WHO GUIDELINES
TECHNOLOGY TRANSFER IN PHARMACEUTICALS
Introduction
• 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
Terminology
The definitions given apply to the terms given in these
guidelines. They may have different meanings in other contexts
Acceptance criteria
• Measurable terms under which a test result will be
considered acceptable
• Numerical limits, ranges, or other suitable measures for acceptance of the results of analytical procedures
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 other 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 extreme
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 installation, testing, operation and maintenance 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
Corrective action
(C/A)
• Any action to be taken when the results of monitoring at a
critical control point indicate a loss of control
Critical
• Having the potential to impact on product quality or
performance in a significant way
Critical control
point (CCP)
• A step at which control can be applied and is essential to
prevent or eliminate a pharmaceutical quality hazard or to reduce it to an
acceptable level
Design space
• The
multidimensional combination and interaction of input variables (e.g. material
attributes) and process parameters that have been demonstrated to provide
assurance of quality
Drug master file
(DMF)
• Detailed information concerning a specific facility,
process or product submitted to the medicines regulatory authority, intended
for incorporation into the application for marketing authorization
Finished
pharmaceutical product (FPP)
• A product that has undergone all stages of production,
including packaging in its final container and labelling. An FPP may contain
one or more APIs
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
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
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
Gap analysis
Identification of critical elements of a process which are available at the SU but are missing from the RU
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
Validation
Action of proving and documenting that any process,
procedure or method actually and consistently leads to the expected results
Validation US-FDA
definition
“Establishing documented evidence which provides a high
degree of assurance that a specific process will consistently produce a product
meeting its pre-determined specifications and quality attributes”
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
➢ It is a pre-production
activity
Validation master
plan (VMP)
• A high-level document that establishes an umbrella
validation plan for the entire project and summarizes the manufacturer’s
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
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
Equipment
Qualification
It is a basic requirement of good analytical chemistry that
balances and other analytical instruments must be suitable for the purpose for
which they are used and that they must be appropriately calibrated
Stages of equipment
qualification
• Design qualification (DQ)
• Installation Qualification (IQ)
• Operational Qualification (OQ)
• Performance Qualification (PQ)
• Maintenance Qualification (MQ)
• Component qualification (CQ)
• Re- qualification (RQ)
Stages of Validation
Design
Qualification (DQ)
Design qualification (DQ) is documented evidence that the premises, supporting systems, utilities, equipment and processes have been designed in accordance with the requirements of good manufacturing practices (GMP)
Design Qualification
(DQ)
➢ Is necessary when planning and
choosing EQ or systems to ensure that components selected will have adequate
capacity to function for the intended purpose, and will adequately serve the
operations or functions of another piece of EQ or operation
➢ DQ states what the laboratory
wants the instrument to do and shows that the selected instrument is suitable
Design Qualification
(DQ) considerations
• Capabilities
E.g. Centrifuge- speed, capacity and temperature
• Requirements
E.g. Voltage, operational specifications, requirements to
work with existing equipments
• Features
E.g. ease of cleaning, self-calibrating, PC interface
SHIMADZU- UV1900
• Ultra-Fast Scan
• USB memory stick
• Hardware Design Based on Ergonomics
• A Diversity of Measurement Modes
• Easy to Operate, Obtain Answers Easily and Rapidly
Specifications
•Resolution of 1 nm
•Stray light is at 0.5 % max. (198 nm), twice as low as the
performance level of the UV-1800. With this stray light reduction, accurate
measurements are possible up to the vicinity of 2 Abs even in the ultraviolet
region
•The correlation coefficient is 0.9997, and correct measured
values are obtained even in the vicinity of 2 Abs
Installation
Qualification (IQ)
Installation Qualification (IQ) ensures that a balance or instrument is received as designed and specified and installed in the selected user environment
• Installation qualification (IQ) is the process of checking
the installation, to ensure that the components meet the approved specification
and are installed correctly, and to see how that information is recorded
• IQ establishes that the instrument is received as designed
and specified, that it is properly installed in the selected environment, and
that this environment is suitable for the operation and use of the instrument.
Before installation
- Obtain manufacturer's recommendations for installation
site requirements.
- Check the site for the fulfillment of the manufacturer's
recommendations (utilities such as electricity, water and gases plus
environmental conditions such as humidity, temperature, vibration level and
dust).
- Allow sufficient shelf space for the equipment itself,
related SOPs, operating manuals, logbooks and software.
Operation
Qualification (OQ)
Operational Qualification (OQ) demonstrates that a balance or instrument will function according to its operational specification in the selected environment
• Establishing confidence that process equipment and
sub-systems are capable of consistently operating within stated limits and
tolerances
• Tests whether the equipment functions in the same way as
described by the manufacturer
Performance
Qualification (PQ)
Performance Qualification (PQ) demonstrates that a balance or instrument consistently performs according to a specification appropriate to its routine use
• Performance Qualifications are a collection of test cases
used to verify that a system performs as expected under simulated real-world
conditions
• Appropriate testing that the finished product or process
produced by a specified process meets all release requirements for
functionality and safety and that procedures are effective and reproducible
• PQ should be performed on a daily (or at least a weekly)
basis, or whenever the instrument is used. The test frequency depends not only
on the stability of the equipment but also on everything in the system that may
contribute to the analysis results.
1. Define the performance criteria and test procedures.
2. Select critical parameters.
3. Define the test intervals.
Maintenance
Qualification (MQ)
Maintenance Qualification (MQ) describes and documents any maintenance required on the equipment
•The MQ describes and documents any maintenance required on
the equipment
• This includes routine servicing and any repairs necessary.
•Details of any maintenance contracts are also documented in
this section, together with a list of authorized service engineers
• In addition, the MQ includes the routine cleaning of the
equipment and also its ultimate disposal.
Component
Qualification (CQ)
• Component qualification (CQ) – is a relatively new term
developed in 2005. This term refers to the manufacturing of auxiliary
components to ensure that they are manufactured to the correct design criteria.
• This could include packaging components such as folding
cartons, shipping cases, labels or even phase change material.
• All of these components must have some type of random
inspection to ensure that the third party manufacturer's process is
consistently producing components that are used in the world of GMP at drug or
biologic manufacturer.
Instrument
Re-Qualification
• Instrument Validation should not be viewed as a one-off
event
– Confidence in analytical results is required for the whole
of the instrument’s working life.
• To ensure that this confidence is retained, the instrument
validation process should be repeated at regular intervals during the
instruments operational life.
• The difference between Installation Validation and
Re-Qualification is that IQ is omitted for the Re-Qualification
• Re-Qualification should be performed at least annually and
should be performed more frequently for applications whose test results have
critical implications
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