Fig. 6.1: The authorities and agencies involved in TOT

88 Industrial Pharmacy II

Government authorities and agencies involved in TOT (Table 6.2)

Table 6.2: Describing government agencies and their functions in TOT process

Name of agency/authority Functions

Government regulatory authority Issue guidelines

(central as well as state) Regulatory inspections

Monitoring of clinical trials

Quality, efficacy, safety checking of technology

WIPO Protect intellectual property rights of both the parties

Contd.

Table 6.1: Describing functions of departments involved in TOT process

Department Functions

R&D i. Supports technical issues

ii. Resolves technical problems

iii. It would direct and train the production trial at RU.

QA i. Review documentation to check compliance with market authorisation

ii. Compile SUs documents for transfer

iii. Initiates, confirm and compare regulatory requirements of both SUs

and RUs to point out if any change is needed.

QC i. Review analytical requirement and ensure availability with instruments

ii. Mainly responsible for analytical method transfer of product.

Engineering It will review:

i. Equipment requirement

ii. Preventive maintenance and calibration impact.

It will initiate:

i. Engineering modifications

ii. Change or part purchasing

Production i. Review process instructions

ii. It will consider if there is any:

a. Safety implications

b. Impact on local SOPs

c. Training requirement of staff of both SU and RU.

Regulatory affairs i. Coordination of regulatory filing

ii. Response to regulatory inquiries

iii. Ensure the compliance with regulatory guidelines

iv. Ensure compliance with guidelines in case of any variation/change

v. Advise on timing and filing document contents

The material i. Strategic planning

management ii. Resource allocation

iii. Supply chain activities

iv. Recommends most favourable manufacturing strategy by keeping

partnership, internal capability and tax saving in consideration

The project i. Overall coordination among departments

management ii. Allocation of responsibilities to other staffs

iii. Communicate with the management

iv. Designate any other role as appropriate

Regulation of Transfer of Technology 89

6.2 PROBLEMS FACED DURING COMMERCIALISATION

Problems faced per the stages of commercialisation/TOT:

1. Problems during the technology justification and selection stage:

i. Wrong selection of technology.

ii. Cost of buying, installing, maintenance and operation is high.

iii. The technology selected is complex for understanding and implementation.

iv. Technology is not adapted to local conditions and needs extensive adaptations.

2. Problems during the planning stage:

i. SU does not fully understand RU’s need.

ii. RU’s manager is not involved in transfer planning.

iii. Less or no attention is given to software or intellectual needs.

iv. Market forecasting is wrong.

v. The objectives of RU and SU are not clear.

vi. The mechanism chosen for the implementation of technology at RU is not

appropriate.

 

3. Problems during negotiations:

i. Difference between RU and SU approaches and strategies related to negotiation.

ii. Lack of trust between RU and SU.

iii. Difficulty in reaching agreements on IP rights and price of technology.

iv. The unrealistic approach of both RU and SU to reach results in a short time period.

4. Problems during technology implementation:

i. Lack of resources such as: Technical staff, equipment, supporting staff, premises

and equipment, financial resources.

ii. Inability to achieve targets.

iii. Lack of funds and cost-overrun due to poor implementation.

iv. Delay or mismanagement of demand and supply chain.

v. High cost or poor quality of locally available material needed for the

implementation of technology.

5. Miscellaneous

i. Local producers are not able to face international challenges.

ii. Lack of skilled labour on the part of one or both parties.

iii. Incomplete process validation.

iv. The high rate of batch rejection.

v. Not fulfilment of demand for supporting staff or labour.

vi. Incomplete or no documentation.

Table 6.2: Describing government agencies and their functions in TOT process (Contd.)

Name of agency/authority Functions

WTO Set trade rule (like excise duty)

Monitor import and export of technology within countries

ICH Issues guidelines related to qualification, validation, clinical

trials, production, quality control, risk management

WHO Issues guidelines related to technology transfer

Tax department Charges tax/duty based on the type of technology (goods

or services)

90 Industrial Pharmacy II

vii. The product does not show specification or up to the limits as expected or

mentioned by SU.

viii. Delay or no regulatory approval of the product.

The success of technology transfer depends upon 5 Cs (Fig 6.2):

i. Communication

ii. Capacity

iii. Co-ordination

iv. Commitment

v. Co-operation

 

Objective Type Questions

1. WHO guidelines for technology transfer are mentioned in which annexure of

WHO technical report series 961,2011.

a. Annexure 9 b. Annexure 7

c. Annexure 5 d. Annexure 4

2. A logical procedure that control the transfer of any process together with its

documentation and professional expertise between development and manufacture

or between manufacture sites is known as:

a. Technology transfer b. Technology development

c. Process modification d. None of the above

3. Which of the following is a characteristic of ToT as per WHO:

a. It is systematic process

b. It involves transfer of documents

c. It involves transfer of knowledge gained through development process

d. All of the above

4. The unit from where a designated product, process or method is expected to be

transferred is known as:

a. Sending unit b. Receiving unit

c. Processing unit d. None

5. Action of proving and documenting that any process procedure or method actually

and consistently leads to the expected results is known as:

a. Validation b. Qualification

c. Installation d. None of the above

86 Industrial Pharmacy II

6. Assessment of risk and controlling of risk are the steps under:

a. Quality risk management b. Quality control

c. Quality assurance d. Validation

7. Arrange the following with respect to their order of occurrence in QRH process:

1. Risk assessment 2. Risk review 3. Risk control

a. 1, 3, 2 b. 1, 2, 3

c. 3, 2, 1 d. 2, 3, 1

8. Risk reduction is a part of:

a. Risk evaluation b. Risk assessment

c. Risk control d. Risk review

9. Which ICH guidelines explain the process of QRM?

a. Q9 b. Q10

c. Q2 d. Q1

10. FTA stands for:

a. Flowchart technical analysis b. Frequent technical analysis

c. Fault tree analysis d. None of the above

11. In which of the following, the vendor has to transfer analytical method to QC:

a. If drug product is pharmacopoeial

b. If drug product is non-pharmacopoeial

c. If drug substance is pharmacopoeial

d. None

12. Match the following:

 

Terminology Belongs to

a. TOT i. QRM tool

b. HACCP ii. Documentation

c. Risk control iii. Open and closed part

d. FMEA iv. Risk acceptance

e. DMF v. Critical control point determination

13. Fill in the blanks

a. “What can be done to reduce or climate risk?” is answered by ___________.

b. __________ ICH guidelines deal with QRM.

c. ___________ QRM tool is based on the assumption that events are caused due to

deviation in design.

d. __________ is a critical step that ensures RU capabilities to produce and test the

same product as by SU.

e. AMT will be started by ___________ department.

f. AMTP stands for __________

ANSWERS

1. b 2. a 3. d 4. a 5. b 6. a 7. a 8. c

9. a 10. c 11. b 12. a (ii), b(v), c(iv), d(i), e(iii)

13. (a) Risk control (b) Q9 (c) HAZOP (d) AMT (e) Analytical (f) Analytical Method

Transfer Protocol.

Regulation of Transfer of Technology 87

6.1 AUTHORITIES AND AGENCIES INVOLVED IN TOT

The main concern of authorities and agencies involved in TOT is to ensure transfer of

efficient, quality, and safe technology. Government, as well as private (belongs to SU

or RU) agencies, and authorities are involved in TOT (Fig. 6.1)

TT team: As we know that technology transfer is a multidisciplinary approach which

involves representatives and individuals from different departments (Table 6.1) like

i. R&D

ii. QA

iii. QC

iv. Production

v. Engineering

vi. Regulatory affairs

vii. The material management

viii. The project management

87

Regulation of Transfer of

Technology

6

 

5.10 PREMISES AND EQUIPMENT

One of the major requirements needed for the manufacturing of a pharmaceutical

product is premises and the other one is equipment. The premises and equipment

Fig. 5.6: The steps involved in the AMT of a drug product

Fig. 5.7: The steps involved in the AMT of a drug substance (non-pharmacopoeial)

82 Industrial Pharmacy II

should be designed, constructed, located, adapted and maintained to suit the operations

needed to be carried out. It is a layout of premises and equipment that have major

effect on cleaning, maintenance, and risk of error during production and finally affect

the quality of the product.

Premises

SU’s responsibilities:

To provide information to RU on

i. Design

ii. Layout

iii. Construction

iv. Services (HVAC, temperature, relative humidity, water, power, etc.)

To provide other information which may directly or indirectly have an impact on

the method, product and process.

Fig. 5.8: The steps involved in the AMT of a drug substance (pharmacopoeial)

WHO Guidelines for Transfer of Technology 83

SU should provide information related to safety, health and related environmental

issues. This includes:

i. Risks inherited in manufacturing processes like exposure limits, chemical hazards,

fire risks, and explosion risks, etc.

ii. Measures or health and safety essentialities to minimize or reduce the operator

exposure. For example, the case of pharmaceutical dust.

iii. Emergency plans in case of non-predictable situations like gas leakage, dust

release, fire, etc.

iv. Waste management plan

RU’s responsibilities: RU should compare all the information with its own premises

details and ensure the production of quality products.

Equipment

Equipment used in the pharma industry includes equipment related to manufacturing,

packaging, processing, and holding of the drug. All equipment should be located,

maintained and designed to suit their intended purposes related to the operation.

SU’s responsibilities: SU should provide RU with the list of equipment (of all units

such as manufacturing, packaging, filling, quality control, etc.) with designs, models

and makers. The list should be updated and recent. SU should also provide qualification

and validation documentation which includes:

Logs (maintenance and calibration), manuals, drawings, procedures related to

equipment set up, cleaning, maintenance, storage, etc.

RU's responsibilities: RU should review the information provided by SU with its

inventory list. This list should include:

i. Qualification status of all systems and equipment

ii. Comparison of equipment (related to functionality, models, makes, and

qualification status) at both sides.

A gap analysis should be performed by RU. The factors that are to be analysed

during gap analysis are as follows:

 

i. Minimum and maximum capacity

ii. The material of construction

iii. Critical operating parameters

iv. Critical equipment components

v. Critical quality attribute

vi. Range of intended use.

The gap analysis helps RU to:

i. Identify requirements for the adaptation of existing equipment.

ii. Identify requirements for the acquisition of new equipment.

iii. Identify requirements for change in the process.

iv. Identify requirements to reproduce the process being transferred.

During gap analysis following points should be kept monitored:

i. The facility and building-specific location of all equipment at the RU should be

considered at the time of drawing up process maps/flowcharts of the

manufacturing process to be transferred, including flows of personnel and

material.

ii. The impact of manufacturing new products on products currently manufactured

with the same equipment should be determined.

84 Industrial Pharmacy II

iii. Any modification of existing equipment that needs to be adapted to become

capable of reproducing the process being transferred should be documented in

the transfer project plan.

5.11 DOCUMENTATION

Documentation is the most essential part of the transfer process. Every key task has to

be documented. WHO guidelines mentioned a list of important documents that need

to be prepared. However, these documents can be amended depending upon the need

of time. The list of documents is given in Table 5.4.

5.12 QUALIFICATION AND VALIDATION

As per WHO guidelines the extent to qualification and/or validation to be performed

should be determined based on risk management principles and should be documented.

Table 5.4: Essential documents to be prepared during TOT process

Sr. no. Key task Name of document Information/documentation provided

by SU

1. Project definition Project implementation Project quality plan protocol, risk

plan. TOT protocol assessments, gap analysis

2. Quality agreement Side-by-side comparison Plans and layout

Facility assessment with RU facility and of facility, buildings

buildings; gap analysis

Qualification protocol

and report

3. Health and safety MSDS Product-specific waste management

assessment plans and contingency plans

4. Skill set analysis Training protocols, SOPs and training documentation

and training assessment results

5. Analytical method Analytical methods Analytical method specifications and

transfer transfer protocol validation

and report

6. Starting material SOPs, stability studies All information related to API

evaluation reports

7. Equipment selection Side-by-side comparison Inventory list of all equipment

and transfer with RU equipment and systems, including makes, models,

 

In an analytical method transfer, both SU and RU have their responsibilities. These

are given in Table 5.3.

Appropriate training should be provided. All training activities and outcomes should

be documented. Reference to compendia monographs (like IP, BP, USP, etc.) where

available, is expected.

Table 5.3: SU and RU responsibilities in analytical method transfer

Responsibilities of Description

SU i. Provide method-specific training for analysts and other quality control

staff, if required;

ii. Assist in analysis of QC testing results;

iii. Define all methods to be transferred for testing a given product, starting

material or cleaning sample;

iv. Define experimental design, sampling methods and acceptance criteria;

v. Provide any validation reports for methods under transfer and

demonstrate their robustness;

vi. Provide details of the equipment used, as necessary (part of validation

report, if available) and any standard reference samples;

vii. Provide approved procedures used in testing; and

viii. Review and approve transfer reports

RU i. Review analytical methods provided by the SU, and formally agree on

acceptance criteria before the execution of the transfer protocol;

ii. Ensure that the necessary equipment for QC is available and qualified

at the RU site. The equipment used by the RU during the analytical

transfer should meet appropriate specifications to ensure the

requirements of the method or specifications are met;

iii. Ensure that adequately trained and experienced personnel are in place

for analytical testing;

iv. Provide a documentation system capable of recording receipt and

testing of samples to the required specification using approved test

methods, and of reporting, recording and collating data and designation

of status (approved, rejected, quarantine);

v. Execute the transfer protocol;

vi. Perform the appropriate level of validation to support the

implementation of the methods;

vii. Generate and obtain approval of transfer report

WHO Guidelines for Transfer of Technology 81

Possible experimental designs and acceptance criteria for the main analytical testing

methods are mentioned in the table in WHO guidelines for transfer of technology. The

table represents high-level guidance to apply the general principle that method transfers

should account for the variability and sensitivity of the method and the specifications

for the quality parameter. Alternative procedures and acceptance criteria may be

applied based on science and the characteristics of the analytical method and the

analyte. The table includes pssible experimental designs and acceptance criteria for

analytical testing (Figs 5.6 to 5.8).

 

In technology transfer process (as per WHO guidelines) analytical method transfer

is a critical step that ensures RU capabilities to produce and test the same product as

by SU. Analytical method transfer comes under the quality control section.

All the analytical testing methods that demonstrate compliance of product

(which is to be transferred) will be transferred with registered specifications. The

analytical method used to test pharmaceutical products, starting material, packaging

components, cleaning should be first implemented at a laboratory before process

validation at RU. Process validation sample may be tested at RU, SU, or any other 3rd

laboratory.

80 Industrial Pharmacy II

There is an analytical method transfer protocol which is to be prepared before

analytical method transfer. It includes:

i. Objectives, scope, roles and responsibilities of both SU and RU

ii. Material and method specification

iii. Experimental design and acceptance criteria

iv. Documentation

v. Reference

vi. Procedure for the handling of deviations

vii. Signed approval from the designated authority

viii. All details regarding reference material (like starting material, FP, intermediates,

etc.)

 

Finished Pharmaceutical Product

Detailed information related to qualitative and quantitative characteristics of the

finished product should be provided by SU to RU. The information includes:

i. Qualitative and quantitative composition

ii. Physical information

iii. Physical characteristics

iv. Method of manufacturing

v. In-process controls

vi. Packaging details

vii. Safety and handling details.

Information on Process (Processing)

History of process and other information should be provided to RU by SU. This is to

enable RU to perform any further development or optimization of the process after

the transfer of technology. This section includes information on:

i. Clinical development

ii. Scale-up activities

iii. Full-scale development act

iv. The history of change and reasons for the change

v. Problem’s investigation and respective outcomes.

SU should provide RU with any information regarding health, safety and

environmental issues. This information is associated with:

i. Manufacturing process

ii. Manufacturing process’s implications like the need for growing, etc

The SU should provide RU information on current processing and testing. This

section includes information regarding:

i. The requirement of facility and equipment

ii. Starting material details

iii. Master safety data sheet

iv. Storage requirements for FP, API, and excipients

v. Manufacturing steps description including flowcharts, narrative maps, master

batch-records, etc

vi. Analytical method description identification and justification of control strategy

which include:

a. Critical performance aspects of specific dosage forms

b. Process control points

c. Product quality attributes

d. Standard process control charts

78 Industrial Pharmacy II

vii. Validation

viii. Product quality reviews and details

ix. Stability information

x. Working protocols

xi. Environmental rules and protocols to be followed

Responsibilities of RU: RU should identify if there are any differences in the

i. Facilities

ii. Systems

iii. Capabilities

 

During the transfer process: If there are any then RU should communicate it with

SU to understand the potential impact on the quality of a product.

After communication, based on the information gained from SU, RU should consider

own capabilities, so that it can be able to develop relevant plant operating procedures,

facilities, equipment and documentation before the start of production.

Process development at RU: Following steps should be there during process

development at RU

i. Suitability and qualification of facility and equipment should be compared and

assessed.

ii. Critical steps like hold times, end-points, sampling points and sampling

techniques should be detained.

iii. SOPs should be written and approved for all production operation, packaging,

cleaning, testing and storage.

iv. Stability, information evaluation should be done with the generation of sitespecific data (if required)

v. Regulatory requirement compliance should be there for any change.

vi. Manufacturing process, the flow of personnel and materials at RU should be

described.

Packaging

Packaging transfer has the same importance as production transfer. The steps to be

followed during packaging transfer are:

a. Procedural patterns during packaging transfer should be the same as in case of

production transfer.

b. SU should transfer the information to RU regarding

1. Specification of a suitable container and closure system

2. Design, processing, packaging and labelling requirements

3. The requirement of tamper-evident and any other anti-counterfeiting measures

which are needed for the qualification of packaging components at RU

c. Specification which includes drawings, material, artworks should be given by SU

to RU for quality control testing of packaging components.

d. Based on the information RU should perform a stability study initial qualification

of packaging components to ensure:

1. Safety

2. Compatibility

3. Performance of packaging material.

WHO Guidelines for Transfer of Technology 79

Cleaning

 

vii. Particle size and distribution, including the method of determination (for solid,

inhaled and transdermal dosage forms);

viii. Bulk physical properties, including data on bulk and tap density, surface area

and porosity as appropriate (for solid and inhaled dosage forms);

ix. Compaction properties (for solid dosage forms);

x. Melting point range (for semisolid or topical dosage forms);

xi. pH range (for parenteral, semisolid or topical, liquid and transdermal dosage

forms);

xii. Ionic strength (for parenteral dosage forms);

xiii. Specific density or gravity (for parenteral, semisolid or topical, liquid and

transdermal dosage forms);

xiv. Viscosity and/or viscoelasticity (for parenteral, semisolid or topical, liquid and

transdermal dosage forms);

xv. Osmolarity (for parenteral dosage forms);

xvi. Water content and determination of hygroscopicity, including water activity data

and special handling requirements (for solid and inhaled dosage forms);

xvii. Moisture content range (for parenteral, semisolid or topical, liquid and

transdermal dosage forms);

xviii. Microbiological considerations (including sterility, bacterial endotoxins and

bioburden levels where the excipient supports microbiological growth) as per

national, regional or international pharmacopoeial requirements, as applicable

(for general and specific monographs);

WHO Guidelines for Transfer of Technology 77

xix. Specifications and justification for release and end-of-life limits;

xx. Information on adhesives supporting compliance with peel, sheer and adhesion

design criteria (for transdermal dosage forms);

xxi. Special considerations with implications for storage and/or handling, including

but not limited to safety and environmental factors (e.g. as specified in material

safety data sheets (MSDS)) and sensitivity to heat, light or moisture; and

xxii. Regulatory considerations, e.g. documentation to support compliance with

transmissible animal spongiform encephalopathy certification requirements

(where applicable)

 

xiii. Ionic strength for parenteral dosage forms;

xiv. Specific density or gravity for parenteral, semisolid or topical, liquid and

transdermal dosage forms;

xv. Viscosity and/or viscoelasticity for parenteral, semisolid or topical, liquid and

transdermal dosage forms;

xvi. Osmolarity for parenteral dosage forms;

xvii. Water content and determination of hygroscopicity, including water activity data

and special handling requirements for solid and inhaled dosage forms;

76 Industrial Pharmacy II

xviii. Moisture content range for parenteral, semisolid or topical, liquid and transdermal

dosage forms;

xix. Microbiological considerations including sterility, bacterial endotoxins and

bioburden levels where the excipient supports microbiological growth

xx. As per national, regional or international pharmacopoeial requirements, as

applicable for general and specific monographs;

xxi. Specifications and justification for release and end-of-life limits;

xxii. Information on adhesives supporting compliance with peel, sheer and adhesion

design criteria (for transdermal dosage forms);

xxiii. Special considerations with implications for storage and or handling, including

but not limited to safety and environmental factors (e.g. as specified in material

safety data sheets (MSDS)) and sensitivity to heat, light or moisture; and

Excipients

Excipients have a potential impact on each aspect of the final product. Any relevant

information, which is of the importance for product manufacturing and is related to

excipients should be given to RU by SU. This information may include:

i. Manufacturer and associated supply chain;

ii. Description of functionality, with justification for the inclusion of any antioxidant,

preservative or any excipient;

iii. Definitive form (particularly for solid and inhaled dosage forms);

iv. Solubility profile (particularly for inhaled and transdermal dosage forms);

v. Partition coefficient, including the method of determination (for transdermal

dosage forms);

vi. Intrinsic dissolution rate, including the method of determination (for transdermal

dosage forms);

 

Facilitate decision making

2. Fault tree Identify the root cause of the Evaluate deviation and

analysis (FTA) problem investigate the complaint

Identify system or subsystem of products

or chain of the system failed

at one time

Process understanding is highly

required to identify factors

3. HAZOP This tool is based on the Used in the assessment of

assumption that events are manufacturing processes, supplies,

caused due to deviation in facilities and equipment.

design and operating intention. Used to identify and evaluate

It uses a systematic approach process safety hazard.

to identify those design and

operation intention.

4. HACCP Mainly focus on identifying Preventive application

critical points from where the Assessment of CCP and execute

hazard can be originated and them for process.

primary focus is on to control

hazard rather than curing it.

It is a bottom-up approach.

5. FMEA (failure mode It aimed at preparing Very beneficial in case of new

effect analysis) organisations to detect failure product, processor, service,

during the design state only by changing existing process, when

identifying all possible failures the goal is a quality improvement,

in a design and manufacturing then one needs to understand the

process. It has two types: process deeply.

Development failure mode

effect analysis (DFMEA) and

production failure mode

effect analysis (PFMEA).

This method requires extensive

knowledge of design and

process.

 

The PQRI (Product Quality Research Institute), MTC (Manufacturing Technology

Committee) has produced several working tools to increase or boost up consistency in

use of ICH Q9. The description of the tools is given in Table 5.2.

Table 5.1: Type of integration of QRM and areas of benefit

Sr. No. Type of integration Facilitation of Areas of benefit

1. QRM integration with key “What to do?” Integrated quality management.

quality system elements Facilities, equipment and utilities.

Supplies, material and contract

service management.

Technology transfer.

2. QRM integration with product “How to do?” Production

manufacturing operation Laboratory control and stability

studies

Packaging and labelling

Storage, transport and distribution

74 Industrial Pharmacy II

5.8 TRANSFER FROM R&D TO PRODUCTION (PROCESS, PACKAGING AND

CLEANING) AND GRANULARITY OF TT PROCESS (API, EXCIPIENTS,

FINISHED PRODUCTS, PACKAGING MATERIAL)

The transfer process is one of the most critical steps in technology transfer. Certain

things that should be ensured by sending unit are as follows:

i. The RU should accommodate the intended production capacity. If possible, the

production capacity should be established (in keeping the view that the production

is in single-batch, or continuous or campaigns) at the beginning of the process.

ii. Consideration should be given to the level and depth of the detail which is to be

transferred to RU. The detail can be to support production or any further process

development or for optimisation at RU as intended in the transfer project plan.

Table 5.2: Tools of QRM

Sr. No Tools Description Application

1. Flowchart, check Simple techniques, use to Compilation of observations.

sheets, etc. gather and organise the data, Sorting out data