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”. In Pharmaceutical Industry, 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. It is basically divided into three phases - Research Phase, Development Phase and Production Phase. The presentation elaborates on the technology transfer taking place in production phase. Production phase mainly concerns with validation studies and scale-up. Validation studies such as performance qualification, cleaning validation and process validation is carried out by R&D department. Scale-up involves the use of results obtained from lab studies for designing prototype of a product and pilot plant process, constructing pilot plant and further using pilot plant data for full-scale commercialization.

1. Optimization and Production
Phase in Technology Transfer
Pranjal Wagh
First Year M. Pharm
Quality Assurance
Poona College of Pharmacy

2. Introduction
•Selection of Excipients
•Process Design
•Pre-formulation
•Improvement of Efficacy
•Product Stability
Research
Phase
•Transfer of Product from
R&D to Product
development lab (PDL)
•TTD (Technology transfer
dossier) is handed over to
PDL
Development
Phase
•Validation Studies
•Scale up Parameters
•Selection of method
•Optimization techniques
Production
Phase
Phases/Steps in Technology Transfer Process

5. Production Phase
o Validation Studies
• Production is implemented after various validation studies verify that, it is able to consistently
manufacture product based on transferred manufacturing formula with a higher degree of stability.
• Validation studies such as performance qualification, cleaning validation and process validation is
carried out by R&D department; after the completion of validation of three batches, R&D prepares
the TTD (Technology transfer dossier) which is reviewed by Head-Production, Head-QC, Head-
Engineering, and approved by Head-QA.
• The TT 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.

6. Performance Qualification
• This involves challenging the system, process, or equipment to provide evidence of appropriate and
viable operation. It should be performed over a long enough period to demonstrate that the system,
process, or equipment is under control and will consistently produce a product with the desired quality
attributes.
• All instruments are tested together according to a detailed test plan and must generate reproducible
results.
• A PQ protocol should be designed to test and challenge the entire system, process, or equipment
based upon its expected use. The process performance qualification protocol will feature verification
and documentation that all equipment is working within the accepted range as specified, does it
perform as expected under real conditions.

7. Process Validation
• Process validation is establishing documented evidence which provides a high degree of assurance that
a specific process (such as the manufacturing of pharmaceutical dosage forms) will consistently
produce a product meeting its predetermined specifications and quality characteristics.
• Process validation is defined as the collection and evaluation of data, from the process design stage
through commercial production, which establishes scientific evidence that a process is capable of
consistently delivering quality product. Process validation involves a series of activities taking place
over the lifecycle of the product and process. This guidance describes process validation activities in
three stages.
1. Stage 1 – Process Design: The commercial manufacturing process is defined during this stage based
on knowledge gained through development and scale-up activities.
2. Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the
process is capable of reproducible commercial manufacturing.
3. Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that
the process remains in a state of control.

8. Cleaning Validation
• Based upon ICH guidelines, cleaning procedures should be validated. Cleaning validation should
be directed toward processing steps in which possible contamination or material carryover poses
a risk to API quality. If residues are removed by subsequent purification steps in the process,
cleaning procedures can be less rigorous.
• Cleaning validation protocols should describe the equipment to be cleaned, procedures,
materials, acceptance criteria, parameters to be monitored and controlled, and the analytical
methods to be employed for testing. Validation of cleaning procedures should reflect equipment
to be used for key and final intermediates and APIs. The selection of cleaning procedures to be
employed should be based on material solubility and cleaning difficulty. The calculation of residue
limits should consider the potency, toxicity, and stability of critical materials.

9. o Technology transfer process in Production phase
• Receiving unit and sending unit both should develop the product transfer protocol jointly to
transfer the product related information.
• Information should be transferred according to the technical expertness of the staff and the
manufacturing site capabilities to run the process smoothly.
1. Raw Materials
The material used for manufacturing on receiving unit should have consistency with the material
used at the sending unit. The properties of the raw material those can alter the quality of the
product should be identified.
i. Active Pharmaceutical Ingredients (API):
Sending unit should provide the drug master file (DMF) and other related information of the active
materials.

10. DMF may include the
following information:
Flowchart of the manufacturing process of the drug
material
Physical properties including bulk and tap density
Moisture content including water activity
Bioburden, endotoxin and sterility as required
Solubility and pH of solution
Particle size distribution and its dissolution profile
Manufacturer and the supply chain of the material
Other information like heat, light and moisture
sensitivity

11. ii. Excipients:
Excipients also have the considerable effect on the final product so their detailed information should also
be provided by the sending unit to receiving unit.
It may include the following
information:
Viscosity of material
Flowchart of the manufacturing process of the drug material
Physical properties including bulk and tap density
Moisture content range
Melting point range
Bioburden, endotoxin and sterility as required
Ion strength of material
Solubility and pH of solution
Specific gravity
Particle size distribution and its dissolution profile
Manufacturer and the supply chain of the material
Compliance with ISE and BSE requirements
MSDS
Heat, light and moisture sensitivity

12. 2. In-process Materials
Sending unit should provide the detailed information of manufacturing process, physical description,
specification and in-process controls.
3. Finished Products
History of the development of the product should also be provided for the further development or
process optimization after the successful technology transfer. Information regarding the environment,
health and safety should also be provided to the receiving unit.
It should also include the information on product quality review, validation, stability and environmental
conditions for manufacturing.
Generally, trial batches are taken at the receiving unit to test the manufacturing parameters and
capability of the manufacturing process before running the validation batch.
4. Packing Process
All the information regarding the packing should be transferred as the manufacturing process. it includes
the specification of foils or containers and closures, and other related information as design labeling,
artwork and drawings.

13. 5. Cleaning Process
To prevent the contamination in the pharmaceutical products, it is essential the follow the adequate
cleaning procedure. It can minimize the risk of Cross-contamination during manufacturing. Receiving
unit should validate the cleaning procedure and sending unit should provide the required information
such as existing cleaning procedure, the solubility of all materials, therapeutic dose, the toxicity of the
API, cleaning agents and recovery studies.
6. Manufacturing Facility
Sending unit should provide the information related to the facility design
i) Premises
It should include the layout of facility. buildings, utility services, fire risk, health and safety
requirements for operators and environmental issues.
ii) Equipment
A list of required equipment with their make and models should be provided by the sending unto. It
should include the manuals, drawings and cleaning, operating and maintenance procedures. IQ, OQ
and PQ of the equipment should be done by the receiving unit.

14. o Analytical Method Transfer
• The analytical method has its own importance because the manufactured product shall be tested
by the developed analytical method and accuracy in the analytical method can save time.
• Receiving unit should implement the method of analysis for the finished product, raw materials,
packing materials and cleaning residues before the starting of the process validation.
• Analytical method transfer protocol should be prepared including responsibilities of both sending
unit and receiving unit, the specification of product, acceptance criteria, interpretation of results,
report formats, reference standards and deviations during analysis. Training should be provided to
the analysts and should be documented in training record.

15. • 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.

16. o Scale-up
• Scale up involves the transfer of technology during the small scale development of the product and
processes. It is essential to consider the production environment and system during development of
process.
• Different operations e.g. dispensing, sifting, blending, compaction/dry granulation/wet granulation,
compression, coating are used in the formulation of solid dosage form.
• From blending to film coating, each process is easy for pharmaceutical professionals to be absorbed in
the particular part of the manufacturing process for which they are directly responsible.
• Operators concentrate on keeping their segment of the production process running smoothly. But the
whole manufacturing line can be improved, even before production begins, if technology transfer is
implemented thoughtfully.
• Effective technology transfer helps to provide process efficiency and control and maintain product quality.

17. • If the compound in question continues to demonstrate tolerability, safety and efficacy then dosing
trials may begin. Again, this requires an order-of-magnitude increase in production. Ultimately,
assuming safety and efficacy remain as expected, production must progress to pilot-scale batches,
followed by production-scale batches.
• Pilot-scale batches are typically used in the process development and optimization phase. Ten
percent of eventual production-scale batch size is typically produced at this phase, for oral solid-
dose forms. Production-scale batches reflect amounts that will be generated during the
standardized pharmaceutical manufacturing process.
• Scaling up smoothly, by a factor of up to 1,000, presents certain technical challenges. It’s essential
that the drug product produced in minuscule amounts exhibit the same properties, behaviors and
characteristics as the product produced during much larger production-scale runs. At various
points during the scale-up process — from small laboratory-scale batches to full production-run
batches — process optimization in pharmaceutical manufacturing studies and quality assurance
testing are typically done to ensure that scale-up will not affect quality and/or efficacy.

18. • Decisions regarding the use of any excipients are investigated during early phases. How they affect the
delivery, route of administration, bioavailability, dosage and other characteristics of the final product is
determined. All of these data are used to optimize the eventual commercial production process.
Parameters that are discovered to have an effect on final CQAs, known as critical process parameters
(CPPs), must be identified and their acceptable ranges delineated.
• The entire scale-up process must be validated every time the process is scaled-up by a factor of at least
10. The path from laboratory-scale batches to production-scale batches typically involves factors of 10
— or even 100 times or more — initial amounts.
• The characteristics of the manufacturing equipment
used, including power, speed and size, may influence
outcomes significantly. The beginning — and finishing
— with consistent equipment that has been certified
by its manufacturer as adept at smooth scale-up
facilitates the development process, and provides for
the enhanced efficiency and success of the scale-up
process.

19. o Mixing issues during Scale-up
• In the manufacture of many pharmaceutical products (especially tablets and capsules),
dry particle blending is often a critical step that has a direct impact on content
uniformity. Tumbling blenders remain the most common means for mixing granular
constituents in the pharmaceutical industry.
• Blending studies start with a small-scale, try-it-and-see approach. For example, during a
small scale production, a 5-ft3-capacity tumble blender filled to 50% of capacity and run
at 15 rpm for 15 minutes produces the desired mixture homogeneity, then the
conditions used to duplicate these results in a 25-ft3 blender for large scale production
are very crucial to be determined. The following aspects regarding mixing are to be
considered for smooth scale up:
1. Rotation rate of blender
2. Filling level
3. How long should the blender be operated?
4. Blender geometry (V-blender, Double cone etc.)

20. o Scale-up in Granulation
• During the scale-up process the quality of the granules may change.
• A change in granule size distribution, final moisture content, friability, compressibility, and
compactibility of the granules may strongly influence the properties of the final tablet, such as
tablet hardness, tablet friability, disintegration time, dissolution rate of the active substance, and
aging of the tablet.
• One of the most common unit operations used in the
pharmaceutical industry is fluid bed processing. Batch size
increase using fluid bed granulation requires a good
understanding of equipment functionality, the theoretical
aspects of fluidization, excipient interactions, and, most of all,
identifying the critical variables that affect the process of
agglomeration.

21. o Compression process during Scale-up
• The most important characteristics of the final formulation to be compacted are particle size and
particle size distribution, density and/or porosity, powder flow, cohesiveness, and lubrication.
• It should be noted, that the influence of particle size on powder flow and, therefore, on uniform die
fill is very important to the compaction operation, but is not a result of it.
• The one consideration to keep in mind during scale-up is the speed of the press, which will directly
affect the time available for the die filling to occur. This is an important parameter to observe
carefully.
• There are many tablet properties to be evaluated, the most
important to observe during the scale-up process are tablet
hardness (or tensile strength) and tablet dissolution. The
former could be affected significantly by press speed. Both
hardness and dissolution are most often a function of
compaction force; they are, of course, related to each other,
and both must be monitored carefully.

22. • With a proper developmental experimental plan or by the use of appropriate
experimental design and/or optimization studies in R&D or in the pilot plant, the product
development scientist should already know the effects of “force” on tablet hardness and
dissolution and the relationship between the two.
• Several special concerns in the scale-up of compaction that relate exclusively to the
compaction step and that cannot be determined on a smaller scale. The list might
include:
1. Press speed for materials that compact by plastic deformation
2. Overmixing of the lubricant by the force feeder
3. Heat build-up over a long run
4. Abrasive materials
5. Tooling care—unmatched sets of tooling

23. o Selection of method
• The method for batch fabrication is selected on the basis of data given from R&D.
• Granulation, blending, compression and coating are critical parameters for technology
transfer.
• Technical information of developed products is obtained from data of a limited amount of
batches.
• Various standards have been established from the limited data and quality evaluation
method established in development phase is not always sufficient for factory production.
• It is highly desired to feed back and accumulate technical information obtained from
repeated production. In addition, it is important to appropriately modify various standards
established before based on this information.
• Accountability and responsibility for design and manufacturing should be executed.

24. o Optimization techniques
• Optimization techniques are used to find either the best possible quantitative formula
for a product or the best possible set of experimental conditions (input values) needed to
run the process.
• Optimization techniques may be employed in the laboratory stage to develop the most
stable, least sensitive formula, or in the qualification and validation stages of scale-up in
order to develop the most stable, least variable, robust process within its proven
acceptable range(s) of operation.

25. References:
• S. Shalini, K. Nijanthan, B. Rajkumar, S. Muthukumar, C. Sankar, G. Arulkumaran; An overview on
technology transfer of pharmaceutical industry; IJPSR (2020), Volume 11, Issue 2.
• B. Bhusan, U. Nautiyal, S. Kumar, A. Bakar; Technology transfer in Pharmaceutical Industry: A
review; Int. J. Pharm. Med. Res. 2014; 2(3).
• WHO guidelines on transfer of technology in pharmaceutical manufacturing, Annex 7.
• https://www.pharmatutor.org/articles/overview-of-technology-transfer-in-pharmaceutical-
industry
• https://www.pharmaguideline.com/2015/07/technology-transfer-in-pharmaceuticals.html
• https://www.quadro-mpt.com/news-and-events/process-scale-up-and-technology-transfer
• Pharmaceutical Process Validation, Third Edition (R. A. Nash, A. H. Wachter)
• Pharmaceutical Process Scale-Up (Michael Levin)