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

 

The main advantage of QRM application is that there can be flexibility in a number

of batches for confirmation or validation, whereas in validation there is a fixed

number of batches to be taken. So, QRM ensures flexibility as per type and depth of

knowledge to be gained. In case of qualification, QRM principles can be used to

determine its scope, monitoring, as well as the optimal schedule for maintenance,

requalification and calibration.

WHO Guidelines for Transfer of Technology 73

5. QRM application during commercial manufacturing: Certain points are to be taken

care while implementing QRM in commercial manufacturing:

a. QRM implementation does not neutralise the manufacturer's obligation to comply

with regulatory requirements.

b. The risk assessment and control responsibilities should be designated to relevant

personnel at the appropriate level of hierarchy within the organisation.

c. Special focus must be given to risk assessment and risk control throughout the

life cycle of a product.

The key areas of focusing are:

a. Product quality risks

b. Adverse effect on patient's health due to quality defects in the product.

c. Interruption in the supply of products to patients.

d. Risk related to GMP and regulatory compliance.

e. Multisite and multiproduct risks.

f. Any change in the existing facility or establishment of new facility.

After risk assessment and risk control, risk review should be done. A report should

be prepared and communicated to stakeholders. The areas of focusing during the

implementation of QRM in commercial manufacturing includes system focus, process

focus and product focus.

QRM should be integrated into two ways to get benefits across a broad spectrum of

operations (Table 5.1).

QRM related guidelines

i. Q9 of ICH

ii. WHO expert committee on specification for pharmaceutical preparations 47th

report, Annexure 2, TRS-981.

Tools of QRM

A variety of tools either alone or in combined form can be used for QRM purposes.

There is no single or combined tool which applies to all the situation. The main criteria

for selecting the tool are that it should support the key attributes of good risk

assessment.

 

3. QRM application during product development: There are various stages in product

development. QRM procedure application evolves through these various stages.

Such as:

a. The first QRM exercise should be done once Quality Target Product Profile (QTPP)

is defined and the candidate medicines pre-formulation work is done. There are

several gaps in knowledge at this stage, so various tools like flowcharts, decision

trees, fault-tree analysis, matrices, cause and effect diagram, etc. are used in such

a situation.

b. When the product has gone through the next stage of development, a detailed

risk analysis should be done, which is associated with API and FP both. Risk can

cover stability, bio-availablity, and patient safety.

c. With the more advancement of product knowledge more detailed exercises of

QRM can be done. These exercises will concentrate on the areas which have high

priority risk.

4. QRM application during validation and qualification: Process validation involves

the generation as well as evaluation of data throughout the process, i.e. from

development scale to full-scale production. This property of process validation

resembles with QRM process because QRM also deals with the product life cycle.

The embracement of the product life cycle concept provides scientific assurance of

consistent delivery of the quality product. This scientific assurance should be build

up from the starting of the product life cycle and should be ensured early in the

development phase in both cases (product and process development).

 

iv. It can be applied in both ways, i.e. either proactively or retrospectively.

WHO Guidelines for Transfer of Technology 69

Principles of QRM

i. The evaluation of the risk to quality should have a basis and ultimately link to

the protection of the patient.

ii. The level of effort, formality and documentation of the quality risk management

process should be commensurate with the level of risk.

iii. When applied, the methodologies of QRM should be dynamic, iterative and

responsive to change.

iv. There should be capability or scope of continual improvement in the QRM process.

QRM Process (Fig. 5.2)

Initiating a QRM process: The initiation of QRM should have a scientific basis. The

possible steps to be taken in initiating and planning a QRM process are shown in

Fig. 5.3.

Fig. 5.2: QRM process

Fig. 5.3: The possible steps to be taken in initiating and planning a QRM process

70 Industrial Pharmacy II

Personnel involved in QRM: The personnel involved in QRM should have productspecific knowledge, experience and expertise. The personnel should be capable of

effective planning, execution and completion of QRM activities. The team can be

multidisciplinary. The duties and responsibility of the team are to:

i. Conduct risk analysis

ii. Identify potential risks

iii. Analyse the potential risks

iv. Evaluate the risks to determine which one should be controlled and which one

should be accepted

v. Recommends risk control methods

vi. Create a procedure for risk review, risk monitoring, and risk verification

vii. Calculate the impact of risk finding on related product/processes.

Knowledge of product or process: A flowchart could be made to assess every step of

product and process. QRM should be based on the knowledge of product and process

concerning to the stage at which product is there in its life cycle.

 

Risk assessment: In this section, there are three questions which need to be solved

during the risk assessment

i. What might go wrong? (Risk identification): It will solve by the systematic use of

information to identify the hazards. It includes use of information like historical

data, theoretical analysis, concerns of stakeholders, informed opinions. The

question gives answer related to the probability of risk refers to its past.

ii. What is the probability it will go wrong? (Risk analysis): It involves both qualitative

as well as quantitative analysis of the risk and severity of risk. It is the estimation

of risk. The question gives answer related with the detectability of risk is present.

The steps involved in risk analysis are shown in Fig. 5.4.

iii. What are the consequences? (Risk evaluation): It involves a comparison of identified

and analysed risk against the given risk criteria. The question gives answer related

with the impact of risk on future (Fig. 5.4).

Risk control: It is a decision-making activity which identifies either to reduce or

accept risk. Its fundamental purpose is to reduce the risk to an acceptable level. It

includes three questions which are to be followed (Fig. 5.5)

Fig. 5.4: The steps involved in risk analysis

WHO Guidelines for Transfer of Technology 71

i. What can be done to reduce or eliminate risk?

ii. What is the appropriate balance between benefit, risk and resources?

iii. Are new risk introduced as a result of identified risk being controlled?

Risk review: Appropriate systems should be in place to ensure that the monitoring

of the output of the QRM process is done effectively. It is done to gather new information

which may have an affect on original QRM decision, e.g. changes to equipment, process,

control systems, suppliers, etc.

Verification of QRM processes and methodologies: The verification of QRM should

be performed and documented by expert QRM team. It involves the following activities:

i. Review of QRM processes and records

ii. Review of deviation and product management control

iii. Confirmation that identified risks are being under control.

 

5.6 QUALITY RISK MANAGEMENT

In most of the countries compliance with GMP throughout the product life cycle largely

gives assurance regarding the good quality of the product. However, any loose control

can put the patient in risk because of the lower quality of medicine. Regulatory

authorities can improve the quality of the product within the limit of resources

available if:

i. Assessment of individual risk related to specific products, starting material is

performed.

ii. Recognition of hazards at specific stages of production and/or distribution are

done

QRM is a process that is related to all countries and has a rationale to understand

risk. It has measures to prevent and mitigate all risks by appropriate and robust controls.

The aim is:

i. To ensure the quality of a product.

ii. To eliminate risk at the patient's end.

iii. To ensure the elimination of risks at the point of origin.

iv. To protect the company from loss generated because of inadequate quality

products.

v. To make industries manufactures to adopt a risk-based approach throughout the

life cycle of the product.

vi. To manage risk to the quality of product throughout its life cycle to maintain

benefit/risk balance.

Characteristics of QRM

i. It is a risk-based approach.

ii. It is a systematic process.

iii. It involves:

a. Assessment

b. Control

c. Communication

d. And a review of the risks to the quality of the product.

 

3. SU or third party should ensure the suitability or degree of preparedness of

RU with respect to premises, equipment and supporting staff/services, etc.

4. SU and RU should jointly verify the satisfactory completion and availability

of validation protocols of following: (a) IQ of all pieces of equipment elated

with manufacturing, packaging and analysis at RU site, (b) OQ of all

equipment elated with manufacturing, packaging and analysis at RU site,

(c) qualification of premises and rooms for both manufacturing and

packaging at RU.

5. The training of the staff/personnel required for specific knowledge (related

with product, process and method) should be implemented by SU and RU

jointly and assessment of training outcomes should also be done jointly.

6. SU and RU should jointly execute the transfer protocol according to checklist

and/or a flow diagram should be prepared which shows a sequence of

steps that are taken to ensure efficient transfer.

68 Industrial Pharmacy II

7. Any change and adaptations made during TOT should be fully documented.

8. The SU and RU jointly documented the execution of TOT protocol in a

summary in the report.

9. There will be a project team which regulate and control the execution of TT

protocol. It consists of experienced staff/personnel of different departments

involved.

10. The transfer of the project will be managed by the team. The members of

the team will be from both SU and RU. Each member is designated with

key responsibilities in writing.

11. The team members should have a necessary and desirable qualification,

experience and knowledge to manage the designated aspect of technology

transfer.

 

Validation

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

and consistently leads to the expected results.

66 Industrial Pharmacy II

Validation master plan (VMP)

A high-level document that establishes an umbrella validation plan for the entire project

and summarizes the manufacturers overall philosophy and approach, to be used for

establishing performance adequacy. It provides information on the manufacturer’s

validation work programme and defines details of and timescales for the validation

work to be performed, including a statement of the responsibilities of those

implementing the plan.

Validation protocol or plan (VP)

A document describing the activities to be performed in a validation, including the

acceptance criteria for the approval of a manufacturing process—or a part thereof—

for routine use.

Validation report (VR)

A document in which the records, results and evaluation of a completed validation

programme are assembled and summarized. It may also contain proposals for the

improvement of processes and/or equipment.

5.5 ORGANISATION AND MANAGEMENT

The transfer of technology includes SU and RU, in some cases an additional unit (which

is responsible for directing, managing and approving the transfer).

The main objective of organisation and management in technology transfer is to

ensure that the main steps of TOT should have been properly executed and documented

as well.

Responsibilities and principles to be followed by RU and SU under this section are

as follows:

i. There will be a formal agreement between RU and SU. This agreement specifies

the responsibilities of both the parties before, during and after TOT.

ii. There should be a project management plan whose main objective is to control

all the necessary activities identified at the start of the undertaking. The project

management plan is generally a document which specifies each phase of a project

like initiating, planning, executing, monitoring, controlling and closing. It can be

called a collection of sub-plans like management plan for scope, quality, human

resources, risk, communication, profit, procurement, etc.

 

iii. There should be technology transfer protocol. The protocol is a set of rules on

which all the involved parties agreed while signing memorandum of

understanding (MoU). The technology transfer protocol should list the intended

sequential stages. The protocol should include:

a. Objective: The objective of TT protocol is to elucidate necessary information to

actual manufacturing from R&D by making it simple (by sorting out the

information).

b. Scope: It applies for complete technology transfer of product within the

respective company.

c. Key personnel and their responsibilities: It involves the details of key personnel

like designation and responsibilities.

d. R&D personnel have responsibilities like the selection of raw material,

development of process, identify the critical control point, etc.

WHO Guidelines for Transfer of Technology 67

e. Production personnel have responsibilities like to provide facility and

equipment, performing operations, cross-checking of SOPs, etc.

f. Maintenance department responsibilities are to calibrate and maintain the

equipment.

g. QC personnel is responsible for quality testing of APT, FP and preparation of

certificate of analysis, etc.

h. A parallel comparison of material, methods and equipment: All the details

related with the material, methods and equipment should be there in the

protocol, e.g. a checklist of raw materials, specifications, checklist of

equipment, quality control details of methods, etc.

i. The transfer stages with documented evidence of each critical stage have been

satisfactorily accomplished before next commences: There are different transfer

stages. So, there should be documented evidence such as source document,

primary document, etc. to ensure that each stage has been in control

qualitatively before it will transfer to the next stage.

 

Quality assurance is a wide-ranging concept covering all matters that individually or

collectively influence the quality of a product. It is the totality of the arrangements

made with the objective of ensuring that pharmaceutical products are of the quality

required for their intended use.

Quality control (QC)

Quality control covers all measures taken, including the setting of specifications,

sampling, testing and analytical clearance, to ensure that starting materials,

intermediates, packaging materials and finished pharmaceutical products conform

with established specifications for identity, strength, purity and other characteristics.

Quality planning

Part of quality management focused on setting quality objectives and specifying

necessary operational processes and related resources to fulfil the quality objectives.

Quality policy

Overall intentions and direction of an organization related to quality as formally

expressed by senior management.

Quality risk management (QRM)

Quality risk management is a systematic process for the assessment, control,

communication and review of risks to the quality of the pharmaceutical product

throughout the product life-cycle.

Receiving unit (RU)

The involved disciplines at an organization where a designated product, process or

method is expected to be transferred.

Sending unit (SU)

The involved disciplines at an organization from where a designated product, process

or method is expected to be transferred.

Spiking

The addition of a known amount of a compound to a standard, sample or placebo,

typically for the purpose of confirming the performance of an analytical procedure.

Standard operating procedure (SOP)

An authorized written procedure giving instructions for performing operations not

necessarily specific to a given product or material (e.g. equipment operation,

maintenance and cleaning, validation, cleaning of premises and environmental control,

sampling and inspection). Certain SOPs may be used to supplement product-specific

master and batch production documentation.

Technology transfer report

A documented summary of a specific technology transfer project listing procedures,

acceptance criteria, results achieved and conclusions. Any deviation should be

discussed and justified.

 

Gap analysis

Identification of critical elements of a process which are available at the SU but are

missing from the RU.

Good manufacturing practices (GMP)

That part of quality assurance which ensures that pharmaceutical products are

consistently produced and controlled to the quality standards appropriate to their

intended use and as required by the marketing authorization.

In-process control (IPC)

Checks performed during production in order to monitor and, if necessary, to adjust

the process to ensure that the product conforms to its specifications. The control of the

environment or equipment may also be regarded as a part of in-process control.

Installation qualification (IQ)

The performance of tests to ensure that the installations (such as machines, measuring

devices, utilities and manufacturing areas) used in a manufacturing process are

appropriately selected and correctly installed and operate in accordance with

established specifications.

Intercompany transfer

A transfer of technology between sites of different companies.

Intracompany transfer

A transfer of technology between sites of the same group of companies.

Operational qualification (OQ)

Documented verification that the system or subsystem performs as intended overall

anticipated operating ranges.

Performance qualification (PQ)

Documented verification that the equipment or system operates consistently and gives

reproducibility within defined specifications and parameters for prolonged periods

(in the context of systems, the term "process validation"may also be used.)

Process validation

Documented evidence which provides a high degree of assurance that a specific process

will consistently result in a product that meets its predetermined specifications and

quality characteristics.

Qualification

Action of proving and documenting that any premises, systems and equipment are

properly installed, and/or work correctly and lead to the expected results. Qualification

is often a part (the initial stage) of validation, but the individual qualification steps

alone do not constitute process validation.

WHO Guidelines for Transfer of Technology 65

Qualification batches

Those batches produced by the RU to demonstrate its ability to reproduce the product.

Quality assurance (QA)

 

iv. These guidelines are applied to all dosage forms. However, needs to be adjusted

case by case basis. Such as certain aspects should be controlled closely in case of

sterile products, aerosols, metered dose. WHO issued different guidance name

as “WHO guidance on manufacture of specific pharmaceutical products” in this

regard.

v. The guideline addresses the following areas related with SU and RU

a. Transfer of development and production (processing, packaging and cleaning)

b. Transfer of analytical methods for QA and QC.

c. Skills assessment and training

d. Management and organisation of the transfer

e. Assessment of premises and equipment

f. Documentation

g. Qualification and validation

These guidelines do have some limitations regarding its scope like:

i. As each transfer is unique, the provision of a comprehensive set of guidelines is

beyond the scope of these guidelines.

ii. These guidelines do not provide guidance on legal, financial or commercial

consideration associated with technology transfer projects.

 

5.4 TERMINOLOGIES SOURCE

The definitions given below apply to the terms used in these guidelines. They may

have different meanings in other contexts.

Acceptance criteria

Measurable terms under which a test result will be considered acceptable.

WHO Guidelines for Transfer of Technology 63

Active pharmaceutical ingredient (API)

Any substance or mixture of substances intended to be used in the manufacture of a

pharmaceutical dosage form and that, when so used, becomes an active ingredient of

that pharmaceutical dosage form. Such substances are intended to furnish

pharmacological activity or another direct effect in the diagnosis, cure, mitigation,

treatment, or prevention of disease or to affect the structure and function of the body.

Bracketing

An experimental design to test only the extremes of, for example, dosage strength.

The design assumes that the extremes will be representative of all the samples between

the extremes.

Change control (C/C)

A formal system by which qualified representatives of appropriate disciplines review

proposed or actual changes that might affect a validated status. The intent is to

determine the need for action that would ensure that the system is maintained in a

validated state.

Commissioning

The setting up, adjustment and testing of equipment or a system to ensure that it

meets all the requirements, as specified in the user requirement specification, and

capacities as specified by the designer or developer. Commissioning is carried out

before qualification and validation.

Control strategy

A planned set of controls, derived from current product and process understanding,

that assures process performance and product quality. The controls can include

parameters and attributes related to materials and components related to drug

substances and drug product materials and components, facility and equipment

operating conditions, in-process controls, finished product specifications, and the

associated methods and frequency of monitoring and control.

 

vi. There should be an effective process and product knowledge transfer.

Technology transfer will be considered successful if:

i. RU is capable of producing/reproducing the product, method or process that

was transferred (it must be proved with documented evidence) on a predefined

set of specifications as agreed with the SU.

Fig. 5.1: Units involved in the transfer of technology

62 Industrial Pharmacy II

ii. The continuous knowledge management system is maintained in case RU faces

any problem with the process during transfer so that RU can easily communicate

back to SU.

iii. There will be no lack of transparency.

iv. Any issues that have legal and economical implications such as IPR’s, royalty,

pricing, confidentiality, interest are expected to have any impact on open

communication, then it must be mentioned before or during the execution of

technology transfer.

5.3 SCOPE OF WHO GUIDELINES FOR TOT

i. The scope of these guidelines is very wide. It covers all the technology transfer

process aspects where a technical agreement exists. The technical agreement can

be between RU manufacturer and SU manufacturer or between SU manufacturers

to RU quality control laboratory. However, many points are not workable and

alternative approaches may be required in case of no such technical agreements.

ii. This document gives guidance in principle. It provides general recommendation

related to the activities required for successful intertransfer or intratransfer of

technology. It addresses the basic consideration for successful transfer to fulfil

the expectation of regulatory authority.

iii. These guidelines are apply to manufacturing API, manufacturing and packaging

of bulk materials, of finished products packaging and analytical testing.