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Technology Transfer and Scale-up in Pharmaceutical Industry


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,
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.

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Technology Transfer and Scale-up 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.


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Technology Transfer and Scale-up in Pharmaceutical Industry

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.

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Technology Transfer and Scale-up in Pharmaceutical Industry





uring and


Fig 3.1: Representation of Technology transfer process

Technology 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:

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Technology Transfer and Scale-up in Pharmaceutical Industry

Analytical Development
and Validation

Research &

Quality Assurance
and Quality

Production and

Product Development

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 used
For packaging, stability profile of packaging and shelf life of packaging.
c) Master formula: It describes formulation order and manufacturing instructions.

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Technology Transfer and Scale-up in Pharmaceutical Industry

Formulation order and Manufacturing Instructions give idea of process order,
environment conditions required and manufacturing instructions for development of
dosage 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)

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Technology Transfer and Scale-up in Pharmaceutical Industry

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):

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Technology Transfer and Scale-up in Pharmaceutical Industry

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:

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Technology Transfer and Scale-up in Pharmaceutical Industry

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

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Technology Transfer and Scale-up in Pharmaceutical Industry

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)

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.

Design of

nt Phase
Research for

function of
nt of
of stability

Quality and
Transfer from
R&D to


transfer of

Fig 4.2: Phases of Technology transfer

a) Post Management:
Monitor compliance to the conditions of the contract and actual inspection and report.
b) Negotiations and contract:
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Technology Transfer and Scale-up in Pharmaceutical Industry

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.


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

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.
Technology 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:

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Technology Transfer and Scale-up in Pharmaceutical Industry

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:
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Technology Transfer and Scale-up in Pharmaceutical Industry

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 India
Research 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.

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Technology Transfer and Scale-up in Pharmaceutical Industry

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
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)

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Technology Transfer and Scale-up in Pharmaceutical Industry

Table I: Some of the Nanotechnology-based products commercialized by Indian


(H. Puroshottam, 2012)

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Technology Transfer and Scale-up in Pharmaceutical Industry

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.

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Technology Transfer and Scale-up in Pharmaceutical Industry

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.

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Technology Transfer and Scale-up in Pharmaceutical Industry

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

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

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

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.

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Technology Transfer and Scale-up in Pharmaceutical Industry

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:

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Technology Transfer and Scale-up in Pharmaceutical Industry

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

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Technology Transfer and Scale-up in Pharmaceutical Industry

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

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Technology Transfer and Scale-up in Pharmaceutical Industry

(Gupta Surbhi et al, 2012)
Technology Transfer Team Member

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.

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.

technologist) to confirm capacity and capability.

Considers any safety implications e.g., solvents, toxic

sanitizing materials.
Considers impact on

Quality Assurance Representative

Production Representative





procedures (SOPs) and training requirements of

supervisors or operators
Reviews (with production representative) equipment

Engineering Representative




modifications, change or part purchase.

Reviews preventative maintenance and calibration
impact e.g. use of more aggressive ingredients, more

Quality Control Representative

temperature sensitive process and modifies accordingly.

Reviews Analytical requirements and availability with

Responsible for Analytical method transfer for drug
substance and drug product.


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

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Technology Transfer and Scale-up in Pharmaceutical Industry

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.

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Technology Transfer and Scale-up in Pharmaceutical Industry

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.


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.
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Technology Transfer and Scale-up in Pharmaceutical Industry

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)


(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.

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Technology Transfer and Scale-up in Pharmaceutical Industry

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 nations

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.


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 longrun 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.

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Technology Transfer and Scale-up in Pharmaceutical Industry

Information development in the field of technology transfer methods; Modification of

cultural value systems in organizations and diffusion of scientific attitude in

Employment of entrepreneur managers and Creation of standards and capabilities in


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.


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.

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Technology Transfer and Scale-up in Pharmaceutical Industry

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

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.
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Technology Transfer and Scale-up in Pharmaceutical Industry

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.
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.
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Technology Transfer and Scale-up in Pharmaceutical Industry

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 Synthesis
Thus, successful technology transfer was implemented.


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
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Technology Transfer and Scale-up in Pharmaceutical Industry

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
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



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)

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Technology Transfer and Scale-up in Pharmaceutical Industry

Pilot scale

plant scale


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

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:

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Technology Transfer and Scale-up in Pharmaceutical Industry

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:

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Technology Transfer and Scale-up in Pharmaceutical Industry

Engineering support and maintenance
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

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Technology Transfer and Scale-up in Pharmaceutical Industry

unapproved areas). Controlled environment space allocated for storage of stability

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.

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Technology Transfer and Scale-up in Pharmaceutical Industry

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.

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Technology Transfer and Scale-up in Pharmaceutical Industry

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 crosscontamination.

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

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Technology Transfer and Scale-up in Pharmaceutical Industry

Steps in Scale-up:

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Technology Transfer and Scale-up in Pharmaceutical Industry


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

For these reasons, screening and/or milling of the ingredients usually makes the
process more reliable and reproducible.

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Technology Transfer and Scale-up in Pharmaceutical Industry

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 Capacity

Parameters to be considered for scale-up:

Optimum Load
Air Flow Rate
Inlet Air Temperature
Humidity of the Incoming Air

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Technology Transfer and Scale-up in Pharmaceutical Industry

Planetary Mixer


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.

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Technology Transfer and Scale-up in Pharmaceutical Industry

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Technology Transfer and Scale-up in Pharmaceutical Industry


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.

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Technology Transfer and Scale-up in Pharmaceutical Industry

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)


Technology 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.

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Technology Transfer and Scale-up in Pharmaceutical Industry

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

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.

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Technology Transfer and Scale-up in Pharmaceutical Industry

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.

Cipla 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 between Farmanginhos in Brazil and Cipla Ltd in 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.
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Technology Transfer and Scale-up in Pharmaceutical Industry

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.
Aventis, Themis Labs sign technology transfer deal
Themis 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.
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
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Technology Transfer and Scale-up in Pharmaceutical Industry

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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Technology Transfer and Scale-up in Pharmaceutical Industry

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SVKMS Dr. Bhanuben Nanavati College of Pharmacy