Unit-II

Technology development and

technology transfer
Introduction

• 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.
Transfer of technology requires:
• Documented, planned approach
• Trained and knowledgeable personnel Compliant quality system
• Documentation of data covering all aspects of development, production
and quality control Usually there is a Sending unit (SU), a receiving unit
(RU) and the unit managing the process, which may or may not be a
separate entity.
Different Terminologies of technology transfer
• Active Pharmaceutical Ingredients (API):
Any ingredients or substances which are used in the manufacturing of a
pharmaceutical formulation and are considered as active ingredient of that
dosage forms, are called as Active Pharmaceutical Ingredients (API)
• Change Control (CC):
Change control can be defined as, “A formal system by which qualified
representatives of appropriate disciplines review proposed or actual changes
that might affect the validated status of facilities, systems, equipment or
processes. The intent is to determine the need for action that would ensure
and document that the system is maintained in a validated state.
Different Terminologies of technology transfer
3. Control Strategy:
The proper sets of control obtained from product and process
understanding to assure the process performance and product quality
which include parameters of products, materials, drug substances,
facilities, equipment availability, standardization process, in process
control, quality of finished goods, etc.
• 4. Critical Control Point (CCP):
Some controls are mandatory in the pharmaceutical industry to
eliminate or to reduce the quality hazards. CCP is a step at which this
control can be applied.
Different Terminologies of technology transfer
5. Corrective Actions (CA):
Corrective actions are taken at CCP while controlling the quality hazards.
6. Quality Assurance (QA):
According to WHO “Quality Assurance” is a wide-ranging concept covering all
matters that individually or collectively influence the quality of a product. It is the
totality of the arrangements made with the object of ensuring that pharmaceutical
products are of the quality required for their intended use. Quality assurance
therefore incorporates GMP and other factors, including those outside the scope of
this guide such as product design and development.
7. Quality Control (QC):
QC is that part of GMP concerned with sampling, specification, testing,
documentation and release procedures which ensure that the necessary and
relevant tests are performed, and the product is released for use only after
ascertaining its quality.
Different Terminologies of technology transfer
8. Design Qualification (DQ):
DQ is a documented verification of the proposed design of the facilities, systems and
equipment that are suitable for the intended purpose.
9. Installation Qualification (IQ):
IQ is an evidence of all key aspects of the process equipment and ancillary system
installation adhere to the manufacturer’s approved specification.
10. Operational Qualification (OQ):
OQ is established by objective evidence process for the control limits and action levels
in product of all predetermined requirements.
11. Performance Qualification (PQ):
PQ is established by verifying a process, under anticipated condition, consistently produces
a product which meets all predetermined requirements.
12. Drug Master File (DMF):
It is detailed information of a specific facility, process or product which has been submitted
to Medicines Regulatory Authority (MRA) for the incorporation into the application for the
marketing-authorization.
Different Terminologies of technology transfer
13. Finished Pharmaceutical Product (FPP):
A finished pharmaceutical product will be considered as a product which
contains one or more APIs and has undergone all steps of production,
standardization, packaging, storing and labeling.
14. Technology Transfer: Inter-Company Transfer:
The transfer of technology between sites of different companies is called as
intercompany transfer.
15. Technology Transfer: Intra-Company Transfer:
The transfer of technology between sites of same group of companies is
called as intracompany transfer.
16. Standard Operating Procedure (SOP):
It is an authorized written procedure with detailed instruction for the
operation of equipment, maintenance of equipment, cleaning of equipment,
validation of equipment, environmental control, sampling and analytical
procedures.
Different Terminologies of technology transfer
17. Technology Transfer Report (TTR):
• A documented report of technology transfer consists of:
• Procedures
• Acceptance criteria
• Obtained results
• Conclusions
• Deviations, if any
18. Sending Unit (SU) and Receiving Unit (RU):
The discipline of any organization involved in transferring of designated
process or method is called as sending unit (SU) and the organization
involved in receiving the same is mentioned as receiving unit (RU).
Phases involved in technology transfer
Technology
transfer

Research Development Production Documentation Exhibit Batches

phase phase phase

Design of procedure Optimization and production 1) Development report

and selection of 1) Validation studies 2) Technology transfer plan
excipients 2) Scale up for production 3) Report

R and D to production
1) Master Formula card
2) Master packing card
3) Master formula
4) Specifications and standard test procedures
QUALITY RISK MANAGEMENT (QRM)
• The risk of quality variation in the pharmaceutical product can be
assessed, controlled and communicated by a systematic process
called QRM. It has been mentioned in ICH guideline Q9.
Principle
• The basic principle of QRM is the assessment and evaluation of the
associated risks based on scientific knowledge and evidence to
maintain the quality of the product and customer satisfaction.
• ICH full form The International Council for Harmonisation of Technical
Requirements for Pharmaceuticals for Human Use
Step (1) QRM initiation:
• To initiate the process of QRM the following plan can be followed:
• Types of risk and problem.
• Questions regarding risks.
• Information regarding quality and potential hazards.
• Information of background and raw data.
• Assessment of required resources.
• Specification of time limit.
Step (2) Risk Assessment:
• This may include the following:
Identification of Hazards:
• Systematic process to identify the risks and hazards.
Analysis of Risks:
• Qualitative and quantitative estimations of hazards.
Evaluation of Risks:
• Comparison of identified and analyzed hazards.
 Step (3) Risk Control:
(a) Reduction of Risks:
The level of risk when exceeds the acceptance criteria, the reduction of
risks should be followed. Detection of risks, risks assessment and the
process control can reduce the level of risks.
(b) Acceptance of Risks:
It is the decision to accept the risk.
Step (4) Results of QRM and Risk Reviews:
The review of result obtained from the QRM process is a part of quality
management system. Results of QRM process should be documented,
reviewed, inspected, audited and possible change control is suggested.
Step (5) Risk Communication:

• This is the communication process of the data of risk management

system. The risk management system can be communicated at any
step of risk management process (Risk assessment, control and
review process
• Risk Reduction: Risk reduction focuses on processes for mitigation or
avoidance of quality risk when it exceeds a specified (acceptable)
level. Risk reduction might include actions taken to mitigate the
severity and probability of harm. Processes that improve the
detectability of hazards and quality risks might also be used as part of
a risk control strategy.
Risk review
• A mechanism to review or monitor events should be implemented.
The output/results of the risk management process should be
reviewed to take into account new knowledge and experience. The
frequency of any review should be based upon the level of risk. Risk
review might include reconsideration of risk acceptance decisions.
Risk management methodology
• Quality risk management supports a scientific and practical approach
to decision-making. It provides documented, transparent and
reproducible methods to accomplish steps of the quality risk
management process based on current knowledge about assessing
the probability, severity and sometimes detectability of the risk. The
pharmaceutical industry and regulators can access and manage risk
using recognized risk management tools and/or internal procedures
(e.g., standard operating procedures).
Risk management methodology ( Continue)
• Below is a non-exhaustive list of some of these tools.
1. Failure Mode Effects Analysis (FMEA): for identifying all possible failures in a design, a
manufacturing or assembly process, or a product or service.
2. Failure Mode, Effects and Criticality Analysis (FMECA): FMECA is a structured method of assessing
the causes of failures and their effect on production, safety, cost, quality
3. Fault Tree Analysis (FTA): approach to root cause analysis, identifying and analyzing the root of asset
issues before equipment breaks down. FTA helps in manufacturing facilities, where understanding
the potential causes of system failures is crucial to preventing them.
4. Hazard Analysis and Critical Control Points (HACCP): In the application of HACCP, the use of
microbiological testing is seldom an effective means of monitoring CCPs because of the time
required to obtain results.
5. Hazard Operability Analysis (HAZOP): Hazard and Operability Analysis (HAZOP) is a systematic
technique used for risk assessment in various industries. It involves examining complex systems to
identify hazards to personnel, equipment, or the environment, as well as operability problems that
could affect efficiency.
6. Preliminary Hazard Analysis (PHA): The content of a PHA mainly includes: the name of subsystem
(unit), operation mode, fault condition that can lead to hazards, hazard description, hazard
consequence, the possibility of a hazard happening , severity degree of hazard, preventive measures,
and so on.
7. Risk ranking and filtering
8. Supporting statistical tools.
Transfer from R & D to production (Process,
packaging and cleaning)
• It should be established at the outset whether the intention is to perform
single-batch manufacture, continuous production or campaigns, and
whether the RU can accommodate the intended production capacity.
• Consideration should be given to the level and depth of detail to be
transferred to support production and any further development or process
optimization at the RU as intended under the transfer project plan.
• The SU and the RU should jointly develop a protocol for the transfer of
relevant information related to the manufacturing process under
consideration from the SU to the RU, as well as the development of an
equivalent process at the RU.
Process
• The SU should provide a detailed characterization of the product,
including its qualitative and quantitative composition, physical
description, method of manufacture, in-process controls and
specifications, packaging components and configurations, and any
special safety and handling considerations.
• Information on clinical development: e.g. information on the rationale for
the synthesis, route and form selection, technology selection, equipment,
clinical tests, and product composition
• Information on scale-up activities: process optimization, statistical
optimization of critical process parameters, pilot report and/or information
on pilot-scale development activities indicating the number and disposition
of batches manufactured.
• Information or report on full-scale development activities: Indicating the
number and disposition of batches manufactured, and deviation and change
control reports which led to the current manufacturing. The SU should
provide to the RU information on any health, safety and environmental
issues associated with the manufacturing processes to be transferred, and
resulting implications, e.g. need for gowning or protective clothing.
Packaging
• Information on packaging to be transferred from the SU to the RU include
specifications for a suitable container/closure system, as well as any
relevant additional information on design, packing, processing or labeling
requirements needed for qualification of packaging components at the RU.
• For quality control testing of packaging components, specifications should
be provided for drawings, artwork, and material (glass, card, fibre board,
etc.).
• Based on the information provided, the RU should perform a suitability
study for initial qualification of the packaging components. Packaging is
considered suitable if it provides adequate protection (preventing
degradation of the drug due to environmental influences), safety (absence
of undesirable substances released into the product), compatibility
(absence of interaction possibly affecting drug quality) and performance
(functionality in terms of drug delivery).
Cleaning
• During the manufacturing process, pharmaceutical products and APIs
can be contaminated by other pharmaceutical products or APIs if
processing different products. To minimize the risk of contamination
and cross-contamination, operator exposure and environmental
effects, adequate cleaning procedures are essential.
Granularity of TT Process (API, excipients, finished
products, packaging materials) Starting materials
• Active Pharmaceutical Ingredients (API): The SU should provide the drug master file (DMF) and any relevant
additional information on the API to the RU to be checked against the specifications of the API.
The following information should be provided:
• Manufacturer;
• flow chart of synthetic pathway, outlining the process, including entry points for raw materials, critical steps,
process controls and intermediates;
• definitive form of the API (including photomicrographs and other relevant data) and any polymorphic and
solvate forms;
• solubility profile;
• partition coefficient (including the method of determination);
• particle size and distribution (including the method of determination);
• bulk physical properties, including data on bulk and tap density, surface area and porosity as appropriate;
water content and determination of hygroscopicity, including water activity data and special handling
requirements;
• microbiological considerations (including sterility, bacterial endotoxins and bioburden levels where the API
supports microbiological growth) in accordance with regional pharmacopoeia requirements.
Excipients
• The excipients to be used have a potential impact on the final product. Their
specifications as well as the DMF should, therefore, be made available by the SU for
transfer to the RU site.
• special considerations with implications for storage and/or handling, including but not
limited to safety and environmental factors (e.g. as specified in material safety data
sheets) and sensitivity to heat, light or moisture solubility.
• description of functionality, with justification for inclusion of any antioxidant,
preservative or any excipient above recommended guidelines;
• manufacturer;
• specifications, i.e. monographs and additional information that may affect product
processing or quality for compendia excipients, or a complete listing of specifications,
including analytical methods and justification for release limits for non-compendial
excipients. For excipients used for the first time in a human drug product or by a new
route of administration, the same level of detail as for a drug substance should be
provided;
Finished Products
• Depending on the type of dosage form, the SU should provide relevant
information on physical properties of excipients to the RU, including:
• definitive form (for solid and inhaled dosage forms);
• solubility profile (for solid, inhaled and transdermal dosage forms);
• Partition coefficient, including the method of determination (for transdermal
dosage forms);
• moisture content range (for parenteral, semi-solid/topical, liquid and transdermal
dosage forms);
• microbiological considerations in accordance with regional pharmacopoeia
requirements (for parenteral, semi-solid/topical, liquid, inhaled and transdermal
dosage forms);
• information on adhesives supporting compliance with peel, sheer and adhesion
design criteria (for transdermal dosage forms).
FINISHED PRODUCTS
• Depending on the type of dosage form, the SU should provide relevant information on physical properties of excipients to the RU,
including:
• Definitive form (for solid and inhaled dosage forms)
• Solubility profile (for solid, inhaled and transdermal dosage forms)
• Partition coefficient, including the method of determination (for transdermal dosage forms)
• Intrinsic dissolution rate, including the method of determination (for transdermal dosage forms)
• Particle size and distribution, including the method of determination (for solid, inhaled and transdermal dosage forms)
• Bulk physical properties, including data on bulk and tap density, surface area and porosity as appropriate (for solid and inhaled
dosage forms)
• Compaction properties (for solid dosage forms)
• Melting point range (for semi-solid/topical dosage forms)
• pH range (for parenteral, semi-solid/topical, liquid and transdermal dosage forms)
• lonic strength (for parenteral dosage forms)
• Specific density/gravity (for parenteral, semi-solid/topical, liquid and transdermal dosage forms)
• Viscosity and/or viscoelasticity (for parenteral, semi-solid/topical, liquid and transdermal dosage forms)
• Osmolarity (for parenteral dosage forms)
• Water content and determination of hygroscopicity, including water activity data
Packaging
• Information on packaging to be transferred from the SU to the RU
include specifications for a suitable container/closure system, as well
as any relevant additional information on design, packing, processing
or labeling requirements needed for qualification of packaging
components at the RU. For quality control testing of packaging
components, specifications should be provided for drawings, artwork,
material.
QUALIFICATION AND VALIDATION
• The extent of qualification and validation to be performed should be determined on the basis of risk
management principles, taking into account the product's life cycle phase. Equipment and instruments
should be qualified and calibrated before using them to support the technology transfer activities. Process
validation should be done according to guidelines as published in current WHO Technical Report Series.
• Production processes and analytical procedures should be appropriately transferred to the RU following
documented procedures. Where validation data exist, these should be included in the transfer. For cleaning
procedures, development and validation should be done in accordance with the guidelines as published in
current WHO Technical Report Series.
• Points to consider when using HBEL in cleaning validation should be taken into account in establishing
cleaning procedures, cleanability studies and setting acceptance limits.
• Analytical procedures should be validated or verified according to the guidelines as published in current
WHO Technical Report Series.
• Qualification and validation procedures, protocols, data and results should be appropriately recorded. The
documents should be as defined in procedures.
• DQ- Design qualification, IQ-Installation qualification, OQ-Operational qualification, PQ- Performance
qualification
Approved regulatory bodies and agencies
country Authority
USA USFDA
UK Medicines and Healthcare products Regulatory Agency
(MHRA)
Australia Therapeutic Goods Administration (TGA)
India Central Drugs Standard Control Organization (CDSCO)
CANADA Health canada
South Africa Medicines Control Council (MCC)
Brazil Agencia Nacional de Vigiloncia Sanitaria (ANVISA)
Pakistan Drugs Control Organization, Ministry of Health
Japan Ministry of Health, Labour & Welfare(MHLW)
Clinical Investigation
US: IND – Investigational New Drug (Application)
EU: CTA / CTX – Clinical Trial Authorization/Clinical Trials Exemption
Marketing Approval
US NDA – New Drug Application ,
ANDA - Abbreviated New Drug Application,
BLA – Biologic License Application
EU MAA – Marketing Authorization Application
CTD–Common Technical Document, Common format for marketing
authorization (registration)
Labelling
US: Primary and Secondary Container, Package Insert (PI), Patient Package
Insert (PPI), Structured Product Labeling (SPL)
EU: Summary of Product Characteristics (SPC), European Public Assessment
Report (EPAR)
Approved regulatory bodies and agencies
• The principal regulatory bodies entrusted with the responsibility of ensuring the
approval, production and marketing of quality drugs in India at reasonable prices
are:
• The Central Drug Standards and Control Organization (CDSCO): located under
the aegis of the Ministry of Health and Family Welfare. The CDSCO prescribes
standards and measures for ensuring the safety, efficacy and quality of drugs,
cosmetics, diagnostics and devices in the country. Regulates the market
authorization of new drugs and clinical trials standards; supervises drug imports
and approves licenses to manufacture the above-mentioned products.
• It is the national regulatory authority for medical & pharmaceuticals devices in
India. CDSCO was formed in 1948.
• CDSCO is headed by the DCGI (Drug Controller General of India) & works under
the ministry of health of health & Family welfare, government of India.
• The Drugs Controller General of India (DCGI): With respect to licensing
and quality control issues, market authorization is regulated by the Central
Drug Controller, Ministry of Health and Family Welfare, Department of
Biotechnology, Ministry of Science and Technology (DST) and Department
of Environment, Ministry of Environment and Forests. State drug
controllers have the authority to issue licenses for the manufacture of
approved drugs and monitor quality control, along with the Central Drug
Standards Control Organization (CDSCO).

• The Food and Drug Administration (FDA or USFDA): is a federal agency of

the United States Department of Health and Human Services, one of the
United States federal executive departments. The FDA is responsible for
protecting and promoting public health through the Control and
supervision of food safety, tobacco products, dietary supplements,
prescription and over the counter pharmaceutical drugs (medications),
vaccines, biopharmaceuticals, blood transfusions, medical, electromagnetic
radiation emitting devices (ERED), cosmetics, animal foods & feed and
veterinary products.
• The Therapeutic Goods Administration (TGA): is part of the
Australian Government Department of Health, and is responsible for
regulates prescription medicines, vaccines, sunscreens, vitamins and
minerals, medical devices, blood and blood products. Almost any
product for which therapeutic claims are made must be entered in
the Australian Register of Therapeutic Goods (ARTG) before it can be
supplied in Australia.

• Medicines and Healthcare products Regulatory Agency (MHRA):

regulates medicines, medical devices and blood components for
transfusion in the UK.
Asian and Pacific Centre for Transfer of
Technology (APCTT)
• It is a United Nations Regional Institution under the Economic and
Social Commission for Asia and the Pacific (ESCAP) established in
1977 in Bangalore, India. In 1993, the Centre moved to New Delhi,
India. APCTT promotes transfer of technology to and from small- and
medium-scale enterprises (SMEs) in Asia and the Pacific. APCTT
implements development projects funded by international donors
aimed at strengthening the environment for technology transfer
among SMEs. The objective of APCTT is to strengthen the technology
transfer capabilities in the region and to facilitate import/export of
environmentally sound technologies to/from the member countries.
 National Research Development Corporation
(NRDC)
• National Research Development Corporation (NRDC) was established in
1953 by the Government of India, with the primary objective to promote,
develop and commercialize the technologies / know-how / inventions /
patents / processes emanating from various national R&D institutions /
Universities and is presently working under the administrative control of
the Dept. of Scientific & Industrial Research, Ministry of Science &
Technology. During the past six decade of its existence and in pursuance of
its corporate goals, NRDC has forged strong links with the scientific and
industrial community in India and abroad. It is recognized as a large
repository of wide range of technologies spread over almost all areas of
industries, viz. Agriculture and Agro-processing, Chemicals including
Pesticides, Drugs and Pharmaceuticals, Bio Technology, Metallurgy,
Electronics and Instrumentation, Building Materials, Mechanical, Electrical
and Electronics etc. It has licensed the indigenous technology to more than
4800 entrepreneurs and helped to establish a large number of small and
medium scale industries. NRDC also undertakes number of activities such
as meritorious inventions awards, Techno Commercial support, Technical
and financial assistance for IPR Protection, Value addition services and
support for further development of technologies and much more.
Technology information, Forecasting and
assessment Council (TIFAC)
• TIFAC is an autonomous organization set up in 1988 under the Department of
Science & Technology to look ahead in technology domain, assess the technology
trajectories, and support innovation by networked actions in selected areas of
national importance TIFAC embarked upon the major task of formulating a
Technology Vision for the country in various emerging technology areas. Under
the leadership of Dr. APJ Abdul Kalam, Technology Vision 2020 exercise led to set
of 17 documents, including sixteen technology areas and one on services. In
more than 25 years of its service to the nation, it has delivered number of
technology assessment and foresight reports. While inaugurating the 103rd
Indian Science Congress in Mysuru, Hon’ble Prime Minister of India Shri Narendra
Modi released the Technology Vision 2035 prepared by TIFAC. This is being
followed by release of Technology Roadmaps in 12 thematic areas of national
priorities and importance • Education, Medical Science & Health Care, Food and
Agriculture, Water, Energy, Environment, Habitat, Transportation, Infrastructure,
Manufacturing, Materials and Information & Communication Technologies (ICT).
Biotech Consortium India Limited (BCIL)
• Biotech Consortium India Limited (BCIL), New Delhi was incorporated as
public limited company in 1990 under The Companies Act, 1956. The
consortium is promoted by the Department of Biotechnology, Government
of India and financed by the All India Financial Institutions and some
corporate sectors BCIL 's major functions include the development and
transfer of technology for the commercialization of biotechnology
products, project consultancy, biosafety awareness and human resource
development BCIL has been successfully managing several Flagship
schemes and Programs of the Department of Biotechnology, Government
of India. Most notable include Biotechnology Industry Partnership
Programs, Biotechnology Industrial Training Programs and Small Business
Innovation Research Initiative
Technology Bureau for Small Enterprises (TBSE)/
Small Industries Development Bank of India (SIDBI)
• The Technology Bureau for Small Enterprises (TBSE) is a platform for
MSMEs to tap opportunities at the global level for the acquisition of
technology or establishing business collaboration. TBSE is a result of the
cooperative initiative of the United Nations’ Asian and Pacific Centre for
Transfer of Technology (APCTT) and Small Industries Development Bank of
India (SIDBI) in 1995. TBSE also receives partial funding from the Office of
DC (SSI), Government of India. Features of TBSE Offering a professionally
managed system for the reasons of technology and collaboration
exploration helping in the building up of confidence between potential
partner. It providing an opportunity to global technology market through
the process of networking. Taking up project appraisal and the preparation
of a business plan. The new technologies for the reason of transfer are
sourced from countries namely China, Philippines, South Korea, Australia,
Germany, as well as the U.S.
TT related documentation - confidentiality
agreement, licensing, MoUs, legal issues
• Confidentiality Agreements: The aim of a confidentiality agreement is to
protect all information of party entering negotiations. Before any concrete
negotiations on the transfer of a technology can really start all parties
involved must be able to evaluate the technology offered. Both the
technological and the commercial possibilities of the offer will thereby be
taken into account. Before giving anybody access to your technology a
confidentiality agreement should be drafted with discussion on the main
topics to be addressed in such agreement keeping in mind that all the
standard clauses of an agreement should also be included (parties, term
and termination, applicable law). The first item in any confidentiality
agreement should be a brief but clear description of the technology that
will be transferred. What are the main specifications of this technology and
what is its relevant application? In this same disposition of the agreement a
reference to the property rights of the party offering can be made.
Licensing
• The legal core of the transfer of technology is constituted by a licensing
agreement. By signing this agreement the owner of a technology, the
licenser, gives the right to another company, the licensee, to make use of
this technology. A license does not alter the property rights of the owner:
he remains the only proprietor of the technology. He could also sell his
technology whereby the buyer becomes the owner and replaces the seller.
But if an owner of a technology prefers to enter into an agreement with a
licensee he will give him limited rights. The licensee cannot dispose of the
technology but he can use it. This use will be more or less limited. A
limitation in time, in geographical market, in product market or in the
application can be introduced in a license. The license will determine the
relationship between the licenser and licensee for the whole duration of
their co-operation and a lot of questions will have to be answered before
this relationship can start.
Memoranda of Understanding (MOUs)
• Often collaborative research efforts with outside institutions are
defined in Memoranda of Understanding (MOU) before other
agreements are executed. An MOU typically defines how intellectual
property will be shared and the roles and responsibilities of the
involved parties. If you are planning to enter into a collaborative
relationship with an outside party, it is important to discuss the
possibility of an MOU. Office of Technology Commercialization is
responsible for drafting MOUs related to collaborative research.
MOUs typically identify a lead institution for managing intellectual
property and provide details on how licensing income will be shared.
Legal Issues
• The following types legal issues are generally observed in technology
transfer.
• Legal contractual agreements
• Tax implications
• Legal issues in intellectual property transaction
• Problems associated with IPR litigation
• Legislations covering IPRs in India