMA SEMESTER 7
Introduction
WHO guidelines for Technology Transfer(TT):
Terminology
Technology transfer protocol, Quality risk management
Transfer from R & D to production & Granularity of TT Process
Quality control: analytical method transfer
Premises and equipment
Documentation
Technology Transfer AGENCIES IN INDIA
reference
Introduction
In recent years, there is a growing awareness that an appropriate transfer of manufacturing technologies
(technology transfer) is important to upgrade drug quality as designed during R&D to be a final product
during manufacture as well as assure stable quality transferred for many reasons between contract giver
and contract acceptor during manufacture.
Technology transfer is a process by which technology developed in one organization, in one area, or for one purpose is applied in another organization, in another area, or for another purpose. Technology transfer is helpful to develop dosage forms in various ways as it provides efficiency in process, maintains quality of product, helps to achieve standardized process which facilitates cost effective production. The crucial aspect in a successful transfer is the actual use of the product or process. Technology transfer is both integral and critical to drug discovery and development for new medicinal products
Technology transfer is defined as “The processes that are needed for successful progress from drug
discovery to product development to clinical trials to full-scale commercialization.” Technology transfer can be considered successful if a Receiving Unit can routinely reproduce the transferred product, process or method against a predefined set of specifications as agreed with a Sending Unit and /or a Development Unit. It is the process by which an original innovator of technology makes its technology available to commercial partner that will exploit the technology.
WHO guidelines for Technology Transfer(TT):
1. Terminology
1.1 acceptance criteria : Measurable terms under which a test result will be considered acceptable.
1.2 active pharmaceutical ingredient (API)
Any substance or mixture of substances intended to be used in the
manufacture of a pharmaceutical dosage form and that, when so used,
becomes an active ingredient of that pharmaceutical dosage form. Such
substances are intended to furnish pharmacological activity or other direct
effect in the diagnosis, cure, mitigation, treatment, or prevention of disease
or to affect the structure and function of the body
1.3 change control (C/C) A formal system by which qualifi ed representatives of appropriate disciplines review proposed or actual changes that might affect a validated status. The intent is to determine the need for action that would ensure that the system is maintained in a validated state.
1.4 control strategy A planned set of controls, derived from current product and process understanding , that assures process performance and product quality. The controls can include parameters and attributes related tomaterials and components related to drug substances and drug product materials
and components, facility and equipment operating conditions, in-process controls, fi nished product specifi cations, and the associated methods and frequency of monitoring and control
1.5 corrective action (C/A) Any action to be taken when the results of monitoring at a critical control
point indicate a loss of control.
1.6 critical control point (CCP) A step at which control can be applied and is essential to prevent or eliminate a pharmaceutical quality hazard or to reduce it to an acceptable level.
1.7 design qualification (DQ) Documented evidence that the premises, supporting systems, utilities,
equipment and processes have been designed in accordance with the requirements of good manufacturing practices (GMP).
1.8 good manufacturing practices (GMP) That part of quality assurance which ensures that pharmaceutical products are consistently produced and controlled to the quality standards appropriate
to their intended use and as required by the marketing authorization.
1.9 in-process control (IPC) Checks performed during production in order to monitor and, if necessary , to adjust the process to ensure that the product conforms to its specifi cations. The control of the environment or equipment may also be regarded as a part of in-process control.
1.10 intercompany transfer A transfer of technology between sites of different companies.
1.11 intracompany transfer A transfer of technology between sites of the same group of companies
1.12 process validation Documented evidence which provides a high degree of assurance that
a specifi c process will consistently result in a product that meets its predetermined specifi cations and quality characteristics.
1.13 quality assurance (QA) Quality assurance is a wide-ranging concept covering all matters that
individually or collectively infl uence the quality of a product. It is the totality of the arrangements made with the objective of ensuring that pharmaceutical products are of the quality required for their intended use.
1.14 quality control (QC) Quality control covers all measures taken, including the setting of specifi cations, sampling, testing and analytical clearance, to ensure that starting materials, intermediates, packaging materials and fi nished pharmaceutical products conform with established specifi cations for identity, strength, purity and other characteristics.
1.15quality risk management (QRM)
Quality risk management is a systematic process for the assessment, control, communication and review of risks to the quality of the pharmaceutical product throughout the product life-cycle.
1.16 receiving unit (RU) The involved disciplines at an organization where a designated product,
process or method is expected to be transferred.
1.17 sending unit (SU) The involved disciplines at an organization from where a designated
product, process or method is expected to be transferred.
1.18 standard operating procedure (SOP) An authorized written procedure giving instructions for performing operations not necessarily specifi c to a given product or material (e.g. equipment operation, maintenance and cleaning, validation, cleaning of premises and environmental control, sampling and inspection). Certain SOPs may be used to supplement product-specifi c master and batch
production documentation.
1.19 validation master plan (VMP)
A high-level document that establishes an umbrella validation plan for the entire project and summarizes the manufacturer’s overall philosophy and approach, to be used for establishing performance adequacy. It provides information on the manufacturer’s validation work programme and
defi nes details of and timescales for the validation work to be performed, including a statement of the responsibilities of those implementing the plan.
1.20 validation protocol (or plan) (VP) A document describing the activities to be performed in a validation, including the acceptance criteria for the approval of a manufacturing process or a part thereof — for routine use.
1.21 validation report (VR) A document in which the records, results and evaluation of a completed
validation programme are assembled and summarized. It may also contain proposals for the improve ment of processes and or equipment.
2.0 Technology transfer protocol, Quality risk management
- Transfer comprises an SU and an RU. In some circumstances there may be an additional unit which will be responsible for directing, managing and approving the transfer.
- There is a formal agreement between the parties, which specifies the responsibilities before, during and after transfer.
- There should be a project management plan which identifies and controls all the necessary activities identified at the start of the undertaking.
- The transfer protocol should list the intended sequential stages of the transfer.
- objective;
- scope;
- key personnel and their responsibilities;
- a parallel comparison of materials, methods and equipment;
- the transfer stages with documented evidence that each critical stage has been satisfactorily accomplished before the next commences;
- identifi cation of critical control points;
- experimental design and acceptance criteria for analytical methods;
- information on trial production batches, qualifi cation batches and process validation;
- change control for any process deviations encountered;
- assessment of end-product;
- arrangements for keeping retention samples of active ingredients, intermediates and fi nished products, and information on reference substances where applicable; and
- conclusion, including signed-off approval by project manager.
The SU should provide the necessary validation documentation for the process and its support functions. Usually, an established process is transferred, and such documentation is already available.
The SU or third party should assess the suitability and degree of preparedness of the RU before transfer, with regard to premises, equipment and support services (e.g. purchasing and inventory control mechanisms, quality control (QC) procedures, documentation, computer validation, site
validation, equipment qualifi cation, water for pharmaceutical production and waste management).
The SU and the RU should jointly verify that the following, satisfactorily completed, validation protocols are available:
• installation qualification (IQ) and operational qualifi cation (OQ) data for manufacturing and packaging equipment at the RU site and analytical equipment; and
• qualifi cation of the rooms for both manufacture and packaging at the RU site.
The SU and the RU should jointly implement any training programmes that may be required specifi c to the product, process or method to be transferred, e.g. on analytical methods or equipment usage,
and assess training outcomes.
The SU and the RU should jointly execute the transfer protocol according to a checklist and or fl ow diagram showing the sequence of steps to be carried out to effect an effi cient transfer.
Any changes and adaptations made during the course of the technology transfer should be fully documented.
The SU and the RU should jointly document the execution of the transfer protocol in a transfer of technology summary in a report.
3.0 Transfer from R & D to production & Granularity of TT Process
The RU should be able to accommodate the intended production capacity. If possible, it should be established at the outset whether the intention is to perform single-batch manufacture, continuous production or campaigns.
Consideration should be given to the level and depth of detail to be transferred to support production and any further process development and optimization at the RU as intended under the transfer project plan.
Consideration should be given to the technical expertise, site technology and site capabilities for the RU. It should be identifi ed upfront by the SU of any process robustness issues so that plans may be put in place at the RU.
The SU and the RU should jointly develop a protocol for the transfer of relevant information related to the process under consideration from the SU to the RU, as well as the development of a comparable process at the RU.
3.1 Starting materials
The specifi cations and relevant functional characteristics of the starting materials (APIs and excipients) to be used at the RU should be consistent with materials used at the SU . Any properties which are likely to influence the process or product should be identified and characterized.
3.2 Active pharmaceutical ingredients (API)
The SU should provide the RU with the open (applicant’s) part of the API master fi le (APIMF or drug master fi le (DMF) or active substance master fi le (ASMF)), or equivalent information and any relevant additional information on the API of importance for the manufacture of the pharmaceutical product. The following are examples of the information which may typically be provided;
however the information needed in each specific case should be assessed using the principles of QRM:
- manufacturer and associated supply chain;
- step of the API to be transferred;
- fl ow chart of synthesis pathway, outlining the process, including entry points for raw materials, critical steps, process controls and intermediates;
- where relevant, defi nitive physical form of the API (including photomicrographs and other relevant data) and any polymorphic and solvate forms;
- solubility profile;
- if relevant, pH in solution;
- partition coeffi cient, including the method of determination;
- intrinsic dissolution rate, including the method of determination;
- particle size and distribution, including the method of determination;
- bulk physical properties, including data on bulk and tap density, surface area and porosity as appropriate;
- water content and determination of hygroscopicity, including water activity data and special handling requirements;
- microbiological considerations (including sterility, bacterial endotoxins and bioburden levels where the API supports microbiological growth) in accordance with national, regional or international pharmacopoeial requirements;
- specifi cations and justifi cation for release and end-of-life limits;
- summary of stability studies conducted in conformity with current guidelines, including conclusions and recommendations on retest date;
- list of potential and observed synthetic impurities, with data to support proposed specifi cations and typically observed levels;
- information on degradants, with a list of potential and observed degradation products and data to support proposed specifi cations and typically observed levels;
- potency factor, indicating observed purity and justification for any recommended adjustment to the input quantity of API for product manufacturing, providing example calculations; and
- special considerations with implications for storage and or handling, including but not limited to safety and environmental factors (e.g. as specifi ed in material safety data sheets) and sensitivity to heat, light or moisture.
3.3 Excipients
the information needed in each specifi c case should be assessed
using the principles of QRM:
- manufacturer and associated supply chain;
- description of functionality, with justifi cation for inclusion of any antioxidant, preservative or any excipient;
- defi nitive form (particularly for solid and inhaled dosage forms);
- solubility profi le (particularly for inhaled and transdermal dosage forms);
- partition coeffi cient, including the method of determination (for transdermal dosage forms); intrinsic dissolution rate, including the method of determination (for transdermal dosage forms);
- particle size and distribution, including the method of determination (for solid, inhaled and transdermal dosage forms);
- bulk physical properties, including data on bulk and tap density, surface area and porosity as appropriate (for solid and inhaled dosage forms);
- compaction properties (for solid dosage forms);
- melting point range (for semi-solid or topical dosage forms);
- pH range (for parenteral, semi-solid or topical, liquid and transdermal dosage forms);
- viscosity and or viscoelasticity (for parenteral, semi-solid or topical, liquid and transdermal dosage forms);
- osmolarity (for parenteral dosage forms);
- special considerations with implications for storage and or handling, including but not limited to safety and environmental factors (e.g. as specifi ed in material safety data sheets (MSDS)) and sensitivity to heat, light or moisture; and
- regulatory considerations, e.g. documentation to support compliance with transmissible animal spongiform encephalopathy certifi cation requirements (where applicable).
3.4 Packaging
- The transfer of packaging operations should follow the same procedural patterns as those of the production transfer.
- Information on packaging to be transferred from the SU to the RU includes specifi cations for a suitable container or closure system, as well as any relevant additional information on design, packing, processing or labelling requirements and tamper-evident and anti-counterfeiting measures needed for qualifiation of packaging components at the RU.
- For QC testing of packaging components, specifications should be provided for drawings, artwork and material (for example, glass, card or fibre board).
- Based on the information provided, the RU should perform a suitability study for initial qualifi cation of the packaging components. Packaging is considered suitable if it provides adequate protection safety (absence of undesirable substances released into the product), compatibility (absence of interaction possibly affecting medicine quality) and performance (functionality in terms of drug delivery).
3.5 Implementation of processing, packaging and cleaning systems
- Trial batch(es) (“demonstration batches”) are normally produced to confirm process capability before initiating formal validation. Where trial batches are produced, at a minimum, all critical processing parameters and finished product specifications should be assessed.
- Once process capability has been established at the RU, assuring that the product, process or method at the RU meets predefined and justified specifications, process validation and cleaning validation can be carried out.
4.0 Quality control: analytical method transfer
4.1 Transfer of analytical methods should accommodate all the analytical testing required to demonstrate compliance of the product to be transferred with the registered specification
4.2 Analytical methods used to test pharmaceutical products, starting materials, packaging components and cleaning (residue) samples, if applicable, should be implemented at the testing laboratory before testing of samples for process validation studies is performed by the RU. Process validation samples may be tested at the RU, the SU or a third laboratory.
4.3 A protocol defi ning the steps should be prepared for transfer of analytical methods. The analytical methods transfer protocol should include a description of the objective, scope and responsibilities of the SU and the RU; a specifi cation of materials and methods; the experimental design and acceptance criteria; documentation (including information to be supplied with the results, and report forms to be used, if any); procedure for the handling of deviations; references; signed approval; and details of reference samples (starting materials, intermediates and fi nished products).
4.4 The SU’s responsibilities for the transfer of analytical methods are to:
- provide method-specifi c training for analysts and other quality controlstaff, if required;
- assist in analysis of QC testing results;
- defi ne all methods to be transferred for testing a given product, starting material or cleaning sample;
- defi ne experimental design, sampling methods and acceptance criteria;
- provide any validation reports for methods under transfer and demonstrate their robustness;
- provide details of the equipment used, as necessary (part of validation report, if available) and any standard reference samples;
- provide approved procedures used in testing; and
- review and approve transfer reports.
4.5 The RU’s responsibilities are to:
- review analytical methods provided by the SU, and formally agree on acceptance criteria before execution of the transfer protocol;
- ensure that the necessary equipment for QC is available and qualifi ed at the RU site. The equipment used by the RU during the analytical transfer should meet appropriate specifi cations to ensure the requirements of the method or specifi cation are met;
- ensure that adequately trained and experienced personnel are in place for analytical testing;
- provide a documentation system capable of recording receipt and testing of samples to the required specifi cation using approved test methods, and of reporting, recording and collating data and designation of status (approved, rejected, quarantine);
- execute the transfer protocol;
- perform the appropriate level of validation to support the implementation of the methods; and
- generate and obtain approval of transfer reports.
4.6 Appropriate training should be provided and all training activities and outcomes should be documented.
4.7 Reference to compendial monographs (e.g. The International Pharmacopoeia , European Pharmacopoeia, British Pharmacopoeia and United States Pharmacopeia), where available, is expected.
5.0 Premises and equipment
Premises
5.1 The SU should provide information to the RU on the layout, construction and fi nish of buildings and services (16,17) (heating, ventilation and airconditioning (HVAC), temperature, relative humidity, water, power, and compressed air), which have an impact on the product, process or method to be transferred.
5.2 The SU should provide information on relevant health, safety and environmental issues, including:
- inherent risks of the manufacturing processes (e.g. reactive chemical hazards, exposure limits, fi re and explosion risks);
- health and safety requirements to minimize operator exposure (e.g. atmospheric containment of pharmaceutical dust);
- emergency planning considerations (e.g. in case of gas or dust release, spillage, fi re and fi rewater run-off); and
- identifi cation of waste streams and provisions for re-use, recycling and/ or disposal.
Equipment
5.3 The SU should provide a list of equipment, makes and models involved in the manufacture, fi lling, packing and or control of the product, process or method to be transferred, together with existing qualifi cation and validation documentation. Relevant documentation may include:
— drawings;
— manuals;
—maintenance logs;
— calibration logs; and
— procedures (e.g. regarding equipment set-up, operation, cleaning, maintenance, calibration and storage).
5.4 The RU should review the information provided by the SU together with its own inventory list including the qualifi cation status (IQ, OQ, PQ) of all equipment and systems, and perform a side-by-side comparison of equipment at the two sites in terms of their functionality, makes, models and qualifi cation status.
5.5 The RU should perform a gap analysis to identify requirements for adaptation of existing equipment, or acquisition of new equipment, or a change in the process, to enable the RU to reproduce the process being transferred. GMP requirements should be satisfi ed and intended production volumes and batch sizes (e.g. same, scaled-up or campaign) should be considered. Factors to be compared include:
—minimum and maximum capacity;
— material of construction;
— critical operating parameters;
— critical equipment components (e.g. fi lters, screens, and temperature/ pressure sensors);
— critical quality attribute; and
— range of intended use.
5.6 The facility- and building-specifi c location of all equipment at the RU should be considered at the time of drawing up process maps or fl ow charts of the manufacturing process to be transferred, including fl ows of personnel and material.
5.7 The impact of manufacturing new products on products currently manufactured with the same equipment should be determined.
5.8 Any modifi cation of existing equipment that needs to be adapted to become capable of reproducing the process being transferred should be documented in the transfer project plan.
6.0 Documentation
6.1 The documentation required for the transfer project itself is wideranging.
6.2 The documented evidence that the transfer of technology has been considered successful should be formalized and stated in a technology transfer summary report. That report should summarize the scope of the transfer, the critical parameters as obtained in the SU and RU and the final conclusions of the transfer. Possible discrepancies should be listed and appropriate actions, where needed, taken to resolve them.
7.0 Technology
Transfer AGENCIES IN INDIA
INTRODUCTION
• The transfer involves cost and expenditure that is
negotiated and agreed upon by the transferee and transferor.
• The transfer may be said to be successful if the
transferee can successfully utilise the technology for business gains and eventually
assimilate it.
• Technology transfer can be vertical or horizontal technology
transfer.
• Vertical transfer refers to transfer of technology
from basic research to applied research, development, and production
respectively
• Horizontal technology transfer refers to the movement
and use of technology used in one place, organisation, or context to another
place, organisation, or context.
• It is also important to view technology transfer
from the perspective of the “technology development chains” of a transferor and
transferee.
7.1.APCTT
(
Asian and Pacific Centre for Transfer of Technology)
• under the Economic and Social Commission for Asia
and the Pacific (ESCAP).
• established in 1977 in Bangalore, India.
• In 1993, the Centre moved to New Delhi, India
• APCTT promotes transfer of technology to and from small-
and medium-scale enterprises (SMEs)
• APCTT implements development projects funded by international
donors aimed at strengthening the environment for technology transfer among
SMEs
• Centre makes special efforts to encourage more participation
of women in the field of technology.
• APCTT undertakes consultancy assignments in
various technology transfer related areas (institution building, human
resources development, studies, business partnership development).
• The objective of APCTT is to strengthen the
technology transfer capabilities in the region and to facilitate import/export
of environmentally sound technologies to/from the member countries.
7.2.NRDC
(
The National Research Development Corporation)
• was nondepartmental government body established (1953)
by the British Government to transfer technology from the public sector to the
private sector
• In 1981, the NRDC was combined with the National Enterprise
Board ('NEB') to form the British Technology Group ('BTG‘).
• Typically the NRDC would patent the product for commercial
exploitation and earn royalties as private sector companies generated sales
from those products.
• Examples of such products include carbon fibre, asbestos-plastic
composites and developments in semi-conductor technology.
• The development of the hovercraft would also not have
taken place without the involvement of the NRDC.
7.3.TIFAC
• TIFAC is an autonomous
organization set up in 1988 under
the Department of Science & Technology to look ahead in technology domain,
assess the technology trajectories, and support innovation by networked actions
in select areas of national importance
Under the
leadership of Dr. APJ Abdul Kalam, ,
Technology Vision 2020 exercise led to set of 17 documents, including sixteen
technology areas and one on services.
• In more than 25 years of its service to the
nation, it has delivered number of technology assessment and foresight reports.
• This is being followed by release of Technology Roadmaps
in 12 thematic areas of national priorities and importance
• Education, Medical Science & Health Care, Food
and Agriculture, Water, Energy, Environment, Habitat, Transportation,
Infrastructure, Manufacturing, Materials and Information & Communication Technologies
(ICT).
• Recently, Hon’ble President of India conferred
Rani Lakshmibai Award (Nari Shakti Puraskar 2015) upon TIFAC for its scheme
KIRAN-IPR that is empowering women in R&D through training on Intellectual Property
Rights (IPR).
7.4.BCIL
(Biotech Consortium India
Limited )
• New Delhi was incorporated as public limited
company in 1990 under The Companies Act, 1956.
• The consortium is promoted by the Department of Biotechnology,
Government of India and financed by the All India Financial Institutions and
some corporate sectors
• BCIL 's major functions include the development
and transfer of technology for the commercialisation of biotechnology products,
project consultancy, biosafety awareness and human resource development
• BCIL has been successfully managing several
Flagship schemes and Programmes of the Department of Biotechnology, Government
of India.
Most notable include:
• 1. Biotechnology Industry Partnership Programme
• 2. Biotechnology Industrial Training Programme
• 3. Small Business Innovation Research Initiative
7.5.TBSE
(The
Technology Bureau for Small Enterprises )
• is a platform for MSMEs to tap opportunities at
the global level for the acquisition of technology or establishing business
collaboration.
• TBSE is a result of the cooperative initiative of
the United Nations’ Asian and Pacific Centre for Transfer of Technology (APCTT)
and Small Industries Development Bank of India (SIDBI).
• TBSE also receives partial funding from the Office
of DC (SSI), Government of India.
Features of Technology Bureau for Small
Enterprises (TBSE)
• Offering a professionally managed system for the
reasons of technology and collaboration exploration
• Helping in the building up of confidence between potential
partners
• Providing an opportunity to global technology
market through the process of networking
• Taking up project appraisal and the preparation of
a business plan.
• Technology Bureau for small enterprises makes available
services to make possible transfer of technology and joint -venture
collaborations.
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