Technology Transfer and Scale-up in Pharmaceutical Industry

Technology Transfer and Scale-up in Pharmaceutical Industry

1. TECHNOLOGY TRANSFER : AN INTRODUCTION

Technology transfer is a process by which a developer of technology makes his technology available to a commercial partner that will exploit the technology. According to WHO, Transfer of technology 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. (Amrita K et al, 2013)It is a systematic procedure that is followed in order to pass the documented knowledge and experience gained during development and or commercialization to an appropriate, responsible and authorized party. (Amrita K et al, 2013)In Pharmaceutical Industry, Technology Transfer refers to a process of successful progress from drug discovery to product development, clinical trials and finally to full scale commercialization. (Gupta Surbhi et al, 2012)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. Technology transfer is both integral and critical to drug discovery and development for new medicinal products. (Gupta Surbhi et al, 2012)The cost of product development raises during pilot scale-up and initial production batch i.e. the critical path for success is dependent on completion of technology transfer to the production site at an affordable cost. There are two types of technology transfer processes: Vertical and Horizontal. (Ali S et al, 2012)Vertical technology transfer refers to transfer of technology from basic research to development and production respectively. Horizontal technology transfer refers to the movement and application of technology for use in one place or context to another place. Commercial technology transfer is mutually agreed and goal oriented. (Ali S et al, 2012)Technology transfer is critical to drug development and development process. The success of any particular technology transfer depends upon process understanding or the ability to predict accurately the future performance of a process. Technology transfer is a broad set of processes in which technology is transferred between different stakeholders like government, private sectors, non-governmental organizations and research institutions.

2. IMPORTANCE OF TECHNOLOGY TRANSFER IN PHARMACEUTICAL INDUSTRY To elucidate necessary information to transfer technology of existing products between various manufacturing places and to exemplify specific procedures and points of concern for smooth technology transfer. The ultimate goal for successful technology transfer is to have documented evidence that the manufacturing process for drug substance and drug products are robust and effective in producing the drug and drug products complying with the specifications and Good Manufacturing Practice requirement. (Gupta Surbhi et al, 2012) Technology transfer is important in extended benefits of R&D to the society. Research is carried out in laboratories on an experimental scale (small batches) before it could be produced for commercial use (large batches). Technology transfer is important for such research to materialize on a larger scale for commercialization especially in the case of developing product. (Gupta Surbhi et al, 2012) Technology transfer includes not only the patentable aspects of production but also includes the business processes, such as knowledge and skills. The transfer of technology for Drug Substance and Drug Product between R&D and the respective Production sites is critical to successful and timely development. The aim is to get to market quickly with the development of a drug and product of the appropriate quality and to do it right first time, every time. (Amrita K et al, 2013) In a pharmaceutical industry drugs or drug products are manufactured with large batch sizes on pilot scale equipment. This pilot scaling up involves the transfer of technology and the transfer of knowledge from labs that are acquired during the small scale development of product and processes. It is essential for a developer of particular technology to make it available to exploit for the progress of development of technology, for better manufacturing capability, marketing capability and commercial capability. (Amrita K et al, 2013) Technology transfer provides an opportunity to reduce cost on drug discovery and development, thus major pharmaceutical companies look for technology transfer opportunities as it reduces the risk, cost and rate of failure.

REASONS FOR TECHNOLOGY TRANSFER Lack of manufacturing capacity: The developer of technology may only have manufacturing equipment which is suitable for small scale operation, and must collaborate with another organization to do large scale manufacturing. Lack of resources to launch product commercially: The original inventor of technology may only have the resources to conduct early-stage research such as animal studies and toxicology study, but doesnt have the resources to take technology through its clinical and regulatory phases. Lack of marketing and distribution capability: The developer of technology may have fully developed the technology and even have obtained regulatory approvals and product registrations, but it may not have the marketing and distribution channels. Exploitation in a different field of application: Each partner may have only half of the solution i.e. the developer of the technology might be capable of exploiting the technology itself in the field of diagnostic applications and may grant exploitation right to commercial partner for the exploitation of therapeutics application.

Fig 3.1: Representation of Technology transfer process

3. STEPS INVOLVED IN TECHNOLOGY TRANSFER IN PHARMACEUTICAL INDUSTRYTechnology Transfer is not a single way process. Whether it is a tablet, a transdermal patch, a topical ointment, or an injectable, the transformation of a pharmaceutical prototype into a successful product requires the cooperation of many individuals. (Gupta Surbhi et al, 2012)The development of new formulation goes through many stages as follows:

Fig 4.1: Stages of development of a new technology in Pharmaceutical industry.

During development of a formulation, it is important to understand procedure of operations used, critical and non-critical parameters of each operation, production environment, equipment and excipient availability, which should be taken into account during the early phases of development of formulation, so that successful scale up can be carried out.The various steps involved in technology transfer are as follows: (Manish Singh et al, 2012)

Development of technology by R & D (Research Phase):a) Design of procedure and selection of excipients by R&D: Selection of materials and design of procedures is carried out by R&D on the basis of innovator product characteristics. For this different tests and compatibility studies are performed.

b) Identification of specifications and Quality by R&D: Quality of product should meet the specifications of an innovator product. For this stability studies are carried out for innovator product and for product which is to be manufactured.

Technology transfer from R & D to production (Development Phase): R&D provides technology transfer dossier (TTD) document to product development laboratory, which contains all information of formulation and drug product as given below: (Amrita K et al, 2013)a) Master formula card (MFC): It includes product name along with its strength, generic name, MFC number, page number, effective date, shelf life and market.b) Master packaging card: It gives information about packaging type, material usedFor packaging, stability profile of packaging and shelf life of packaging.c) Master formula: It describes formulation order and manufacturing instructions.Formulation order and Manufacturing Instructions give idea of process order, environment conditions required and manufacturing instructions for development ofdosage form.d) Specifications and Standard test procedures (STPs): These help to know active ingredients and excipients profile, in process parameters and specifications, product release specifications and finished product details.

Table I: Business units of donor and receptor sides implicated in a technology transfer process. (Luis Alberto del Rio et al, 2007)

Table II: Active Pharmaceutical Ingredients, Pharmacopoeial and scientific data (Luis Alberto del Rio et al, 2007)

Table III: Specifications on quality of starting materials, intermediate products, finished products and Packaging materials. (Luis Alberto del Rio et al, 2007)

Optimization and Production (Production Phase):a) Validation studies: Validation studies verify that the process will stabilize the product based on transferred manufacturing formula and production is implemented after validation studies. Manufacturing department is accepting technology and responsible for validation. (Manish Singh et al, 2012)The research and development department transferring technology should take responsibility for validation such as performance qualification, cleaning and process validation.

b) Scale up for production: Scale up involves the transfer of technology during small scale development of the product and processes. It is essential to consider the production environment and system during development of process. Operators should concentrate on keeping in mind that the production process will run smoothly if technology transfer is implemented thoughtfully. Effective technology transfer helps to provide process efficiency and maintain product quality. (Manish Singh et al, 2012)

Table IV: Manufacturing procedure: Facilities, equipment, documentation, quality and production. (Luis Alberto del Rio et al, 2007)

Technology Transfer Documentation:Technology transfer document demonstrates the contents of technology transfer from transferring and transferred parties. Every step from research and development to production should be documented, task assignments and responsibilities should be clarified and acceptance criteria for completion of technology transfer concerning individual technology to be transferred. It is duty of Quality Assurance department to check and approve the documentation for all processes of technology transfer. (Manish Singh et al, 2012)

a) Development report: The ultimate goal for successful technology transfer is to have documented evidences. The R&D 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 for the quality design of drug substances and drug specifications and test methods. The development report is not prerequisite for the application for approval; it can be used at the pre-approval inspection as valid document for quality design of new drug. In addition, this report can be used as raw data in case of post-marketing technology transfer. The development report contains the following: (Manish Singh et al, 2012) Data of pharmaceutical development of new drug substances and drug products at stages from early development phase to final application of approval. Information of raw materials and components Rational for dosage form and formula designs and design of manufacturing methods Change in histories of important processes and control parameters Stability profile, specifications and test methods of drug substances, intermediates, drug products, raw materials, and components, which also include validity of specification range of important tests such as contents impurities and dissolution. Rational for selection of test methods, reagents and columns Verification of results.

b) Technology transfer plan: The technology transfer plan describes the items and contents of technology to be transferred and detailed procedures of individual transfer and transfer schedule, and to establish judgment criteria for the completion of the transfer. (Manish Singh et al, 2012)The transferring party should prepare the plan before implementation of the transfer and reach an agreement on its contents with the transferred party.

c) Report: Report completion of technology transfer is to be made once data are taken accordingly to the plan and are evaluated to confirm that the predetermined judgment criteria are met. Both transferring and transferred parties can document the technology transfer report; however, they should reach an agreement on its contents. (Manish Singh et al, 2012)

Exhibit: After taking scale up batches of the product, manufacturing of exhibit batches takes place. In case of exhibit, batch sizes are increased along with equipment and their processes. (Manish Singh et al, 2012)This is done for filling purpose in regulatory agencies.

Fig 4.2: Phases of Technology transfer4. VARIOUS PROCEDURES FOR TECHNOLOGY TRANSFERa) Post Management: Monitor compliance to the conditions of the contract and actual inspection and report.

b) Negotiations and contract: Propose the transfer conditions and establish negotiation strategy Negotiate on technology transfer conditions and details Draw-up and analyse draft contract depending on the type and form of technology.

c) Marketing activities: Prepare marketing materials for technology transfer Conduct activities such as the participation in Techno mart Analyse methods to expect maximum effect with minimum cost Discovery and contact of potential demanding parties Research and analysis of demanding party Prior-proposal of technology transfer conditions to the parties seeking to receive the technology transfer.

d) Packaging: Draw-up technology information document for the smooth execution of technology marketing

e) Technology valuation and demand selection: Analyse possibility of clash with a third party owned technology. Establish transfer strategy in accordance with the technology type and form Preliminary matching of technology demand/supply. Pre-analysis of whether the transferred technology can secure competitiveness if seeking to transfer overseas.

f) Discovery of technology: Transfer request or arranging and securing technology that is possible to transfer but is not possessed in-house.

FACETS AND METHODS OF TECHNOLOGY TRANSFERTechnology transfer can take place in any of the following manner: Government labs to private sector firms: This type of Technology Transfer is advantageous as the Govt. labs can get good financial support and funds from the govt. for their research work and the technology developed by them reaches the private sector. Between private sector firms of the same country:This type of Technology Transfer generally occurs due to lack of appropriate financial resources or inadequate knowledge of regulatory requirements. Thus the private sector that develops the technology is paid by other sector that absorbs the technology. Between private sector firms of different countries: From academia to private sector firms:Academic sectors that are actively involved in research develop the technology and make it available to private firms. By collaboration of private firms with the institutions, finances can be saved. Academia, government and industry collaboration:In this type of Technology Transfer govt. provides necessary funds to the academic institutions in developing technology that can be transferred to the industry.

Different Methods of Technology Transfer: a. By sale or transfer of technology When the transfer of rights is carried out in agreement with a contract, it is called the sale of technology. By this inclusive control and management is handed over to the buyer who pays the price (sales price). The owner demands a high and fixed price for full transfer of rights to the buyer but the buyer will not easily agree unless the buyer is convinced of the economic value and potentiality of utilization of the patent.The reason for sale or transfer of technology arises when: The owner of patent does not have the capability to execute and there are problems in licensing to a third party. There is a problem in developing a basic patent into a commercial product. It is difficult to produce the finished goods, based on partial patent. Sales by specialized technology development and sales companies are in the ordinary course of their business. An individual inventor raises research and invention funds.A contractual agreement between the two parties is required for this kind of technology transfer but it is only possible when the patent is registered with Intellectual Property Rights Organisation. (Amrita K et al, 2012)

b. By licensing of technology:Licensing covers the broad spectrum of permissions that are granted for the use of patents, technology, and trademarks. Of the various methods of transferring technology internationally, licensing is the most versatile. It offers flexibility in technology choice and an opportunity for the source and the receiving institution to negotiate.Licensing means permissions that are granted for the execution of patents, technology and trademarks. Both the parties that give and take the execution and usage of the rights enter into a licensing contract under specified conditions including payment of technical fees for a specified period etc. After the period is over, execution and usage becomes invalid. (Amrita K et al, 2012)

c. By combination of capital, management and know-how:In case of highly advanced and improved technology, the success of commercialization is not guaranteed, so the technology is transferred together with the capital, management know how and core components. (Amrita K et al, 2012)

d. By sale of technology data such as plans, microfilms etc.:Uses a part of technology information for solving simple technological problems in case of small scale projects. (Amrita K et al, 2012)

e. By using technical personnel as the medium:Here the technical personnel are directly involved in the technology transfer through invitation and deployment of technical personnel, resolution of technological issues through the employment. (Amrita K et al, 2012)

Case Study: 1

Transfer of Nanotechnologies from R&D to Small and Medium Enterprises in IndiaResearch has shown that small and medium sized enterprises play an important role in the economic development of countries worldwide.Because of limited resources and relative inability to bear the costs and risks associated with in-house technology development, small and medium sized enterprises often utilize the process of technology transfer from public funded R&D laboratories to take advantage of the benefits gained by technology and innovation.Nanotechnology is emerged as an important enabling technology, capable of impacting almost all sectors of the industry. Nanotechnology has promised significant social benefits, including enhancements in medical diagnosis and treatment, more efficient energy sources, novel sensors for agriculture, security and other areas, lighter, stronger and cheaper materials, smarter electronic products and cleaner cheaper potable water.500 companies are working on nanotechnology in India, while more than 50 companies have commercialized nanotechnology-based products. Indian companies like Biocon, Bharat Biotech, Dabur, Cadila, Lupin, Cipla, Sun Pharma, Ranbaxy, Crompton Greaves, Resil Chemicals, KMML, I-CAN Nano, Tata Group, Mahindra & Mahindra, Reliance Industries, Ashok Leyland, Asian Paints etc., have started commercializing nanotechnology-based products either developed through in-house R&D or acquired under licensing agreements from public funded Indian research institutions or foreign collaborations.University of Delhi, IITs (Mumbai, Kharagpur, Delhi, Madras, etc), NCL Pune, NML Jamshedpur, NIPER Chandigarh, BARC Mumbai are some of the R&D laboratories, actively involved in nanotechnology development and transfer.Nanotechnology R&D being capital intensive, the Government of India has taken a lead role in promoting nanotechnology research and application development through several mechanisms.Considering the huge market potential for nanomaterials/products/services in India, many companies from USA, Europe, China, Japan, Republic of Korea, and Islamic Republic of Iran have entered the domestic market through tie-ups for introducing nanoproducts in the Indian market. (H. Puroshottam, 2012)

Table I: Some of the Nanotechnology-based products commercialized by Indian SME/Institutions (H. Puroshottam, 2012)

5. MODELS OF TECHNOLOGY TRANSFER

The difficulties and complexities faced by managers of technology transfer projects, researchers, consultants and practitioners of technology transfer have been proposing models of technology transfer that could facilitate the effective planning and implementation of technology transfer projects. Two types of technology transfer models are: Qualitative and Quantitative. Qualitative models often have as their objective the delineation of activities involved in managing technology transfer and the elicitation of factors and issues that can influence the success and/or effectiveness of technology transfer.Quantitative models, on the other hand, aim at quantifying parameters of significance in technology transfer and analysing them with a view towards minimizing goal incompatibility between the transferors and transferees of technology.

Qualitative models of technology transfer:

a) The Bar-Zakay Model: (Ali S et al, 2012) Bar-Zakay (1971) developed a rather comprehensive TT model based on a project management approach. He divided the TT process into the Search, Adaptation, Implementation and Maintenance stages. He depicted the activities, milestones, and decision points (go or no-go) in each of the stages. The upper half of the figure delineates the activities and requirements of the transferor (referred to as the donor by Bar-Zakay) and the lower half that of the transferee or the recipient. The activities to be carried out are specified in detail in this model and the importance of both the transferor and transferee acquiring skills to undertake technological forecasting, long-range planning, and gathering of project-related intelligence is emphasised. The Bar-Zakay model also suffers from another disadvantage. Jagoda (2007) points out that, The model has limited relevance today since many of the activities, terms, and ideas expressed reflected the setting of the late 1960s to early 1970s, when buyers of technology were mainly passive recipients who depended greatly on aid programs for the purchase of technology. It was also an era when government controls were instrumental in determining the rate, direction, and scope of technology flows.

The lessons that can be learnt from the Bar-Zakay model are the following: There is a need for a comprehensive examination of the entire TT process from search right through to post-implementation activities. A process approach must be adopted in planning and implementing TT projects. It is important to have milestones and decision points so that activities can be strengthened, mistakes corrected, or even the project terminated at any point in time.

b) The Behrman and Wallender Model: (Ali S et al, 2012)Behrman and Wallender (1976) have proposed a seven stage process for international technology transfer that may be more relevant to multinational corporations. Manufacturing proposal and planning to arrive at decisions regarding location and preparing a business case including good resource assessments. Deciding the product design technologies to be transferred. Specifying the details of the plant to be designed to produce the product and other aspects related to construction and infrastructure development. Plant construction and production start-up. Adapting the process and product if needed and strengthening production systems to suit local conditions. Improving the product technology transferred using local skills. Providing external support to strengthen the relationship between the transferor and transferee.

c) The Dahlman and Westphal Model: (Ali S et al, 2012)Dahlman and Westphal (1981) model has proposed a nine stage process as follows: Pre-investment feasibility is carried out to gather information and establishing project viability that are carried out for techno-economic use. Need to carry out a preliminary identification of technologies. Carry out basic engineering studies that involve the preparation of process flow diagrams, layouts, material and energy balances and other design specifications of the plant and machinery and then core technology to be transferred. Carry out a detailed engineering study that involves preparation of a detailed civil engineering plan for the facility, including construction and installation specifications and identification of peripheral technology needed. The subcontracting services are carried out for the selection of suppliers to assemble the plant machinery, equipment and plan for the co-ordination of work among various parties. The education plan and training are executed in consultation with the suppliers of technology for the workers who would be employed in the technology transfer project. The plant is constructed. The operations are commenced. Develop trouble-shooting skills and put in place arrangements to solve design and operations problems as they arise, especially during the early years of operation. Its major weakness is that it assumes that the transferee will have access to high-level engineering skills.

d) The Schlie, Radnor, and Wad Model: (Schlie et al, 1987)Schlie, Radnor, and Wad proposed a simple, generic model that delineates seven elements that can influence the planning, implementation, and eventual success of any TT project. The seven elements are listed below. The transferor, which is the entity selling the technology to the recipient. The transferee, which is the entity buying the technology. The technology that is being transferred. The transfer mechanism that has been chosen to transfer the chosen technology. The transferor environment which is the immediate set of conditions, in which the transferor is operating. Attributes of the transferor environment that can influence the effectiveness of the transfer process include, among others, economic status, business orientation (inward versus outward), stability, attitude and commitment to the transfer project, and operating policies. The greater environment which is that surrounding both the transferor and the transferee. There may be layers of this environment that are sub-regional, regional, and global. Even if the immediate operating environments of the transferor and the transferee are favourable to the technology transfer, if the layers of the greater environment are not supportive, then cross-border and international technology transfer could be adversely affected. Factors in the greater environment such as political relationships between countries, exchange rates, investment climates, trade negotiations, balance of trade, relative technological levels, and the status of intellectual property protection regimes could have a great influence on the success of a TT project.The valuable lessons that emerge from this model are as follows: The many changes that have taken place and are taking place in the global business setting today have made it imperative for managers of technology to gain good insights into the transferee environment, transferor environment, and the greater environment when planning and implementing a TT project. The choice of the technology transfer mechanism should be based on a sophisticated understanding of the other six elements.

e). Chantramonklasri Model: The Dahlman and Westphal Model had been further improved by Chantramonklasri (1990 who proposes a five phase model.

The five phases of this model are as follows: Carrying out a pre-investment and feasibility study Developing engineering specifications and design based on the feasibility study Commence capital goods production based on the engineering specifications and designs that have been developed. Commissioning and start-u including comprehensive of the workforce Commence commercial production

Fig 7.1: Bar-Zakay Model of Technology transfer (Samuel N. Bar Zakay, 1970)

6. TECHNOLOGY TRANSFER TEAM AND THEIR RESPONSIBILITIES (Gupta Surbhi et al, 2012)

Technology Transfer Team MemberResponsibilities

Process Technologist Central focus for transfer activities Collates documentation from donor site Performs initial assessment of transferred project for feasibility, compatibility with site capabilities and establishes resource requirements.

Quality Assurance Representative Reviews documentation to determine compliance with Marketing Authorization. Reviews Analytical methods with Quality Control to determine capability, equipment training requirements. Initiates conversion of donor site documentation into local systems or format. Initiates or confirms regulatory requirements.

Production Representative Reviews process instructions (with process technologist) to confirm capacity and capability. Considers any safety implications e.g., solvents, toxic sanitizing materials. Considers impact on local standard operating procedures (SOPs) and training requirements of supervisors or operators

Engineering Representative Reviews (with production representative) equipment requirement. Initiates required engineering modifications, change or part purchase. Reviews preventative maintenance and calibration impact e.g. use of more aggressive ingredients, more temperature sensitive process and modifies accordingly.

Quality Control Representative Reviews Analytical requirements and availability with instruments. Responsible for Analytical method transfer for drug substance and drug product.

7. FACTORS INFLUENCING TECHNOLOGY TRANSFER

a) Drivers for Technology Transfer: (Gupta Surbhi et al, 2012)

Good Business and Manufacturing Practices: A companys success is primarily the result of its adoption of good business and manufacturing practices particularly in the areas of product identification and formulation technology.

Potential for competitive pricing: Balance cost to remain competitive by having higher private sector prices and very low public sector prices.

Strong economy and Environment: For technology transfer to be successful there needs to be supportive business and scientific environment in the recipient country, and that environment should include skilled workers, economic and political stability, supportive regulatory environment, market size and potential and a well-developed national infrastructure of natural resources and transport.

Transparent and efficient regulation: Pharmaceuticals from a highly regulated industry and the regulatory function must be efficient and transparent for technology transfer to be economically viable.

Opportunities for contingency supply: Multinational pharmaceutical companies are inclined to transfer technology to local manufacturers when they foresee an inability to meet time scales and volume demand from large procurers

Access to new machinery, training, knowhow and business partnership: This makes the prospect of technology transfer very desirable to local pharmaceutical manufacturers since the technology, equipment, etc. could be applied profitably beyond the initial purpose.

b) Barriers of Technology Transfer (Gupta Surbhi et al, 2012) Lack of efficiency: Automation of production processes to improve efficiency and lower costs.

Low market share: Local producers face significant challenges in meeting International Quality Standards and capturing a critical market share. Greater market share would increase profitability.

Labour issues: The pharmaceutical sector demands relatively skilled labour. High labour turnover and absenteeism owing to unattractive conditions of service is negative contributor.

ISSUES IN TECHNOLOGY TRANSFER There is increasing competition among the pharmaceutical industry as they are outsourcing the production, manufacturing networks and in-licensing activities to less costly contract research organisations. These premeditated initiatives involve effective technology transfer. Technology transfer also affects companies' ongoing operations-from research through commercial production. It underlies all key development and manufacturing activities needed to successfully bring a product to market. (Amrita K et al, 2012)Main issues with technology transfer process are as follows:

Effective Scale-up and Timely allocation of Resources:Pharmaceutical industries transfers the process in the form of documents or in other words it can be said as procedural exchange of process documents between sending and receiving parties. If the technology developed in the laboratory is not scaled up then the companies are again forced to reinvent the scalable processes. This process leads to various inefficiencies, such as suboptimal allotment of resources, unmitigated cycle times, higher development costs and quality compliance issues. (Amrita K et al, 2012)

Outsourcing of technology by Pharmaceutical companies:As more and more big pharmaceutical companies are outsourcing early research and scale-up activities to contract manufacturing organizations, a process to manage information exchange with contract manufacturing organization in the remote locations becomes even more critical. Due to time difference and language barriers, many companies their initial expectations of significant cost reduction often fall short. (Amrita K et al, 2012)

APPROACHES TO OVERCOME BARRIERS IN TECHNOLOGY TRANSFER (Gupta Surbhi et al, 2012)

Commercializing publicly funded technologies: The basic pattern envisioned is to give institutions receiving public research funds the right to obtain and exploit patents on inventions developed in the course of research.

Research tool patents and freedom to operate for the public sector:Patents sometimes make it difficult for public researchers to carry out their research or to make the products of that research available. It is intensified by the tendency of some publicly funded research laboratories to avoid use of a patented technology without permission even in nations where no relevant patent is in force.

Web access and scientific publication:Limited access to scientific journals led to enormous problems for developing nationsScientists

National security issues and restrictions on exports of particular technology:International controls designed to protect national security and to prevent the proliferation of important technologies also restrict the flow of technologies.

Inadequate funding in important areas and possible treaties:There are areas of research of importance to the developing world that are being funded inadequately.

Co-operative research agreements:Global support for public sector research might be encouraged through co-operative research agreements designed to meet specific goals. It would seem more feasible to focus efforts on technologies of significant social benefit to the developing nations.

8. FACTORS FOR EFFECTIVE TECHNOLOGY TRANSFER

In technology transfer process, technological evaluation, requirements, capacities recognition and selection of technology methods are of utmost importance. The effective factors of technology transfer process are as follows: (Amrita K et al, 2012) Proper development of managerial and organizing skills in organizations with a long-run strategic planning in technology development, Investment in R&D. A proper relationship has to be established between production and research and training of individual related to technology must be provided along with interaction with different international centers in technology cooperation areas. Information development in the field of technology transfer methods; Modification of cultural value systems in organizations and diffusion of scientific attitude in organizations. Employment of entrepreneur managers and Creation of standards and capabilities in companies. Infrastructure related to organization, equipment, information and humans. Training in international companies and employment of international specialist in the field of technology. Technological factors such as degree of achieving the technology, its price, simplicity and complicacy of technology and development of technology.

In the technology transfer process, the entire element of technology triangle is to be transferred into organizations. They should be fully aware of their capabilities and requirements before launching technology transfer. Actually, technological evaluation, requirements and capacities recognition and selection of technology methods are of vital importance in the technology transfer process. Thus, the awareness of effective factors on technology transfer is of great importance for technology recipients.

KEYS AND WAYS OF SUCCESSFUL TECHNOLOGY TRANSFER

Strategy, organization and processes both within and across organizations which should be customer-focused. Customer focussed strategy helps ensure configuration of regulatory requirements and filing strategies. To augment the competence of technology transfers and minimize the risk of late-stage site changes, the companies must strategically select sites to match their product's technology, process, and capacity requirements early in the development process. (Amrita K et al, 2012) Establishment of timeline and cost-savings objectives for the transfer. Highly skilled, dedicated technology transfer teams with excellent managerial skills.Technology transfer takes place during one of the stages in the product's lifecycle: early discovery, toxicological evaluation, clinical development, scale-up and commercial manufacturing, and in-line production. At every stage it requires different type of transfer, rationale, and key participants. So a road map is required to translate the transfer strategy into unambiguous activities. (Amrita K et al, 2012)

Technology Transfer success criteria:

To success the given technology transfer the data should be match with the flow of procedure in formulation and production department. All the process and control parameter should be stated at given set of procedure. To develop the drug the material supplier should be with their Certificate of Analysis, Health, safety and environmental concerns, compliance with all registered commitments. Technology Transfer must also be completed safely. The process being transferred runs as expected (yield, purity, cycle time, etc.) On time (product launch) -On budget -No CRISIS situations.For the success of technology transfer the Communication should be: Open communication between all team members. Direct communication between the technical members Effectively and timely communication with the technical and non-technical members.

Case Study: 2

Technology Transfer of API Manufacturing to India (Vivek K et al, 2012)

The PolyPeptide Group is an international manufacturer of peptide-based active pharmaceutical ingredients with manufacturing facilities in five countries (Denmark, France, India, Sweden and USA). The site close to Mumbai in India is newly operational and has finalized the first two all functional product technology transfers from the USA and two are ongoing from Scandinavia.In 2005, the PolyPeptide Group started planning the development of a new manufacturing site in India with the ambition of participating in the rapidly expanding pharmaceutical industry in Asia. The location selected was Ambernath, Northeast of Mumbai, state of Maharashtra, in a newly established industrial area.After the site inauguration and a period of commissioning, qualification, validation, operational training and technical fine-tuning, the PolyPeptide Group initiated the product technology transfer to the new facility with two generic peptide APIs from one of the existing facilities in the USA.Technology transfer plan included activities like compilation of detailed process information at the receiving unit, key elements such as equipment, raw material specifications and packing materials, Analytical method transfer. Master batch records were prepared at the receiving site and were then reviewed by the sending unit. Risk assessments, training of the work force at the unit and process validation were done.

Technical Aspects:Elements such as material of construction of equipment and utensils, type of filters or stirrers and dimensions of equipment were examined. Care was also taken in evaluating that parameters like temperature and stirring ranges of the equipment were matching the process requirements. A technical assessment was performed wherein it was determined whether adjustments or changes were needed to be implemented at the receiving unit.Activities related to Analytical method transfer were communicated to PolyPeptide India early in the project in order to facilitate the initial method testing, preparation of the method description and the necessary SOPs. Purchases of reagents, solvents, analytical columns were also carried out prior to the method transfer.For analytical method transfers and particularly for chromatographic methods, care was taken that details such as analytical column type, oven temperature and buffer preparations were well documented.

Training:The initial assessment of the manufacturing process defined whether equipment, analytical, or process-specific training was needed, which often necessitated the relocation of personnel from one site to the other for a select period of training. Production chemists from PolyPeptide India were trained at PolyPeptide USA where they observed the execution of GMP manufacture of the product that was to be transferred.Analytical chemists were sent to PolyPeptide USA to be comprehensively trained in the establishment of intricate analytical HPLC release methods.

Currently, the facility operates on multiple manufacturing lines with multi-kg batch size. Production: Solid Phase Peptide SynthesisThus, successful technology transfer was implemented.

SCALE UP: AN INTRODUCTION

Scale-up is generally defined as the process of increasing batch size. Scale-up of a process can also be viewed as a procedure for applying the same process to different output volumes. There is a subtle difference between these two definitions: batch size enlargement does not always translate into a size increase of the processing volume. In mixing applications, scale-up is indeed concerned with increasing the linear dimensions from the laboratory to the plant size. On the other hand, processes exist (e.g., tableting) where the term scale-up simply means enlarging the output by increasing the speed. To complete the picture, one should point out special procedures (especially in biotechnology) where an increase of the scale is counterproductive and scale-down is required to improve the quality of the product. In moving from research and development (R&D) to production scale, it is sometimes essential to have an intermediate batch scale. This is achieved at the so-called pilot scale, which is defined as the manufacturing of drug product by a procedure fully representative of and simulating that used for full manufacturing scale. This scale also makes it possible to produce enough products for clinical testing and to manufacture samples for marketing. However, inserting an intermediate step between R&D and production scales does not, in itself, guarantee a smooth transition. A well-defined process may generate a perfect product both in the laboratory and the pilot plant and then fail quality assurance tests in production. Any significant change in the process of making a pharmaceutical dosage form is subject to regulatory concern. Scale-Up and Post-approval Changes (SUPAC) are of special interest to the Food and Drug Administration (FDA) as is evidenced by a growing number of regulatory documents released in the last several years by the Centre for Drug Evaluation and Research (CDER), including Immediate Release Solid Oral Dosage Forms (SUPAC-IR), Modified Release Solid Oral Dosage Forms (SUPAC-MR), and Semisolid Dosage Forms (SUPAC-SS).

9. PILOT PLANT SCALE-UP METHODOLOGY

Pilot plant: It is that part of the Pharmaceutical industry where a lab scale formula is transformed into a viable product by the development of liable practical procedure for manufacture. (Leon Lachman, Joseph Kanig, 1991)

Reasons for conducting Pilot plant studies: A pilot plant allows investigation of a product and process on an intermediate scale before large amount of investment is committed to full-scale production. It is not possible to design a large complex pharmaceutical manufacturing plant from laboratory data alone with any degree of success. (Leon Lachman, Joseph Kanig, 1991)

Uses of a Pilot Plant: To evaluate the results of laboratory studies, make product and process corrections and improvements. Producing small quantities of product for sensory, chemical, microbiological evaluations, limited market testing or furnishing samples to potential customers, shelf life and storage stability studies To determine possible by-products or waste stream that requires treatment before discharge. To provide data that can be used in making a decision on whether or not to proceed to a full-scale production process; and in the case of a positive decision, designing and constructing a full-size plant or modifying an existing plant.

Objectives of pilot plant scale-up studies: To produce physically and chemically stable therapeutic dosage forms. Review of the processing equipment. Guidelines for production and process control. Evaluation and validation. To identify the critical features of the process. To provide master manufacturing formula.

Significance of Scale-up in Pharmaceutical manufacturing: Sound scientifically based scaling principles can reduce the need for costly late stage full scale studies, decreasing the risk associated with product. Quality must be designed into the process and this can be accomplished by knowledge of physicochemical process that transforms the incoming materials into the final drug product. The inability to predict the effects of scale-up is now recognized by regulatory agencies as an area requiring improvement in the current state of pharmaceutical manufacturing. (James Swarbrick, Pilot plant design, Vol 12)

Pilot Plant studies include the close examination of the formula to determine: Its ability to withstand batch scale and process modification. Compatibility of the equipment with the formulation. Availability of raw materials meeting the specifications required to produce the product. Cost factor and Market requirement. Physical space required and the layout of the related functions.

Thus, during the pilot plant scale-up efforts: Production and process controls are evaluated, validated and finalized Product reprocessing procedures are developed and validated. Appropriate records and reports are issued to support cGMP.

In short, all critical features of a process must be identified so that as the process is scaled up, it can be adequately monitored to provide assurance that the process is under control and that the product produced at each level of the scale up maintains the specified attributes originally intended.

Operational aspects of a Pilot plant: A pilot plant design should support formulation and process development, clinical supply manufacture and technology evaluation, scale-up and transfer. Key attributes playing a role in achieving the objectives are: CGMP compliance, flexible highly trained staff, equipment to support multiple dosage form development and those at multiple scales based on similar operating principles to those in production. (James Swarbrick, Pilot plant design, Vol 12) Operational aspects of a pilot plant include the following:

Validation

Training

Engineering support and maintenance

Calibration

Material and inventory control

Orders and labelling

Process and Manufacturing Activities

Quality Control and Quality Assurance

General Considerations:Personnel Requirements: Personnel should consist of scientists with experience in pilot plant operations as well as in actual production area are the most preferable as they have to understand the intent of the formulator as well as understand the perspective of the production personnel. There should be personnel with engineering knowledge as scale up also involves engineering principles.Space Requirements:Separate area is required for the following: Administration and processing information Physical testing area Standard equipment floor space Storage area Separate provisions for API and excipients further segregated into approved and unapproved areas according to GMP. Storage area for in process materials, finished bulk products, retained samples, experimental production batches, packaging materials (segregated into approved and unapproved areas). Controlled environment space allocated for storage of stability samples.

Review of the formula: A thorough review of the each aspect of formulation is important. The purpose of each ingredient and its contribution to the final product manufactured on the small-scale laboratory equipment should be understood. Then the effect of scale-up using equipment that may subject the product to stresses of different types and degrees can more readily be predicted, or recognized.

Raw Materials: One purpose or responsibility of the pilot-plant is the approval and validation of the active ingredient and excipients (raw materials). Raw materials used in the small scale production cannot necessarily be the representative for the large scale production.

Relevant Processing Equipment: The most economical and the simplest and efficient equipment which are capable of producing product within the proposed specifications are used. The size of the equipment should be such that the experimental trials run should be relevant to the production sized batches. If the equipment is too small the process developed will not scale up. Whereas if equipment is too big then the wastage of the expensive active ingredients may take place.

Production Rates: It can be determined by the immediate future market requirements. Equipment and the process should be chosen on the basis of production of a batch at a frequency that takes into consideration the following factors. Product loss in the equipment during manufacture. The time required to clean the equipment between batches. The number of batches that will need to be tested before release.

Process Evaluation:

Fig 15.1: Process evaluation parameters

Process needs to be documented. Process is validated only if there are no changes in the formula, quality of the ingredients, or the equipment configuration. Revalidation needs to be done to ensure that any changes have not taken place.

Preparation of Master manufacturing procedures: It includes the chemical weight sheet. It should clearly identify the chemicals required in a batch and present the quantities and the order in which they will be used. The sampling directions and in-process and finished product specifications. Batch Record Directions should include specifications for addition rates, mixing times, mixing speeds, heating and cooling rates and temperature.

Product Stability and Uniformity: The primary objective of the pilot plant is to ensure physical as well as chemical stability of the products. Hence, each pilot batch representing the final formulation and manufacturing procedure should be studied for stability. Stability studies should be carried out in finished packages as well according to ICH Guidelines.

GMP Considerations:The GMP considerations that form a part of scale-up and pilot plant are as follows: Equipment qualification Process validation Regular schedules of preventative maintenance Regular process review and revalidation Relevant written standard operating procedures Employment of technically competent qualified personnel Adequate provision for training of personnel A well-defined technology transfer system Validated cleaning procedures. An orderly arrangement of equipment so as to ease material flow and prevent cross- contamination.Transfer of Analytical Method to Quality Assurance:Analytical methods developed in research must be transferred to QA department. Transfer process includes the following: Review of the process to ensure that proper analytical instrument is available. Personnel should be trained to perform the test. Reliability of the test should be checked. At last assay procedure should be reviewed before transfer

Steps in Scale-up:

10. REVIEW OF SCALE-UP FOR SOLID DOSAGE FORMS Pilot Plant design for Tablets: The primary responsibility of the pilot plant staff is to ensure that the newly formulated tablets developed by product development personnel will prove to be efficiently, economically, and consistently reproducible on a production scale. The design and construction of the pharmaceutical pilot plant for tablet development should incorporate features necessary to facilitate maintenance and cleanliness. If possible, it should be located on the ground floor to expedite the delivery and shipment of supplies. Dry Blending: Powders to be used for encapsulation or to be granulated must be well blended to ensure good drug distribution. Inadequate blending at this stage could result in discrete portion of the batch being either high or low in potency. Steps should also be taken to ensure that all the ingredients are free of lumps and agglomerates. For these reasons, screening and/or milling of the ingredients usually makes the process more reliable and reproducible.Equipment used for blending mainly includes the following: V- blender Double cone blender Ribbon blender Slant cone blender Bin blender Orbiting screw blenders, vertical and horizontal high intensity mixers.Scale-up considerations: Time of blending. Blender loading. Size of blender.

Fluidized Bed Granulations: Process Inlet Air Temperature Atomization Air Pressure Air Volume Liquid Spray Rate Nozzle Position and Number of Spray Heads Product and Exhaust Air Temperature Filter Porosity Cleaning Frequency Bowl CapacityParameters to be considered for scale-up: Optimum Load Air Flow Rate Inlet Air Temperature Humidity of the Incoming Air

Planetary Mixer V-Blender

Fig 15.2: Equipments used for blending operations

Parameters to be considered for scale-up in case of Tray dryer operation: Air flow and Air temperature Depth of the granulation on the trays Monitoring of the drying process by the use of moisture and temperature probes Drying times at specified temperatures and air flow rates for each product. This is done because some of these additives, especially magnesium stearate, tend to agglomerate when added in large quantities to the granulation in a blender.In scale up of blending, following parameters should be considered: Blender loads and Blender size Mixing speed and Mixing times Bulk density of the raw material (must be considered in selecting blender and in determining optimum blender load) Characteristics of the material

Following are the parameters to be considered while choosing speed of the press: Granulation feed rate. Delivery system should not change the particle size distribution. System should not cause segregation of coarse and fine particles nor should it induce any static charges.

WAYS OF IMPROVING THE LIKELIHOOD OF SCALIBILITY Identifying the physical and chemical phenomena involved in pharmaceutical manufacturing process. Understanding whether and how these phenomena are affected by a change in scale whether they are dependent on volume, area or length. Identifying the predominant or controlling process mechanism. Identifying the critical process variables that affect scalability. Identifying or determining the physicochemical properties (e.g.: density, particle size, viscosity) of the formulation components and the products relevant to scalability. Using dimensional analysis to reduce the number of variables required to characterize a process as the manufacturing scale changes. Using software that enables the estimation of equipment performance and material characteristics. (James Swarbrick, Pilot plant design, Vol 12)

11. CASE STUDIESCASE: 1Technology Transfer Process carried out by Carbogen Amcis:Carbogen Amcis, a part of a multi-site, transcontinental organization, offers a comprehensive range of chemical and manufacturing solutions from one single supplier. This extends from rapid Active Pharmaceutical Ingredients (APIs) supply for preclinical use to large-scale manufacture of intermediates and APIs.Complex, multi-step processes under both Good Manufacturing Practice and non-GMP had been successfully transferred. A specialist team followed a three-stage procedure: Initiation: The scope and goals were agreed upon by all parties preparation of technology transfer master plan, definition of responsibilities, as well as preparation and transfer of technical information package. Piloting: The process was trailed in the lab and in small production runs and was extensively reviewed for compliance with regulatory and quality standards. Sign-off: The mutually agreed process was accepted by all parties production against established batch instructions.Clear definitions of the responsibilities of the technology transfer team members during the transfer process minimized the time and effort needed for the critical step in the successful scale-up of intermediates or APIs.Cost Advantages and Continuous Management: The first three steps from a registered process, previously run in Switzerland on 1,600 Litres scale, were successfully transferred to operations in India within a timeframe of five months. The intermediate of an API that was going to be generic in a few years required the company to provide larger quantities at lower costs. The process was then performed on a scale up to 4,000 L. This approach offered the maximum flexibility in handling the cost and quantity demands of the product in development and commercialization life cycles. The customers benefited from cost advantage and continuous local project management.

Cost Savings and Project Scale: For a US customer, a three-stage process to manufacture an intermediate GMP starting material of a launched product was transferred within six months from the Carbogen Amcis Ltd site in Manchester, where it was successfully produced in 600 kg (several batches up to 200 kg), to India. The process was scaled up in campaigns of 1,500 kg. The companys commercial product required a very high purity and the team was able to successfully duplicate the process. This was another critical step toward the projected demand of approximately eight metric tons per year.

Cost and Feasibility Aspects: For a Japanese customer, a multi-stage production process for a non-GMP intermediate was performed at Carbogen Amcis Manchester site and subsequently transferred to India within six months. A chemist from Manchester supported the transfer on-site. There, the production now runs in 300 kg batches toward a five metric ton campaign. Carbogen Amcis at present has a manufacturing facility at Bavla, India that operates with a manufacturing capacity of 3200 L.

CASE: 2Cipla Ltd, India entered into a technology transfer agreement with Farmanginhos, Brazil for fixed dose combination of Artesunate + Mefloquine.In order to facilitate access of ASMQ in Southeast Asia, a South-South technology transfer betweenFarmanginhos in Brazil andCipla Ltdin India, the agreement for which was signed in 2008, came to completion in 2010.This technology transfer for the artesunate + mefloquine fixed-dose combination was the first of its kind between a company in Brazil and one in India, and was even more unique in that it involved a transfer from a public entity, Farmanguinhos, to a private company, Cipla Ltd. The Farmanguinhos- Cipla technology transfer required the alignment of procedures to Good Manufacturing Practices (GMP) to achieve similar and comparable products that meet international requirements in order to benefit patients in all endemic countries. ASMQ was registered in India in 2011 and in Malaysia in 2012.CASE: 3Aventis, Themis Labs sign technology transfer dealThemis Laboratories signed a technology transfer agreement with Aventis Pharma for fixed-dose combinations comprising of glibenclamide (Daonil) and glimepiride (Amaryl), two products of the Aventis research pipeline with sustained-release metformin for the treatment of Type II diabetes.Following a bio-study and transfer of Themis Laboratories patented technology to the manufacturing site of Aventis in Goa, the product was launched in the market by Aventis as Amaryl M and Daonil M.The product is in the form of a bi-layered tablet with Glibenclamide / Glimepiride as the immediate release layer and metformin as a sustained release layer. This allows for 'once a day' administration of the formulation.12. CONCLUSION:Appropriate technology transfer is important to upgrade the quality of design to be the quality of product, and ensure stable and high quality of the product. The technology transfer does not mean onetime actions taken by the transferring party toward the transferred party, but means continuous information exchange between both the parties to maintain the product manufacturing. 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 agreed with a sending unit and/or a development unit. The three primary considerations to be addressed during an effective technology transfer are the plan, the persons involved, and the process. A plan must be devised to organize the personnel and the process steps. Once prepared, the plan must be communicated to the involved parties in research, at the corporate level and at the production site.In order to scale up and transfer a process successfully from laboratory scale to pilot scale and multiple commercial manufacturing scales, a thorough understanding of the integration of scale factors, facility design, equipment design and process performance is necessary.

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