Technology Transfer in Pharma Industry

TECHNOLOGY TRANSFER PROCESS IN
PHARMACEUTICAL INDUSTRIES
Shaik. Naseeb Basha
Asst. Professor, Dept. of Pharmaceutics
G. Pulla Reddy College of Pharmacy
Hyderabad-500028

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 INTRODUCTION/ WHAT IS TECHNOLOGY TRANSFER?
 FACETS OF TECHNOLOGY TRANSFER
 CONSTITUENTS OF TECHNOLOGY TRANSFER
 TECHNOLOGY TRANSFER FROM VARIOUS SECTORS
 TECHNOLOGY TRANSFER PROCESS FLOW CHART
 GUIDELINES/ IMPORTANCE OF TECHNOLOGY TRANSFER
 WHY/ REASONS OF TECHNOLOGY TRANSFER AND WHEN IT WILL BE DONE?
 FACTORS AND BARRIERS INFLUENCING ON TECHNOLOGY TRANSFER &
APPROCHES TO OVERCOME THE BARRIERS
 TECHNOLOGY TRANSFER PROCESS AND ITS STEPS AND PROCEDURE
 TECHNOLOGY TRANSFER TEAM & RESPONSIBILITY
TECHNOLOGY TRANSFER DOCUMENATION
TECHNOLOGY TRANSFER CHECKLIST
 TECHNOLOGY TRANSFER DOCUMENATION
 PROBLEMS IN TECHNOLOGY TRANSFER
 TECHNOLOGY TRANSFER OF TEST METHODS
 EXAMPLE OF TECHNOLOGY TRANSFER PROBLEMS IN TABLETS MANUFACTURING
CONTENTS

INTRODUCTION / WHAT IS TECHNOLOGY TRANSFER?
• 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”
• Technology transfer is both integral and critical to the
drug discovery and development process for new
medicinal products.
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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. It is the process
by which an original innovator of technology makes its technology available to
commercial partner that will exploit the technology. Technology transfer is both
integral and critical to drug discovery and development for new medicinal
products.
In pharmaceutical industry, “Technology Transfer” refers to the processes of
successful progress from drug discovery to product development, clinical trials
and ultimately full-scale commercialization.
“Technology transfer” refers to the processes that are needed for successful
progress from drug discovery to product development to clinical trials to full-
scale commercialization or it is the process by which a developer of technology
makes its technology available to commercial partner that will exploit the
technology.
Technology transfer is important for such research to materialize on a larger
scale for commercialization especially in the case of developing product.
Technology transfer includes not only the patentable aspects of production but
also includes the business processes, such as knowledge and skills.
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Facets of technology transfer
The transfer of technology could happen in any of following ways:
1. Government labs to private sector firms.
2. Between private sector firms of same country.
3. Between private sector firms of different country.
4. From academia to private sector firms.
5. Academia, government and industry collaborations.
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6 P
CONSTITUENTS OF TECHNOLOGY TRANSFER

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Proper Research – By proper research we mean firstly that in which the result are
reproducible and issues such as scale up, stability etc and other practical now has
been addressed, also that in which problem were taken up in first place
Proper work- This refer to institutional and guidelines regarding IP Protection
licensing modalities etc. which must be in place beforehand. In the absence of these,
decision get delayed, lack of fairness in decision e.g. case of X institute, which came
up with good technology but since no guidance were there, kept running around for
two years and then gave up.
Pricing – most difficult and critical area of Transfer of technology.
- Too high price can put off buyer, leaving the technology unsold.
- Too price a result in revenue loss.
- There are basically two model regarding pricing
1)Price charged for a technology should depend upon market force i.e. impact of
the technology irrespective of amount spent on developing it.
2)Price charged should include all expenses involved in developing it.

Publicity – It is important to identify and then approach buyer i.e. adopt targeted
Publicity and not blanket publicity. Specific journal, website, letters to manufacturer,
personal selective visit etc. are some common approach which help in locating buyer
Partnership – this means working along with industry. Industry takes it up,
manufacturer and makes available to society. Partnership are important to ensure
your technology is successfully adopted simply conveying the details may not be
sufficient.
People’s Acceptance – It is no use trying to develop a technology which people will not
accept e.g. due to religious reason/social concern etc. genetically modified food,
irradiated vegetables processed beef in India, improved capsule made of non-
vegetarian material.
LIST OF INSTITUTE IN INDIA ASSISSTING IN TECHNOLOGY TRANSFER
 Asia pacific centre for Transfer of technology ( APCTT)
 Technology Bureau for small enterprises ( TBSE)
 National Research & Development corporation
 Foundation for Innovation and Technology Transfer
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IDEA
Research
Development
Production
Manufacturing
Distribution
Start-up
Firms
R & D
Firms
Larger
Companies
Larger
Companies
Universities
Research
Institutes
MARKET
(Commercialization)
TECHNOLOGY TRANSFER FROM VARIOUS SECTORS
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TECHNOLOGY TRANSFER PROCESS FLOW CHART
TECHNOLOGY TRANSFER
PROCESS

GUIDELINES/ IMPORTANCE OF TECHNOLOGY
TRANSFER
 To elucidate necessary information to transfer technology from R&D to actual
manufacturing by sorting out various information obtained during R&D.
 Demonstration of necessary information to technology transfer from research and
development to actual manufacturing.
 To elucidate necessary information to transfer technology of existing products between
various manufacturing places.
 To exemplify specific procedures and points of concern for smooth technology
transfer. For the smooth manufacturing of commercialized products.
 This is applicable to the technology transfer through R&D and production of drug
(chemically synthesized drug substances and drug products) and the technology transfer
related to post-marketing changes in manufacturing places.
 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 registered
specifications and Good Manufacturing Practice requirement.
 General impact of the technology transfer program.
i. Improvement of the research pertinence and its promotion in foreign countries.
ii. Contribution with the creation and consolidation of research groups and centers for
technology development, involving the training of young research students.
iii. Promote interdisciplinary projects to be developed in the region of interest.
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Why/ Reasons of technology transfer?
Many reasons exist why a company would like to transfer its technology to other parties:
1)Due to lack of manufacturing capacity, the developer of the technology may only have
manufacturing equipment that suitable for lab and small scale operations and must partner
with another organization to do large scale manufacturing.
2) Due to lack of resources to launch product commercially. The original inventor of
technology may only have resources to conduct early-stage research and Phase-I and II
clinical trials.
3) Due to lack of marketing distribution and distribution capability. The developer of
the 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 and must collaborate with another organization that has the capability.
4)Forming alliances with partners that can progress the development of the technology to
take it to market.
5)Forming alliances with partners with manufacturing capability.
6)Forming alliances with partners with marketing and distribution capability.
7)Exploitation in a different field of application.
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WHEN TECHNOLOGY TRANSFER IS DONE ?
• Idea to Discovery Lab
• Discovery Lab to Development Lab
• Development Lab to Pilot Plant
• Kilo Lab to Pilot Plant
• Pilot Plant to Semi-works (other pilot plant)
• Pilot Plant to Manufacturing
• Manufacturing to Manufacturing
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Various stages of formulation development were as follows
• Preformulation studies.
• Bench scale - (1/1000th
of X)
• Lab scale – (1/100th
of X)
• Scale up- (1/10th
of X or 0.1M whichever is maximum)
• Commercial (X)
Where X is the final commercial scale batch size.

FACTORS INFLUENCING TECHNOLOGY TRANSFER
Drivers for Technology Transfer –
(A) Good business and manufacturing practices – The company’s 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.
• Strategic planning – Create an enabling environment for vertical integration, with
prospects for higher capacity utilization and eventual lowering of production costs.
• 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 are necessarily a high
regulated industry, the regulatory function must be efficient and transparent for
technology transfer to be economically viable.
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• Opportunities for contingency supply – Multinational pharmaceutical
companies are inclined to transfer technology to local manufacturers with the
potential to receive when they foresee an inability to meet time scales and volume
demand from large procurers.
• Access to new machinery, training, know-how 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.
• Lack of efficiency – Automation of production processes to improve efficiency
and lower costs.
• Low market share – Local producers face significant challenges in meeting
International Quality Standards and capturing a critical market share. Greater
market share would increase profitability.
• Cost of prequalification – There is benefit in meeting International Standards
since it opens up the opportunity for trading across the entire world.
• Labour issues – The pharmaceutical sector demands relatively skilled labour.
High labour turns over and absenteeism owing to unattractive conditions of service
is negative contributor.
FACTORS INFLUENCING TECHNOLOGY TRANSFER Cont…
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Approaches to overcome barriers in technology transfer
1. 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.
2. 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.
3. Web access and scientific publication:
Limited access to scientific journals led to enormous problems for developing nations scientists.
4. 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.
5. Inadequate funding in important areas and possible treaties:
There are areas of research of importance to the developing world that are being funded inadequately.
6. Co-operative research agreements:
Global support for public sector research might be encouraged is 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.
7. Possible treaty on scientific access:
There has also been a proposal for an international treaty on access to knowledge and technology
negotiated on the basis of the type of reciprocity found in normal international trade negotiations. The
concept is mean to be non- zero sum in the sense that, like free trade in goods, free trade in scientific ideas
benefits all, and such arrangements could be made bilaterally as well as multilaterally.
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Technology Transfer Process
Technology transfer is both integral and critical to the drug discovery and
development process for new medicinal products. The decision to transfer
products between manufacturing sites is frequently driven by economics.
Key stages of the process include data collection, data review, regulatory impact
with particular emphasis on any change approvals, analytical validation, pilot
or full-scale process batch, stability set down (if required).
Technology Transfer Flow chart 18

Representation of Technology Transfer Process
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TECHNOLOGY TRANSFER PROCESS
The processes are classified into the three categories.
• Research Phase
– Quality by design
• Development Phase
– Research for Factory Production
– Consistency between Quality and Specification
– Assurance of consistency through development and
manufacturing
– Technology Transfer from R&D to Production
• Production Phase
– Validation & Production
– Feed back from Production and Technology Transfer of Marketed
Products
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STEPS IN TECHNOLOGY TRANSFER PROCESS
During development of a formulation, it is important to understand the procedure of
operations used, critical and non-critical parameters of each operation, production
environment, equipment and excipients availability should be taken into account during the
early phases of development of formulation so that successful scale up can be carried out.
(A) Development of technology by R&D. (Research Phase)
(a) Design of procedure and selection of excipients by R&D
(b) Identification of specifications and quality by R&D
(B) Technology transfer from R&D to production (Development Phase)
(a) Master Formula Card (MFC)
(b) Master Packing Card
(c) Master Formula
(d) Specifications and Standard Test Procedures (STP’S)
(C) Optimization and Production (Production Phase)
(a) Validation Studies
(b) Scale up for production
(D) Technology Transfer Documentation
(a) Development Report
(b) Technology Transfer Plan
(c) Report
(E) Exhibit
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(A) 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 developed by R&D
on the basis of innovator product characteristics.
(b) Identification of specifications and quality by R&D–
Quality of product should meet the specifications of an innovator
product.
TECHNOLOGY TRANSFER PROCESS Cont…
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(B) 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 follows
(a)Master Formula Card (MFC)–
Includes product name along with its strength, generic name, MFC number, page
number, effective date, shelf life and market.
(b) Master Packing Card–
Gives information about packaging type, material used for packaging, stability profile
and shelf life of packaging.
(c) Master Formula–
Describes formulation order and manufacturing instructions. (Process order and
environment conditions)
(d) Specifications and Standard Test Procedures (STP’S)–
Helps to know active ingredients and excipients profile, in-process parameters, product
release specifications and finished product details.
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(C) Optimization and Production (Production Phase)
(a) Validation Studies–
Production is implemented after validation studies that can verify that process is
able to stabilize the product based on transferred manufacturing formula.
Manufacturing department accepting technology is responsible for validation and
the R&D department transferring technology should take responsibility for
validation such as performance qualification, cleaning and process validation.
(b) Scale up for production–
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
their segment of the production process running smoothly.
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(D) Technology Transfer Documentation
Generally interpreted as document indicating contents of technology transfer for
transferring and transferred parties. Each step from R&D 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.
(a) Development Report–
The R&D report is a file of technical development, and R&D department is in-charge
of its documentation. This report is an important file to indicate rationale for the
quality design of drug substances and its specifications and test methods. The
development report is not prerequisite for the application for approval; it can be used
at the pre approval an inspection as valid document for quality design of new drug.
The development report contains
(1) Data of pharmaceutical development of new drug substances and drug products at
stages from early development phase to final application of approval.
(2) Information of raw materials and components.
(3) Design of manufacturing methods.
(4) Change in histories of important processes and control parameters.
(5) Specifications and test methods of drug substances.
(6) Validity of specification range of important tests such as contents impurities and
dissolution. (7) Verifications of results.
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(b) Technology Transfer Plan–
The technology transfer plan is to describe items and contents of technology to be transferred
and detailed procedures of individual transfer and transfer schedule, establish judgment
criteria for the completion of the transfer. The transferring party should prepare the plan
before the implementation of the transfer and reach an agreement on its contents with the
transferred party.
(c) Report–
Completion of technology transfer is to be made once data are taken accordingly to the
technology plan and are evaluated to confirm that the predetermined judgment criteria are
met. Both transferring and transferred parties should document the technology transfer report.
(E) Exhibit
After taking scale up batches of the product, manufacturing of exhibit batches takes
place. In case of exhibit, batch sizes are increased along with equipments and their
processes. This is done for filling purpose in regulatory agencies.
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TECHNOLOGY TRANSFER PROCEDURE
1. Procedure for Manufacturing and Packaging:
• After the completion of three validation/commercial batches, R&D shall prepare the
technology transfer dossier (TTD), which shall be reviewed by Head- Production,
Head-QC, Head- Engineering and approved by Head-QA.
• The dossier shall contain the details of unitary formula, process flow chart, raw
material and packing material specifications, in-process and finished product
specifications, master formula card, safety parameters, critical process steps, critical
process parameters and their specifications and measured response, process validation
protocol, process validation report, stability data, deviation and change controls,
product development report.
• After successful transfer of technology (manufacturing process), manufacturing of
the respective product is the responsibility of production department. If any problem
arises, QA shall investigate and refer to R&D through investigation report in the form
of Inter Office Communication (IOC).
• Any deviation in the process shall be supported by deviation/change control form as
applicable.
• For third party and loan license products, respective organization will provide the
TTD to QA and manufacturing process shall be demonstrated to production personnel
on minimum of two or three batches.
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TECHNOLOGY TRANSFER PROCEDURE Cont….
2. Procedure for Analytical Method Transfer:
A) For Drug Product:
• Analytical method transfer shall be initiated by analytical department for all the validated
methods.
• Analytical department analyst along with quality control analyst has to perform analysis as
per the analytical method transfer protocol.
• The transfer activity shall be established on the optimization batch or process batch with the
final formula.
• Analytical method transfer activity shall be initiated with analytical method transfer protocol
prepared by AR&D, reviewed by DQA/QC and finally approved by QA.
• The analytical method transfer protocol shall explain the transfer activities of the drug product
and also the parameters that shall be transferred are Assay, Dissolution, Related substances,
Content uniformity and Residual solvents.
• In case of multiple strengths, analytical method transfer shall be performed for lower strength.
• All chromatograms, record of results and other information have to be interlinked and records
have to be maintained.
• A report has to made with summarized results and conclusions and the same shall be reviewed
by Head-DQA and Head-QC, approved by Head-QA.
• The analytical method transfer process is considered to be completed upon the certification by
analytical department, quality control & quality assurance that the method under consideration
meets the acceptance criteria.
• Finally analytical method transfer report shall be prepared. 28

TECHNOLOGY TRANSFER PROCEDURE Cont….
2. Procedure for Analytical Method Transfer:
B) For Drug Substances:
i) Non Pharmacopoeial Methods:
The vendor has to transfer the analytical methods to QC. In case, if the analytical method
transfer activity was not performed by the vendor the same shall be prepared by AR&D as per
the STP.
ii) Pharmacopoeial Methods:
The vendor has to transfer the analytical methods to QC. If the methods are same as per
respective pharmacopoeia, the method suitability shall be performed by AR&D. Suitability of
the analytical method shall verified by performing the specificity (RRT verification) and
precision study (Triplicate) and the same shall be reviewed by DQA and communicated to QC.
• Analytical method transfer protocol and report shall be prepared.
• The analytical method transfer protocol shall explain the transfer activities of the drug
substance and also the parameters that shall transferred are assay, residual solvents and related
substances.
• All chromatograms, record of results and other information have to be interlinked and records
have to be maintained.
• A drug substance analytical method transfer report has to be made with summarized results
with conclusions as per drug product method transfer report.
• The limits and parameters described for drug product/drug substance are indicative, but shall
altered based on customer’s requirements and nature of drug product/drug substances to be
followed as per respective analytical method transfer protocol.
• Documentation for analytical method transfer activity shall be done by analytical R&D
department.
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TECHNOLOGY TRANSFER TEAM
The technology transfer team consists of
– R&D Process Technologist
– QA Representative
– Production Representative
– Engineering Representative
– QC Representative
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Technology Transfer
Team member
Responsibilities
Process Technologist a) Central focus for transfer activities.
b) Collates documentation from donor site
c) Performs initial assessment of transferred project for Feasibility,
Compatibility with site capabilities and Establishes resource
requirements.
QA Representative a) Reviews documentation to determine compliance with marketing
authorization (MA).
b) Reviews analytical methods with QC to determine capability,
equipment training requirements.
c) Initiates conversion of donor site documentation into local systems
or format.
d) Initiates or confirms regulatory requirements, e.g., change to
manufacturing license; variations to MA if process changes needed,
etc.
Production Representative a) Reviews process instructions (with process technologist) to
confirm capacity and capability.
b) Considers any safety implications, e.g., solvents; toxic; sanitizing
materials.
c) Considers impact on local standard operating procedures (SOPs).
d) Considers training requirements of supervisors or operators.
Constitution of technology transfer team and their responsibilities
31

Technology Transfer
Team member
Responsibilities
Engineering Representative a) Reviews (with production representative) equipment
requirement.
b) Initiates required engineering modifications, change or
part purchase.
c) Reviews preventative maintenance and calibration impact,
e.g., use of more aggressive ingredients; more temperature
sensitive process, and modifies accordingly.
QC Representative a) Reviews analytical requirement.
b) Availability with instruments.
c) Responsible for analytical method transfer for drug
substance and drug product.
Constitution of technology transfer team and their responsibilities Cont…
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TECHNOLOGY TRANSFER DOCUMENATION
1 Organization for Technology Transfer
2 Research and Development Report
3 Product Specification File
4 Technology Transfer Plan
5 Technology Transfer Report
6 Verification of Results of Technology Transfer
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TECHNOLOGY TRANSFER CHECKLIST
It consists of
• Production master formula
• Manufacturing instructions
• Dispensing instructions
• Analytical methods
• Previous process validation
• Previous analytical validation
• Cleaning instructions and previous cleaning validation
• Stability reports
• Excipients specifications and source
• Active specifications and source
• Primary packaging material specifications and source
• Packaging instructions
• Process deviations file, Analytical deviations file
• Reject and rework file
• Specimen manufacturing batch record. 34

PROBLEMS IN TECHNOLOGY TRANSFER
1. Problems during the technology justification and selection stage.
i. Wrong selection of technology based on misjudgment when preparing a business case
for a technology transfer project.
ii. Cost of buying, installing, operating and maintaining the technology is also high.
iii. The technology selected is also complex for easy understanding and assimilation of the
transferee.
iv. The technology needs extensive adaptation to suit local conditions.
2. Problems during the planning stage.
i.Transferor (seller) underestimates the problems in transferring the technology to a
developing country setting.
ii.Transferor does not fully understand transferee needs.
iii.Transferee managers are not involved in the planning which is carried out only by the
transferor.
iv.Too much attention is paid to the hardware to be purchased and not enough attention is
paid to skills and information acquisition.
v.Overestimation of the technological capabilities of the transferee by the transferor
thereby leading to unrealistic expectations on how well the transferee can meet target
dates.
vi.Poor market demand forecasting by the transferee of the outputs to be produced by
using the transferred technology.
vii.The objectives of the transferor and transferee are not compatible.
viii.Mechanisms chosen for implementing the transfer are not appropriate. 35

PROBLEMS IN TECHNOLOGY TRANSFER Cont…
3. Problems during negotiations.
i. Differences in negotiation approaches and strategies.
ii. Lack of trust between the transferor and transferee.
iii. Goal incompatibility during negotiations.
iv. Inability to reach agreements on pricing, product and marketing strategies.
v. Both parties try to achieve results in an unrealistically short period of time.
4. Problems during technology transfer implementation.
i.Shortage of experienced technology transfer managers.
ii.Lack of trust in transferor developed systems by the transferee.
iii.Inability to achieve quality targets.
iv.Delay in obtaining supplementary materials, from the local environment, needed
for quick implementation.
v. High cost and poor quality of locally available materials needed to implement the
technology transferred.
vi.Inadequate tracking of the technology during implementation.
vii.Cost overrun due to poor implementation.
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Success of Technology Transfer
Its depends on
• Communication
– Open communication between all team members
– Direct communication between technical members
– Effective and timely communication with regulators
• Sending and Receiving Unit
– Technology transfer is not a “one way street”
– The sending unit and receiving unit must be equally
involved in the process to ensure success
• Team work at all time
37

Technology Transfer of Test Methods
Test methods subject to technology transfer
include the following
• Test methods for drug substances
• Test methods for drug products
• Test methods for raw materials and components
• Test methods for in-process tests
• Test methods for drug residue tests
• Test methods for environmental tests
38

Technology Transfer Plan
• For technology transfer of test methods, it is required to clarify
validation range and acceptance criteria of conformity of
technology transfer regarding individual test methods to be
transferred.
• The validation range (e.g. full validations, reproducibility,
etc.) should be judged on the basis of results of evaluation of
technologies, facilities and equipments of transferred party,
and the range may be influenced by information to be
contained in the technology transfer documentation.
• To compare test results, samples (including dose range,
number of batches, etc.), specific test methods and evaluation
methods to be used in the transferring and transferred parties
should be specified.
39

Technical information to be described in or
attached to the technology transfer plan
Information of Raw Materials
 Summary including physical and chemical properties and stability
• Name and structural formula
• Stability data
 Specifications and test methods
• Specific test methods and specifications
• Change history of specifications and test methods and its
rationale
• Results of analytical validation
 List of reference standards (Test results should be attached.)
 Information of toxicity and stability for laboratory use
 List of subject samples for comparative evaluation and their test
results
40

Information of Drug Substances
Summary including physicochemical properties and
stability
• Name and structural formula
• Elucidation of chemical structure
• Possible isomers
• Physical and chemical properties (including
physicochemical properties)
• Stability data (including severe test data)
41

Batch records
• Chemical synthesis methods of subject batches
• Analytical data of batches
• Impurity profile of representative batch
42

Specifications and test methods
• Specific test methods and specifications (including
items related to efficacy such as particle size
distribution, polymorphism, crystallinity, and
hygroscopicity)
• Change history of specifications and test methods and
their rationales
• Results of analytical method validation
43

Information of Drug Products
􀂾 Summary including formula and stability
• Elucidation of dissolution profile
• Stability data (including severe test data)
• Storage conditions and expiry date (if established)
􀂾 Analytical data of batches
􀂾 Specifications and test methods
• Specific test methods and specifications (including items
related to efficacy such as particle size distribution and
hygroscopicity)
• Change history of specifications and test methods and its
rationale
• Results of analytical method validation
􀂾 List of reference standards (Test results should be attached.)
44

Information on Implementation of
Technology Transfer
􀂾 Persons in charge of planning, checking and settlement of technology transfer
􀂾 Test methods (test method number
􀂾 Objectives
􀂾 Persons in charge of transferring and transferred parties
􀂾 Training plan (including explanation of test methods and demonstration)
􀂾 Plan of comparative evaluation study
• Samples: Lot No. (including rationale for the number of lots), storage
condition during test, and handling after the completion of the test (disposal or
return to the transferred party, etc.)
• Test period
• Number of repeated tests
• Handling of data (Handling method)
• Retest and handling of outlier
• Acceptance criteria
• Storage of raw data (storage department, storage place, and duration,
45

Items Concerning Manufacturing Methods
• Information on manufacturing methods (synthetic
routes and purification methods)
• Information on operating conditions (control
parameters and acceptable range)
• Information on important processes and parameters
(identification of processes and parameters which will
affect quality)
• Information on in-process control
• Information on reprocess and rework (places and
methods)
46

Items Concerning Facilities and Equipments
• Information on equipment cleaning (cleaning
methods, cleaning solvents, and sampling methods)
• Information on facilities (selection of materials,
capacity, and equipment types, and necessity of
special equipments)
47

Items Concerning Test Methods and
Specifications
• Information on specifications and test methods of
drug substances, intermediates, and raw materials
(physical and chemical, microbiological, endotoxin
and physicochemical properties, etc.)
• Validations for test methods of drug substances and
intermediates
48

Problem in tablets are either related to
imperfections in any one or more of the
following during transfer of technology
I. Tableting Process
II. Excipient
III. Machine
49

PROCESS RELATED PROBLEMS :
• CAPPING: It is due to air-entrapment in the granular
material.
• LAMINATION: It is due to air-entrapment in the
granular material.
• CRACKING: It is due to rapid expansion of tablets
when deep concave punches are used.
50

EXCIPIENT RELATED PROBLEMS :
• CHIPPING: It is due to very dry granules.
• STICKING: It is due to excess moisture
present in the granules.
• PICKING: It is due to the improper drying of
the granules.
• BINDING: It is due to the excessive binder
present in the granules.
51

MACHINE RELATED PROBLEMS :
• DOUBLE IMPRESSION: It is due to free
rotation of the punches, which have some
engraving on the punch faces.
52

CAPPING:
Capping happened when the upper or lower segment
of the tablet separates horizontally, either partially or
completely from the main body of a tablet and comes
off as a cap, during ejection from the tablet press, or
during subsequent handling.
Reason: Capping is usually due to the air–
entrapment in a compact during compression, and
subsequent expansion of tablet on ejection of a tablet
from a die.
53

CAPPING RELATED TO ‘FORMULATION’
(GRANULATION)
Sr.No. CAUSES REMEDIES
1.
Large amount of fines in
the granulation
Remove some or all fines through 100 to 200
mesh screen
2.
Too dry or very low
moisture content (leading
to loss of proper binding
action).
Moisten the granules suitably. Add hygroscopic
substance e.g.: sorbitol, methyl- cellulose or PEG-
4000.
3.
Not thoroughly dried
granules.
Dry the granules properly.
4.
Insufficient amount of
binder or improper binder.
Increasing the mount of binder OR
Adding dry binder such as pre-gelatinized starch,
gum acacia, powdered sorbitol, PVP, hydrophilic
silica or powdered sugar.
5.
Insufficient or improper
lubricant.
Increase the amount of lubricant or change the
type of lubricant.
6.
Granular mass too cold to
compress firm.
Compress at room temperature.
54

CAPPING RELATED TO ‘MACHINE’ (DIES, PUNCHES
AND TABLET PRESS)
Sr.No CAUSES REMEDIES
1. Poorly finished dies
Polish dies properly. Investigate other
steels or other materials.
2.
Deep concave punches or
beveled-edge faces of punches.
Use flat punches.
3.
Lower punch remains below the
face of die during ejection.
Make proper setting of lower punch
during ejection.
4.
Incorrect adjustment of sweep-
off blade.
Adjust sweep-off blade correctly to
facilitate proper ejection.
5. High turret speed.
Reduce speed of turret (Increase
dwell time).
55

Lamination / Laminating
• Definition: ‘Lamination’ is the separation of a
tablet into two or more distinct horizontal
layers.
• Reason: Air–entrapment during compression
and subsequent release on ejection.
• The condition is exaggerated by higher speed
of turret.
56

LAMINATION RELATED TO FORMULATION (GRANULATION)
LAMINATION RELATED TO MACHINE (DIES, PUNCHES AND
TABLET PRESS)
Sr. No CAUSES REMEDIES
1.
Oily or waxy materials in
granules
Modify mixing process. Add
adsorbent or absorbent.
2.
Too much of hydrophobic
lubricant e.g.:
Magnesium-stearate.
Use a less amount of lubricant or
change the type of lubricant.
Sr. No. CAUSES REMEDIES
1.
Rapid relaxation of the
peripheral regions of a
tablet, on ejection from a die.
Use tapered dies, i.e. upper part of
the die bore has an outward taper
of 3° to 5°.
2. Rapid decompression
Use pre-compression step. Reduce
turret speed and reduce the final
compression pressure.
57

CHIPPING
• Definition: ‘Chipping’ is defined as the
breaking of tablet edges, while the tablet
leaves the press or during subsequent handling
and coating operations.
• Reason: Incorrect machine settings, specially
mis-set ejection take-off.
58

CHIPPING RELATED TO FORMULATION (GRANULATION)
CHIPPING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)
1. Sticking on punch faces
Dry the granules properly or
increase lubrication.
2. Too dry granules.
Moisten the granules to plasticize.
Add hygroscopic substances.
3.
Too much binding causes chipping at
bottom.
Optimize binding, or use dry
binders.
1.
Groove of die worn at compression
point.
Polish to open end, reverse or
replace the die.
2.
Barreled die (center of the die wider
than ends)
Polish the die to make it
cylindrical
3.
Edge of punch face turned
inside/inward.
Polish the punch edges
4.
Concavity too deep to compress
properly.
Reduce concavity of punch faces.
Use flat punches. 59

MOTTLING
• Definition: ‘Mottling’ is the term used to
describe an unequal distribution of colour on a
tablet, with light or dark spots standing out in
an otherwise uniform surface.
• Reason: One cause of mottling may be a
coloured drug, whose colour differs from the
colour of excipients used for granulation of a
tablet.
60

CAUSES AND REMEDIES OF MOTTLING:
Sr.No. CAUSES REMEDIES
1.
A coloured drug used
along with colourless or
white-coloured
excipients.
Use appropriate colourants.
2.
A dye migrates to the
surface of granulation
while drying.
Change the solvent system,
Change the binder,
Reduce drying temperature and
Use a smaller particle size.
3.
Improperly mixed dye,
especially during
‘Direct Compression’.
Mix properly and reduce size if it is of a larger
size to prevent segregation.
4.
Improper mixing of a
coloured binder
solution.
Incorporate dry colour additive during powder
blending step, then add fine powdered
adhesives such as acacia and tragacanth and
mix well and finally add granulating liquid.
61

Double impression Double impression
• Definition: ‘Double Impression’ involves only those
punches, which have a monogram or other engraving
on them.
• Reason: At the moment of compression, the tablet
receives the imprint of the punch. Now, on some
machines, the lower punch freely drops and travels
uncontrolled for a short distance before riding up the
ejection cam to push the tablet out of the die, now
during this free travel, the punch rotates and at this
point, the punch may make a new impression on the
bottom of the tablet, resulting in ‘Double
Impression’.
• If the upper punch is uncontrolled, it can rotate during
the short travel to the final compression stage and
create a double impression. 62

CAUSES AND REMEDIES OF DOUBLE
IMPRESSION:
Sr. No. CAUSE REMEDIES
1.
Free rotation of either
upper punch or lower
punch during ejection of
a tablet.
-Use keying in tooling, i.e. inset a key
alongside of the punch, so that it fits the
punch and
prevents punch rotation.
-Newer presses have anti-turning devices,
which prevent punch rotation.
63

1. Encylopedia of Pharmaceutical Technology : James Swarbrick ,
James C Boylan : Volume 1, 3rd
edition : Technology Transfer
Considerations for Pharmaceuticals – Page No: 3717- 3725.
2. Encyclopedia of Pharmaceutical Technology DOI: 10.1081/E-EPT-
100200043
3. Ira R. Berry, “Technology Transfer Consideration for
Pharmaceuticals”, Encyclopedia of Pharmaceutical Technology,
Third Edition, 02 october 2006, pp. no. 20-30.
4. http://www.gdrc.org/uem/techtran.html
5. Luis Alberto del Río, Salazar N., and Trives C.“Guidelines for a
pharmaceutical technology transfer towards a drug manufacturing
plant”, Comunicaciones técnicas, Bol. Soc. Quím. Méx. 2007, 1(1),
pp no. 27-31
6. http://bud.tic.ab.ca/venquest/yqt_home.htm
References
64

Technology Transfer in Pharma Industry

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