logical procedure that controls the transfer of any process together with its documentation and professional expertise between developments or between manufacture sites.

1. 1
A SEMINAR REPORT SUBMITTED ON
“TECHNOLOGY TRANSFER FROM R&D TO PILOT PLANT
TO PLANT FOR LIQUID ORALS”
Submitted in partial fulfillment of the requirements of
Master of Pharmacy (SEM-I)
In
PHARMACEUTICS
In the faculty of science and technology
Savitribai Phule Pune university, Pune.
Submitted by
Mr. Ashish Dilip Sutar
Roll no. 14
Guided by
Mrs. Dyandevi M. Mathure
Assistant Professor, Dept. of Pharmaceutics.
S.T.E.S.’S
SMT. KASHIBAI NAVALE COLLEGE OF PHARMACY,
KONDHWA (BK), PUNE- 411048
APRIL 2021

2. 2
INDEX
Sr.no. Content Page no.
1 Introduction 3
2 Importance and reason of technology transfer 11
3 Documentation involved in technology transfer 12
4 SUPAC guidelines 15
5 Scale up consideration of liquid oral dosage form 19
6 Case study 26
7 Conclusion 28
8 References 29

3. 3
1. Introduction
Technology transfer: In Industry, “Technology Transfer” refers to a method of victorious
steps forward from drug development to product development, clinical trials and at last to
largescale commercialization [1]
.
Plant: It is a place where the 5 M’s like money, material, man, method and machine are brought
together for the manufacturing of the products[1]
.
Pilot plant: It is the part of the pharmaceutical industry where a lab scale formula is
transformed into a viable product by development of liable and practical procedure of
manufacture[1]
.
Scale up: The art for designing of prototype using the data obtained from the pilot plant
model[1]
.
1.1 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
developments or between manufacture sites.”[2]
• Technology transfer is both integral and critical to the drug discovery and development
process for new medical products[2]
.
• 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 by an
original innovator of technology makes it technology available to commercial partner
that will exploit the technology[2]
.
• 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[2]
.
• Technology transfer is important for such researcher to materialize on a larger scale for
commercialization especially in the case of developing product. Technology transfer
includes not only patentable aspects of production but also includes the business
processes such as knowledge and skills[2]
.
Technology transfer is transferring of details of concerning formulation and analytical
strategies from one area to another area that’s from R&D to Production department and
succeeding drug product from the laboratory scale to the production scale. In Pharmaceutical
Industry, “Technology Transfer” refers to a method of victorious steps forward from drug
discovery to product development, clinical trials and at last to full-scale commercialization.
Researcher of technology creates his technology existing to a commercial collaborator which
will make use of the technology. It’s an organized procedure that’s followed to pass the
Research and development
Pilot plant
Production (plant)

4. 4
documented information and know-how knowledge gained throughout development.
According to WHO outlined as a logical procedure that controls the transfer of any method
alongside its documentation and professional expertise between development and manufacture
or b/w manufacturer site. It is useful to build up dosage form in various ways because it
provides efficiency in development, maintains quality of product, helps to realize a
standardized process that facilitates price-effective production[3-8]
.
There are 3 standards in the definition of technology:
• First, knowledge must be systematic. This means that it must be organized in terms of
providing solutions to problems[3-8]
.
• Second, knowledge must exist in certain places like in someone’s head or documents
and must be able to be presented, so no matter what it means it must be able to be
transferred from one person to another[3-8]
.
• Third, it must have purpose-orientation, so that it can be utilized for useful purposes
in industry, farming, and commercial fields[3-8]
.
1.2 There are two sorts of technology transfer processes [9]
:
• Vertical
• Horizontal
Vertical technology transfer refers to the transfer of data from basic study to development and
production respectively. Horizontal technology transfer refers to the movement and application
of technology is to be used in one place or context to a different place. Commercial technology
transfer is mutually agreed, and goal destined. The achievement of any specific technology
transfer depends upon method understanding or the flexibility to predict exactly the long term
performance of a process[4]
.
Designing drug product ® Developing ® drug product ® Technology transfer ®
manufacturing site
1.3 These guiding principles on transfer of technology are intended to serve as a
framework which can be applied in a flexible manner rather than as strict rigid guidance.
Focus has been placed on the quality aspects, in line with WHO’s mandate[10]
.
A. Transfer of processes to an alternative site occurs at some stage in the life-cycle of most
products, from development, scale-up, manufacturing, production and launch, to the post-
approval phase[10]
.
B. 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”. 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.
Technology transfer embodies both the transfer of documentation and the demonstrated
ability of the receiving unit (RU) to effectively perform the critical elements of the
transferred technology, to the satisfaction of all parties and any applicable regulatory
bodies[10]
.

5. 5
C. Literature searches revealed little information on the subject originating from national or
regional regulatory bodies. Guidance on intracompany transfers was prepared by the
International Society for Pharmaceutical Engineering (ISPE) [10]
.
D. The ever changing business strategies of pharmaceutical companies increasingly involve
intra- and intercompany transfers of technology for reasons such as the need for additional
capacity, relocation of operations or consolidations and mergers. The WHO Expert
Committee on Specifications for Pharmaceutical Preparations, therefore, recommended in
its forty- second report that WHO address this issue through preparation of WHO
guidelines on this matter[10]
.
E. Transfer of technology requires a documented, planned approach using trained and
knowledgeable personnel working within a quality system, with documentation of data
covering all aspects of development, production and quality control. Usually there is a
sending unit (SU), a receiving unit and the unit managing the process, which may or may
not be a separate entity. For “contract manufacturing” please see good manufacturing
practices (GMP) [10]
.
F. For the transfer to be successful, the following general principles and requirements should
be met[10]
:
• The project plan should encompass the quality aspects of the project and be based upon
the principles of quality risk management;
• The capabilities of the SU and at the RU should be similar, but not necessarily identical,
and facilities and equipment should operate according to similar operating principles;
• A comprehensive technical gap analysis between the SU and RU including technical
risk assessment and potential regulatory gaps, should be performed as needed;
• adequately trained staff should be available or should be trained at the RU:
• regulatory requirements in the countries of the SU and the RU, and in any countries
where the product is intended to be supplied, should be taken into account and
interpreted consistently throughout any transfer programme project; and there should
be effective process and product knowledge transfer.
G. Technology transfer can be considered successful if there is documented evidence that the
RU can routinely reproduce the transferred product, process or method against a predefined
set of specifications as agreed with the SU[10]
.
H. In the event that the RU identifies particular problems with the process during the transfer,
the RU should communicate them back to the SU to ensure continuing knowledge
management[10]
.
I. Technology transfer projects, particularly those between different companies, have legal
and economic implications. If such issues, which may include intellectual property rights,
royalties, pricing, conflict of interest and confidentiality, are expected to impact on open
communication of technical matters in any way, they should be addressed before and during
planning and execution of the transfer[10]
.
J. Any lack of transparency may lead to ineffective transfer of technology[10]
.
K. Some of the principles outlined in this document may also be applicable to manufacturing
investigational pharmaceutical products for clinical trials as part of research and
development, but this is not the main focus of this guidance and has been excluded due to
the complexity of the processes[10]
.
L. Some of the responsibilities outlined in this document for the SU may also be considered
to be part of the management unit responsibilities[10]
.

6. 6
1.4 Facets of Technology Transfer: The technology transfer could happen any of these
following ways[3,11]
:
• Government labs to the private sector
• Between the private sector firms of the same country
• From academia to private sector firms
• Academia, government, and industry collaborations.
Government Labs to Private Sector: This type of technology transfer is advantageous as the
government 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 the 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 another
sector that absorbs the technology
From Academia to Private Sector: 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, money can be saved.
Between Academy, Private and Government Sectors: In this type of technology transfer
government provides necessary funds to the academic institutions in developing technology
that can be transferred to the industry.
1.5 Steps in Technology Transfer Process[12,13,14]
Technology Transfer is not a single way process. The development of new formulation goes
through many stages. During development of a formulation, it is important to understand
procedure of operations used, critical and noncritical 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.
Appropriate care during technology transfer is important to enhance drug quality as developed
by R&D in final formulation as well as to assure quality for predetermined period of time. The
processes are classified into the three categories:
• Research phase,
• Development Phase
• Production Phase.

7. 7
1.5.1 Research Phase (Development of Technology by R&D) [12,13,14]
:
• Design and Choice of Excipients by R&D: choice of materials and design of procedures
are carried out by R&D on the premise of innovator product characteristics. For this
completely different tests and compatibility, studies are performed.
• Identification of Specifications and Quality by R&D: Quality of product ought to meet
the specifications of an innovator product. For this stability, studies are carried out for
innovator product and for product that is to be manufactured.
1.5.2 Technology Transfer from R & D to Production (Development Phase) [12,13,14]
:
R&D provides technology transfer dossier (TTD) document to a product development
laboratory that contains all data of formulation and drug product as given below:
• Master Formula Card (MFC): It includes product name along with its strength,
• The generic name, MFC number, page number, effective date, shelf life, and market.
• Master Packaging Card: It provides data regarding packaging sort, the material used for
packaging, stability profile of packaging and shelf life of packaging.
• Master Formula: It describes formulation order and manufacturing instructions.
Formulation order and Manufacturing Instructions offer the plan of process order,
surroundings conditions needed and manufacturing instructions for the development of
dosage form.
• 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.
Quality
control and
assurance
Product development
and laboratory
Production and
commercialization
Research and
development
Analytical
development and
validation
Figure no. 1 Representation Of Technology Transfer

8. 8
1.5.3 Production Phase[12,13,14]
Validation & Production- Production is implemented after various validation studies verify
that it is able to stably product based on transferred manufacturing formula.
While the manufacturing facility accepting technology is responsible for validation, the
research and development department transferring technology should take responsibility for
validation such as performance qualification; PQ, cleaning validation, and process validation;
PV unique to subject drugs.
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 these things in mind that their segment of the production process running smoothly if
technology transfer is implemented thoughtfully. Effective technology transfer helps to provide
process efficiency and maintain product quality.
Feedback from Production and Technology Transfer of Marketed Product
• To accumulate technical information obtained from repeated production.
• The information of modify various standards.
• The improvement of process and products.
• The changes of specifications and methods.
• The technical information of reviewed and updated at regular intervals.
• Establish of adequate Feedback system.
Exhibit Batches[12,13,14]
:
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’s and their processes. This is
done for filling purpose in regulatory agencies. The Purpose behind to run three consecutive
batches are to shows process consistency, reproducibility and to demonstrate that the
manufacturing process is under control throughout all the stages.

9. 9
1.6 Flow Chart of Technology Transfer in the Pharmaceutical Industry[15]
:
Technology developer
¯
Technology receiving site
¯
Feasibility studies
¯
Scale up
¯
Exhibit batch
¯
Stability studies
¯
Process validation batches
¯
Production batches
1.7 Project team[16]
:
Any transfer project will be managed by a team comprising members with clearly defined key
responsibilities. The team should be drawn from members of relevant disciplines from both the
SU and RU sites.
The team members should have the necessary qualifications and experience to manage their
particular aspect of the transfer.
1.7.1 Technology Transfer Team[16]
:
As the team concept is always the best approach to achieve successful technology transfer
projects. The core technology transfer team must be commissioned immediately following the
decisions of the executive management to pursue the drug candidate to commercialization. A
typical technology transfer core team will likely be comprised of individual’s representatives
of the different segments of the business. The technology transfer team consists of the
following members, and their responsibilities are given below:

10. 10
Technology transfer team and their responsibilities[16,17]
:
TECHNOLOGY
Transfer Team
Members
RESPONSIBILITIES
Process Technologist • Central focus for transfer activities.
• Collates documentation from the donor site
• Performs initial assessment of the transferred project for
Feasibleness, Compatibility with site capabilities and Establishes
resource needs.
QA Representative • Reviews documentation to work out compliance with marketing
authorization (MA)
• Reviews analytical strategies with QC to work out capability,
instrumentation training requirements.
• Initiates conversion of donor site documentation into local systems
or format.
• Initiates or confirms regulatory needs, e.g., an amendment to
manufacturing license; variations to MA if method changes needed,
etc.
Production
Representative
• Reviews process instructions (with process technologist) to verify
capacity and capability.
• Considers any safety implications, e.g., solvents; toxic; sanitizing
materials.
• Considers the impact on local standard operating procedures
(SOPs).
• Considers the training requirements of supervisors or operators.
Engineering
Representative
• Reviews (with production representative) instrumentation
requirement.
• Initiates required engineering modifications, change or part
purchase.
• Reviews preventative maintenance and calibration impact, e.g., use
of a lot of aggressive ingredients; more temperature-sensitive
method, and modifies consequently.
QC Representative • Reviews analytical requirement.
• Availability with instruments.
• Responsible for analytical technique transfer for drug substance and
drug product.

11. 11
2. Importance and reason of technology transfer
2.1 Reason for technology transfer[18]
• Due to 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. the developer of
the technology could solely have to produce instrumentation that appropriates for lab and
small scale operations and should partner with another organization to try to do massive
scale manufacturing.
• Due to lack of marketing distribution and distribution capability- The developer of the
technology could have absolutely developed technology and even have obtained
regulative approvals and product registration, but it may not have the marketing and
distribution channels and should collaborate within another organization that has the
capability.
• Due to lack of resources to launch product commercially- The original inventor of
technology may only have resources to conduct early stages research and phase - I and II
clinical trials.
• Forming alliances with partner.
• Forming alliances with partners with marketing and distribution capability.
• 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.
• Avoidance of the problems associated with the scale-up[2]
.
• Production and process controls guidelines preparation[2]
.
• To identify the critical features of the process[2]
.
• Preparation and providing of Master Manufacturing Formula for manufacturing[2]
.
• Evaluation and Validation for process and equipment[2]
.
• Examination of the formula to assess the batch stability[2]
.
2.2 Importance of technology transfer[19]
• 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.

12. 12
3. Documentation involved in technology transfer
Technology transfer document demonstrates the contents of technology transfer from
transferring and transferred parties. Each step from research and development to production
should be documented, task assignments and responsibilities ought to be processed and
acceptance criteria for completion of technology transfer regarding individual technology to be
transferred. Its duty of the Quality Assurance department to examine and approve the
documentation for all processes of technology transfer[2,3]
.
R&D provides technology transfer dossier; TTD document to product development laboratory;
PDL, which contains all information of formulation and drug product as given below[2,3]
:
• Master formula card; MFC: It includes product name along with its strength,
generic name, MFC number, page number, effective date, shelf life and market.
• Master packaging card: It gives information about packaging type, material used
for packaging, stability profile of packaging and shelf life of packaging.
• Master formula: It describes formulation order and manufacturing instructions.
Formulation order and Manufacturing Instructions gives idea of process order,
environment conditions required and manufacturing instructions for dosage form
development.
• Specifications and standard test procedure; STPs: It helps to know active
ingredients and excipients profile, in- process parameters and specifications,
product release specification and finished product details.
Development Report[2,3]
: It is used at the pre- approval examination as a valid document for
quality design of new drug. The ultimate goal for successful technology transfer is to possess
documented evidence. The R&D report may be a file of technical development, and also the
research and development department is accountable for its documentation. This report is a
crucial file to point rationale for the quality design of drug substances and drug specifications
and test methods. Additionally, this report can be used as raw data just in case of post-marketing
technology transfer. The development report contains the following:
• Data of pharmaceutical development of new drug substances and drug products at
stages from the early development phase to final application of approval.
• Data for raw materials and components
• Rational for the dosage form and formula designs and design of manufacturing
ways. modification in histories of vital processes and control parameters
• Stability profile, specifications and test methods of drug substances, intermediates,
drug products, raw materials, and components, which also include the 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.
Technology Transfer Plan[2,3]
: The technology transfer plan describes the things and contents
of technology to be transferred and elaborate procedures of individual transfer and transfer
schedule, and to determine judgment criteria for the completion of the transfer. The transferring
party ought to prepare the plan before the implementation of the transfer and reach an
agreement on its contents with the transferred party.

13. 13
Report[3]
: Report completion of technology transfer is to be created once information is taken
consequently to the plan and are evaluated to substantiate that the planned judgment criteria
are met. Both transferring and transferred parties will document the technology transfer report;
but, they must reach an agreement on its contents.
Exhibit[3]
: After taking a scale-up batch of the product, manufacturing of exhibit batches take
place. In case of exhibit, batch sizes are increased along with equipment, and their process is
involved. They are done for filing purposes in different regulatory agencies.
The documentation required for the transfer project itself is wide- ranging. Examples of
documentation commonly required are summarized in Table
The documented evidence that the transfer of technology has been considered successful
should be formalized and stated in a technology transfer summary report. That report should
summarize the scope of the transfer, the critical parameters as obtained in the SU and RU
(preferably in a tabulated format) and the final conclusions of the transfer. Possible
discrepancies should be listed and appropriate actions, where needed, taken to resolve them.

14. 14

15. 15
4. SUPAC guidelines
4.1 PURPOSE OF GUIDANCE[20]
This guidance provides recommendations to sponsors of new drug applications (NDA's),
abbreviated new drug applications (ANDA's), and abbreviated antibiotic applications
(AADA's) who intend, during the post approval period, to change: 1) the components or
composition; 2) the site of manufacture; 3) the scale-up/scale-down of manufacture; and/or 4)
the manufacturing (process and equipment) of an immediate release oral formulation.
The guidance defines: 1) levels of change; 2) recommended chemistry, manufacturing, and
controls tests for each level of change; 3) in vitro dissolution tests and/or in vivo bioequivalence
tests for each level of change; and 4) documentation that should support the change. For those
changes filed in a ―changes being effected supplementǁ [21 CFR 314.70(c)], the FDA may,
after a review of the supplemental information, decide that the changes are not approvable.
This guidance thus sets forth application information that should be provided to CDER to
assure continuing product quality and performance characteristics of an immediate release solid
oral dose formulation for specified post approval changes.
4.2 DEFINITION OF TERMS[20]
Batch- A specific quantity of a drug or other material produced according to a single
manufacturing order during the same cycle of manufacture and intended to have uniform
character and quality, within specified limits [21CFR 210.3(b)(2)]. Contiguous Campus
Continuous or unbroken site or a set of buildings in adjacent city blocks.
Dissolution Testing
• Case A: Dissolution of Q = 85% in 15 minutes in 900 millilitres (mL) of 0.1N
hydrochloride (HCl), using the United States Pharmacopeia (USP) <711> Apparatus 1
at 100 revolutions per minute (rpm) or Apparatus 2 at 50 rpm.
• Case B: Multi-point dissolution profile in the application/compendia medium at 15, 30,
45, 60, and 120 minutes or until an asymptote is reached for the proposed and currently
accepted formulation.
• Case C: Multi-point dissolution profiles performed in water, 0.1N HCl, and USP buffer
media at pH 4.5, 6.5, and 7.5 (five separate profiles) for the proposed and currently
accepted formulations. Adequate sampling should be performed at 15, 30, 45, 60, and
120 minutes until either 90% of drug from the drug product is dissolved or an asymptote
is reached. A surfactant may be used with appropriate justification.
Drug Product- A drug product is a finished dosage form (e.g., tablet, capsule, or solution) that
contains a drug substance, generally, but not necessarily, in association with one or more other
ingredients [21 CFR 314.3(b)]. A solid oral dosage form includes tablets, chewable tablets,
capsules, and soft gelatin capsules.
Drug Substance- An active ingredient that is intended to furnish pharmacological activity or
other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or to
affect the structure of any function of the human body, but does not include intermediates used
in the synthesis of such ingredient [21 CFR 314.3(b)].

16. 16
Equipment- Automated or non-automated, mechanical or non-mechanical equipment used to
produce the drug product, including equipment used to package the drug product.
Formulation- A listing of the ingredients and composition of the dosage form.
Justification- Reports containing scientific data and expert professional judgment to
substantiate decisions.
New Drug Substance- Any substance that, when used in the manufacture, processing, or
packing of a drug, causes that drug to be a new drug, but does not include intermediates used
in the synthesis of such substance [21 CFR310.3(g)].
Operating Principle- Rules or concepts governing the operation of the system.
Pilot Scale- The manufacture of either drug substance or drug product by a procedure fully
representative of and simulating that used for full manufacturing scale. For solid oral dosage
forms this is generally taken to be, at a minimum, one-tenth that of full production, or 100,000
tablets or capsules, whichever is larger
Process- A series of operations and/or actions used to produce a desired result.
Ranges - The extent to which or the limits between which acceptable variation exists.
Same - Agreeing in kind, amount; unchanged in character or condition.
Scale-up - The process of increasing the batch size.
Scale-down - The process of decreasing the batch size.
Similar - Having a general likeness.
Significant body of information - A significant body of information on the stability of the
drug product is likely to exist after five years of commercial experience for new molecular
entities, or three years of commercial experience for new dosage forms.
Validation- Establishing through documented evidence a high degree of assurance that a
specific process will consistently produce a product that meets its predetermined specifications
and quality attributes. A validated manufacturing process is one that has been proven to do
what it purports or is represented to do. The proof of validation is obtained through collection
and evaluation of data, preferably beginning from the process development phase and
continuing through the production phase. Validation necessarily includes process qualification
(the qualification of materials, equipment, systems, buildings, and personnel), but it also
includes the control of the entire processes for repeated batches or runs.
I. Site Changes
Site changes consist of changes in location of the site of manufacture for both company- owned
and contract manufacturing facilities and do not include any scale-up changes, changes in

17. 17
manufacturing (including process and/or equipment), or changes in components or
composition. Scale-up is addressed in Section V of this guidance. New manufacturing locations
should have a satisfactory current Good Manufacturing Practice (CGMP) inspection.
A. Level 1 Changes Definition: Level 1 changes consist of site changes within a single facility
where the same equipment, standard operating procedures (SOP's), environmental conditions
(e.g., temperature and humidity) and controls, and personnel common to both manufacturing
sites are used, and where no changes are made to the manufacturing batch records, except for
administrative information and the location of the facility. Common is defined as employees
already working on the campus who have suitable experience with the manufacturing process.
B. Level 2 Changes Definition: Level 2 changes consist of site changes within a contiguous
campus, or between facilities in adjacent city blocks, where the same equipment, SOP's,
environmental conditions (e.g., temperature and humidity) and controls, and personnel
common to both manufacturing sites are used, and where no changes are made to the
manufacturing batch records, except for administrative information and the location of the
facility.
C. Level 3 Changes Definition: Level 3 changes consist of a change in manufacturing site to
a different campus. A different campus is defined as one that is not on the same original
contiguous site or where the facilities are not in adjacent city blocks. To qualify as a Level 3
change, the same equipment, SOP's, environmental conditions, and controls should be used in
the manufacturing process at the new site, and no changes may be made to the manufacturing
batch records except for administrative information, location and language translation, where
needed.
II. Changes in Batch Size (Scale-Up/Scale- Down)
Post-approval changes in the size of a batch from the pivotal/pilot scale bio batch material to
larger or smaller production batches call for submission of additional information in the
application. Scale-down below 100,000 dosage units is not covered by this guidance. All scale-
up changes should be properly validated and, where needed, inspected by appropriate agency
personnel.
A. Level 1 Changes Definition of Level: Change in batch size, up to and including a factor
of 10 times the size of the pilot/bio batch, where:
1) The equipment used to produce the test batch is of the same design and operating principles;
2) The batch is manufactured in full compliance with CGMP's;
3) The same standard operating procedures (SOP's) and controls, as well as the same
formulation and manufacturing procedures, are used on the test batch and on the full-scale
production batch.
B. Level 2 Changes Definition of Level Changes in batch size beyond a factor of ten times
the size of the pilot/bio batch, where:
1) The equipment used to produce the test batch is of the same design and operating principles;

18. 18
2) The batch is manufactured in full compliance with CGMP'S; and
3) The same SOP's and controls as well as the same formulation and manufacturing procedures
are used on the test batch and on the full-scale production batch.
III. Manufacturing
Manufacturing changes may affect both equipment used in the manufacturing process and the
process itself.
A. Equipment
1. Level 1 Changes
a. Definition of Change This category consists of:
1) Change from non-automated or non- mechanical equipment to automated or mechanical
equipment to move ingredients; and
2) Change to alternative equipment of the same design and operating principles of the same or
of a different capacity.
2. Level 2 Changes
a. Definition of Level Change in equipment to a different design and different operating
principles.
B. Process
1. Level 1 Changes
a. Definition of Level This category includes process changes including changes such as
mixing times and operating speeds within application/validation ranges.
2. Level 2 Changes
a. Definition of Level This category includes process changes including changes such as
mixing times and operating speeds outside of application/validation ranges.

19. 19
5. Scale up consideration of liquid oral dosage form
The physical form of a drug product that can be incorporated demonstrates Newtonian or
Pseudoplastic flow behaviour. It conforms to its container at room temperature. Liquid dosage
forms may be dispersed systems or solutions. In dispersed systems there are two or more
phases, where one phase is distributed in another. A solution refers to two or more substances
mixed homogeneously[1]
.
5.1 Steps of liquid manufacturing process[1]
:
• Planning of material requirements.
• Liquid preparation.
• Filling and Packing.
• Quality assurance.
5.2 Critical aspects of liquid manufacturing
• Physical Plant.
• Heating, ventilation and air controlling system.
The effect of long processing times at suboptimal temperatures should be considered in terms
of consequences on the physical or chemical stability of ingredients as well as product.
Solution:
• Impeller diameter.
• Tank size (diameter).
• Number of impellers.
• Impeller type.
• Mixing capability of impeller.
• Rotational speed of the impeller.
• Height of the filled volume in the tank.
• Number of baffles.
Figure no.2[25]

20. 20
• Transfer system.
• Clearance between Impeller Blades and wall of the mixing tank.
• Filtration equipment (should remove desired materials but should not remove active
or adjuvant ingredients).
• Passivation of Stainless Steel (Pre-reacting the SS with acetic acid or nitric acid
solution to remove. the surface alkalinity of the Stainless Steel).
Suspension[1]
: The parameters to be considered are for scale up of suspension are;
• Versator (To avoid air entrapment).
• Wetting of suspending agent.
• Addition and dispersion of suspending agents.
• Selection of the equipment according to batch size.
• Time and temperature required for hydration of the suspending agent.
• Mixing speeds (High speed should not be used as it leads to air entrapment).
• Mesh size (Must be able to remove the foreign particulates and sieve selected based on
production batch size trials).
Emulsion[1]
: The parameters to be considered are for scale up of emulsion are;
• Homogenizing equipment.
• Temperature.
• Mixing equipment.
• Phase densities.
• In-process or final product filters.
• Phase volumes.
• Screens, pumps and filling equipment.
• Phase viscosities.
Impeller[21]
- mixing device are technically called as impellers. Impellers are classified on the
basis of the shape and pitch of the blades that are attached to the central shaft. Three main types
are used namely propellers, turbines and paddles.
Propellers-
Propellers may be either right or left handed, depending on the direction of slant of their blade
Four bladed or toothed or similar design propellers are used for special purposes. In a deep
tank, push-pull propeller is used in which two or more propellers may be attached to the same
shaft. These work in opposite directions to create a zone of
high Turbulence, the size of the propeller is small, i.e., the ratio of diameters between propeller
and container of 20 is sufficient for low viscous ds. However. for large tanks the maximum
size of 0.5 metres upetter is used. Small propellers turn at full motor speed up to 8000
revolutions per minute. The propeller produces axial (longitudinal) movement of the liquid.
The flow currents leaving the propeller continue through the liquid in a given direction until
deflected by the floor or wall of the tank.
Uses : Propellers are used when high mixing capacity is needed. These are effective in handling
liquids having a maximum viscosity of about 2 pascals seconds and slurries up to 10% solids
of fine mesh size. They can be used upto 3.5 metre cube (or 3500 litres). Effective gas liquid

21. 21
dispersion is possible at the laboratory scale. Multivitamin elixir, disinfectant solutions are
manufactured using propellers.
Turbines-
A turbine consists of a circular disc to which a number of short blades are attached . The
diameter of the turbine ranges from 30-50 percent of the diameter of the vessel. It rotates at a
lower speed than propeller (50-200 revolutions per minute). Different forms of turbines are
shown in Figure. The blades may be straight, curved, pitched or vertical.
Uses- Turbines are effective for, high viscous solutions with a very wide range of viscosities
upto 700 pascal-seconds. A few examples are syrups, liquid paraffin, glycerine etc. In low
viscosity materials of large volumes, turbines generate strong currents (intense shear) which
spread throughout the tank destroying stagnant pockets. They can handle slurries with 60%
solids. Turbines are suitable for liquids .of large volume and high viscosity, if the tank is
baffled.
Figure no.3[24]
Figure no.4[24]

22. 22
Paddles-
Paddles with two blades or four blades are common. Sometimes, the blades are pitched. In
some paddles, the blades are dished or hemi spherical in shape and have a large surface area in
relation to the tank in which they are used. Because of this shape, paddles pass close to the tank
walls and effectively mix viscous liquids, avoiding dead spots and deposited solids.
Uses- Paddles are used in the manufacture of antacid suspensions (aluminium hydroxide gel
and magnesium hydroxide), agar and pectin related purgatives, antidiarrheal mixtures such as
bismuth-kaolin.
Height of filled tank[21]
-
Substances in tank for mixing is filled in controlled manner so they can not spilled out while
mixing. Marking should be done for amount of filling in tank to overcome problems like spill
out of the solution and formulation of dead spots.
Tank size, material[21]
-
Tank size is selected as per the batch size if we need large quantity we can select big size tank.
Size depend on condition like material of tank should be inert to solution and drug product.
Material used is stainless steel or glass linted tank
Transfer system[21]
-
New batches should not be started until complete transfer of each tank is done. Complete
emptying of tank is important.
Figure no.5[24]

23. 23
Versator and deaerator[21]
-
During operation the versator chamber is under high vacuum disc is rotating and air, foam, gas
removed from the liquid through vacuum pump exhaust. Deaerator remove air by vacuum
exhaust and thermal method.
Wetting agent and suspending agent[21]
-
Wetting agent are added to facilitate connection between API and vehicle. Suspending agent
or flocculating agent are added to maintain appearance of suspension.
Ingredients like buffering system, polymers, antioxidants are added to protect API and
sweeteners and flavouring agent are added to mask the unpleasant smell. And order of addition
is followed as per master formula.
Selection of equipment[21]
-
Small units of mixers are also available they are chosen according to batch size.
Homogenizing equipment[21]
-
It work by applying high shear force and formation of high turbulence. It force liquid to pass
through the pores on head of homogenizer and reduction of size. We can choose homogenizer
as per the batch size.
Figure no.6[23]
Figure no.7[23]
Figure no.8[24]

24. 24
Temperature[21]
-
Temperature can affect emulsion stability significantly. Temperature affects the physical
properties of oil, water, interfacial films. This in turn affect the stability of the emulsion and
the most important effect of temperature is on viscosity of emulsion because viscosity decrease
with increase in temperature.
Phase volume[21]
-
To maintain phase volume ratio is also important because as volume of dispersed phase
increase stability of emulsion will decrease. And there may be chances of phase inversion can
occur.
Mixing equipment[21]
-
In this mixing is done by production of intense shearing and turbulence . there are various size
of mixers available form millilitres to several thousand litters.
Time gap[21]
-
It is important to maintain time gap between two successive batches because we cannot start
new batch without complete cleaning of system. All the tank, pipelines are rinsed with water
before start of new batch.
Production rate[21]
-
Production rate depend on market sale of the product. If there is high requirement we can
increase the production rate.
Space requirement[21]
-
It is main consideration because for tanks and mixer we require more space than solid
manufacturing plant.
Figure no.9[24]

25. 25
Filtration equipment[21]
-
Filtration is essential step in the production of liquid oral for obtaining clear solution. For
filtration meta filters are used. Choice of filters done as per the size of batch and viscosity of
product. For syrup we can use meta filter it functions as strainer for separation of particles in
this methods metals rings contains semi-circular projection which are arranged as a nest to
form channels this channels resist flow of solid particle.
Filling equipment[21]
-
There are three type of equipment:
• Volumetric-specific volume is filled
• Gravimetric- specific weight is filled
• Constant volume
For large scale production there are multiple station filling machines are available.
Figure no.10[24]
Figure no.11[24]

26. 26
6. Case study
Production of cough mixture and pharmaceutical syrup-
Traditional cough mixture are formulated around a syrup at 60-75% concentration which is
made from sucrose, maltodextrin, glucose, invert syrup, etc[22]
.
The reminder is made up of thickening agent, stabilizers and active ingredients.
The Process
Manufacturers of cough mixtures generally produce their own syrups as this offers greater
control of product quality. The manufacturing process must achieve several functions[22]
:
• Dissolving of the sugars to form a syrup.
• Hydration of powdered ingredients.
• Blending ingredients of widely different viscosity.
• Suspension or dissolving of active ingredients.
• The end product must be smooth, agglomerate-free and homogeneous.
• Equipment should conform to GMP standard
The Problem using conventional mixers and agitators for this process leads to several
potential problems:
• Conventional agitators cannot dissolve high concentrations of sugars at ambient
temperature.
• Heating of the mixture will be required to aid solution. This is energy inefficient.
• The cooling process after this further adds to costs and process time.
• Crystallization of the syrup can occur during heating/cooling.
• Active ingredients can be damaged by heat.
• Thickening ingredients will form agglomerates which conventional equipment cannot
disperse the Solution
These problems can be overcome by using a Silverson High Shear mixer. The 3 stage mixing
cycle illustrated below allows the sugars and active ingredients to be dissolved at ambient
temperatures[22]
.
Stage 1
The vessel is charged with liquid and the mixer is started. The
powdered ingredients are added without prior heating of the
liquid. The high speed rotation of the rotor blades creates a
powerful suction which draws liquid and solid ingredients into
the work head and rapidly mixes them.
Figure no.12[24]

27. 27
Stage 2
The high shear action of the mixer rapidly breaks down the
sugar granules in the gap between the rotors and the stator wall,
exposing the largest possible surface area of sugar to the water.
This greatly accelerates the solubilization process. The active
ingredients are similarly reduced to a low particle size and fully
dispersed into the surrounding liquid.
Stage 3
As the product is forced out through the stator, fresh powdered
and liquid ingredients are drawn into the workhead and
processed as before. A circulatory mixing pattern is set up
within the vessel, ensuring all material is passed through the
workhead many hundreds of times. This rapidly creates a very
fine and stable suspension.
The Advantages
• A Silverson high shear mixer can produce 66% sucrose syrup at ambient temperature.
• The heat of dissolution is imparted in the form of shear.
• Consistent product quality and repeatability is obtained.
• An agglomerate-free mixture is produced.
• The batch size, formulation, type of ingredients and the viscosity of the end product
dictate which machine from the Silverson product range is best suited to individual
processing requirements.
Figure no.13[24]
Figure no.14[24]

28. 28
7. Conclusion-
Traditional methods of manufacturing like use of mortar pestle and old mixers they are limited
to lab scale and not suitable for large scale production. Mixing is the main problem sometimes
agglomerates are formed and they are not good for stability of product. That’s why good mixing
equipment are required for large scale production. To overcomes this various problems like air
entrapment, contamination etc. we need modification and upgradation in procedure and
equipment and this information is given by technology transfer dossier from R&D to plant.

29. 29
8. Reference:
1. Bhabani S. Pilot plant scale-up technique. BP 702 T INDUSTRIAL PHARMACYII
(Theory). 2021. p. 11-12.
2. John R. Technology transfer in pharmaceutical industry. The pharma innovation journal.
2017;6(3):237-238
3. An Overview On Technology Transfer Of Pharmaceutical Industry. International Journal
Of Pharmaceutical Sciences And Research. 2020;11(2):573-575.
4. Sajid A, Vinay P and Chander S: Technology transfer in Pharmaceuticals. IRJP 2012; 3(6):
43-48.
5. Gupta, Surbhi S and Seema: Technology transfer in the pharmaceutical industry - an
overview. International Pharmaceutica Sciencia 2012; 2(3): 1-6.
6. Mohite PB and Sangle SV: Technology transfer in the pharmaceutical industry- a review.
International Journal of Advances in Pharmaceutics 2017; 06(01): 01-07.
7. Patil RP: Technology Transfer in Pharmaceutical Industry: objectives, Issues and Policy
Approaches. Int J Pharm Res Dev 2010; 2(10): 43-48.
8. Waghmare YS and Mahaparale SP: The important role of technology transfer in the
pharmaceutical industry-a review. World Journal of Pharmaceutical Research 2017; 6(9):
310-29.
9. Amanjeet S and Geeta A: Technology transfer in the pharmaceutical industry: a discussion.
International Journal of Pharma and Bio Sciences 2010; 1(3):1-3.
10. Millili G. Scale-up & Technology Transfer as a Part of Pharmaceutical Quality Systems.
Pharmaceutical Quality system (ICH Q10). Brussels Belgium: WHO; 201
11. Sajid A, Vinay P and Chander S: Technology transfer in Pharmaceuticals. IRJP 2012; 3(6):
43-48.
12. Singh A and Aggarwal G: Technology transfer in the pharmaceutical industry: a discussion.
IJPBS 2009; 1-3.
13. http://www.amuasi-paper-edited.pdf.
14. Sagar P, Akshay K, Pankaj P, Mayur G and Shivram J: Review article on technology
transfer. International Journal of pure and applied Bioscience 2014; 2(3): 145-53.
15. Patil RP: Technology Transfer in Pharmaceutical Industry: objectives, Issues & Policy
Approaches. Int J Pharm Res Dev 2010; 2(10): 43-48.
16. Souder WE, Nashar AS and Padmanathan V: A guide to the best technology transfer
practices. Journal of Technology Transfer 1990; 15: 1-2.
17. Anuj A and Bhuvnesh KS: A review on the importance of technology transfer in
pharmaceutical industry. An International Journal of Pharmaceutical Research 2016; 1(4):
141-42.
18. Biswajit D and Rao N: Transfer of technology for successful integration into the global
economy. a case study of the pharmaceutical industry in India. UNCTAD 2002.
19. Patil PR: Technology transfer in pharmaceutical industry: objectives, issues and policy
approach. International Journal of Pharma Research and Development 2010; 3: 43- 8.
20. WHO guidelines on transfer of technology in pharmaceutical manufacturing [Internet].
Who.int. 2011 [cited 27 March 2021]. Available from:
https://www.who.int/medicines/areas/quality_safety/quality_assurance/TransferTechnolo
gyPharmaceuticalManufacturingTRS961Annex7.pdf
21. Subrahmanyam C, Setty J, Sarasija S, Devi V. Pharmaceutical Engineering principle and
practice. Delhi: Vallabh Prakashan; 2001.
22. Production of cough mixture and pharmaceutical syrup. silverson. 2021.
23. Lachman, L., Liebermann, H. and Kanig, J., 1987. The Theory and practice of industrial
pharmacy. 3rd ed. Dadar Bombay: Varghese publishing house, pp.703-708.

30. 30
24. Google [Internet]. Google.com. 2021 [cited 27 March 2021]. Available from:
https://www.google.com/
25. Torotwa I, Ji C. A Study of the Mixing Performance of Different Impeller Designs in
Stirred Vessels Using Computational Fluid Dynamics. Designs. 2018;2(1):Figure 1.