Granularity of TT Process

(API, excipients, finished products, packaging materials) Starting materials

The specifications of the starting materials (APIs and excipients) to be used at the
RU should be
consistent with reference batches (development batches, bio batches or batches
manufactured at
the SU). Any properties which are likely to influence the process or product
should be identified
and characterized.

Active Pharmaceutical Ingredients (API)

The SU should provide the drug master file (DMF) and any relevant additional
information on
the API to the RU to be checked against the specifications of the API. The following
information
should be provided:
• Manufacturer;
• Flow chart of synthetic pathway, outlining the process, including entry points
for raw materials, critical steps, process controls and intermediates;
• Definitive form of the API (including photomicrographs and other relevant data)
and any polymorphic and solvate forms;
• Solubility profile;
• Partition coefficient (including the method of determination);
• Intrinsic dissolution rate (including the method of determination);
• Particle size and distribution (including the method of determination);
• Bulk physical properties, including data on bulk and tap density, surface area
and porosity as appropriate;
• Water content and determination of hygroscopicity, including water activity
data and special handling requirements;
• Microbiological considerations (including sterility, bacterial endotoxins and bio
burden levels where the API supports microbiological growth) in accordance
with regional pharmacopoeial requirements;
• Specifications and justification for release and end-of-life limits;
• Summary of stability studies conducted in conformity with current guidelines,
including conclusions and recommendations on retest date;
• Listing of potential and observed synthetic impurities, with data to support
proposed specifications and typically observed levels;
• Information on degradants, with a listing of potential and observed degradation
products and data to support proposed specifications and typically observed
levels;
• Potency factor, indicating observed purity and justification for any
recommended adjustment to the input quantity of API for product
manufacturing, providing example calculations; and
• Special considerations with implications for storage and/or handling, e.G. Safety
and environmental factors and sensitivity to heat, light or moisture.
Excipients
• The excipients to be used have a potential impact on the final product. Their
specifications as well as the DMF should, therefore, be made available by the SU
for transfer to the RU site. The following information should be provided for all
types of excipients:

• Description of functionality, with justification for inclusion of any antioxidant,

preservative or any excipient above recommended guidelines;

• Manufacturer;

• Specifications, i.e. Monographs and additional information that may affect

product processing or quality for compendia excipients, or a complete listing of
specifications, including analytical methods and justification for release limits
for non-compendial vexcipients. For excipients used for the first time in a
human drug product or by a new route of administration, the same level of
detail as for a drug substance should be provided;
• 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) and sensitivity to heat, light or moisture solubility; and

• Regulatory considerations, i.e. Compendial status and appropriate regulatory

information for non-compendial excipients; information on residual solvents or
organic volatile impurities; and documentation to support compliance with
transmissible animal spongiform encephalopathy certification requirements
(where applicable).
Finished Products
Depending on the type of dosage form, the SU should provide relevant
information on physical properties of excipients to the RU, including:

• Definitive form (for solid and inhaled dosage forms);

• Solubility profile (for solid, inhaled and transdermal dosage forms);

• Partition coefficient, including the method of determination (for transdermal

dosage forms);

• Intrinsic dissolution rate, including the method of determination (for

transdermal dosage forms);

• Particle size and distribution, including the method of determination (for solid,
inhaled and transdermal dosage forms);
• Compaction properties (for solid dosage forms);

• Melting point range (for semi-solid/topical dosage forms);

• Ph range (for parenteral, semi-solid/topical, liquid and transdermal dosage

forms);

• Ionic strength (for parenteral dosage forms);

• Specific density/gravity (for parenteral, semi-solid/topical, liquid and

transdermal dosage forms);

• Viscosity and/or viscoelasticity (for parenteral, semi-solid/topical, liquid and

transdermal dosage forms);
• Osmolality (for parenteral dosage forms);

• Water content and determination of hygroscopicity, including water activity

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

• Moisture content range (for parenteral, semi-solid/topical, liquid and

transdermal dosage forms);

• Microbiological considerations in accordance with regional pharmacopoeial

requirements (for parenteral, semi-solid/topical, liquid, inhaled and
transdermal dosage forms); and

• Information on adhesives supporting compliance with peel, sheer and adhesion

design criteria (for transdermal dosage forms).
Packaging
• Information on packaging to be transferred from the SU to the RU include
specifications for a suitable container/closure system, as well as any relevant
additional information on design, packing, processing or labeling requirements
needed for qualification of packaging components at the RU. For quality control
testing of packaging components, specifications should be provided for
drawings, artwork, material.
Documentation: The documents used in technology transfer are presented in
table 1.
Table 1. Documentation for transfer of technology (TOT)
Premises and Equipment
Premises
• The SU should provide information to the RU on the layout, construction and
finish of all buildings and services (heating, ventilation and air-conditioning
(HVAC), temperature, relative humidity, water, power, compressed air)
impacting the product, process or method to be transferred.
• The SU should provide information on relevant health, safety and
environmental issues, including:
• Inherent risks of the manufacturing processes (e.g. reactive chemical hazards,
exposure limits, fire and explosion risks).
• Health and safety requirements to minimize operator exposure (e.g.
atmospheric containment of pharmaceutical dust).
• Differences in building, construction layout and services between the SU and
the RU should be listed and compared in view of the following considerations:
• Buildings and services at the RU should be capable of accommodating the
product, process or method under transfer to the agreed quality standard and
production volume in compliance with GMP;
DQ, design qualification; IQ, installation qualification; OQ, operational
qualification; API, active
pharmaceutical ingredient; SOPs, standard operating procedures; RU, receiving
unit.

• Quality control laboratories should be equipped and capable of testing all APIs,
excipients, intermediate and finished products, packaging components and
cleaning validation samples;
• Buildings intended for production of a highly sensitizing nature (e.g. penicillin's
and cytotoxic materials) should be dedicated for this purpose and located in a
different facility from other production units; and
• Health, safety and environmental issues, including waste management,
emergency planning, minimization of operator exposure and environmental
impact, should be addressed at the RU in compliance with any regulatory or
company-developed rules, regulations and limits.
Equipment
The SU should provide a list of equipment, makes and models involved in the
manufacture,
filling, packing and/or control of the product, process or method to be transferred,
together with
existing qualification and validation documentation. Relevant documentation
may include:

• Drawings;
• Manuals;
• Maintenance Logs;
• Calibration logs; and
• SOPs (e.g. equipment set up, operation, cleaning, maintenance, calibration,
storage).
The RU should review the information provided by the SU together with its own
inventory list

including the qualification status (IQ, OQ, PQ) of all equipment and systems, and
perform a side by-side comparison of equipment at the two sites in terms of their
functionality, makes, models and qualification status.

Based on the side-by-side comparison, the RU should perform a gap analysis to

identify

requirements for adaptation of existing equipment, or acquisition of new

equipment, to enable

the RU to reproduce the process being transferred. GMP requirements should be

satisfied, and
Factors to be compared include:

• Minimum And Maximum Capacity;

• Material Of Construction;

• Critical Operating Parameters;

• Critical Equipment Components (E.G. Filters, Screens, Temperature/Pressure

Sensors); And

• Range of intended use.

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

the time of drawing up process maps or flow charts of the manufacturing process
to be

transferred, including movement of personnel and material.

The impact of manufacturing new products on products currently manufactured

with the same

equipment should be determined.

Where existing producing equipment needs to be adapted to be capable of

reproducing the

process being transferred, a detailed development project should be included in

New equipment should be designed and constructed to facilitate the process and
ease cleaning

and maintenance operations. Any newly acquired equipment should undergo a

qualification

protocol up to and including OQ level.

Applicable operating procedures for set-up, operation, cleaning, storage and

maintenance should

be developed by the conclusion of OQ. Supporting documents such as drawings of

equipment

and piping installations, manuals, maintenance logs and calibration logs should
Qualification and Validation
General
• Qualification and validation of facilities, equipment, systems and procedures
are essential to demonstrate that all critical stages of the transfer project have
been completed successfully, enabling the RU to reproduce the product, process
or method routinely to the specifications agreed with the SU.

• Validation performed as part of the transfer project should be documented in a

validation master plan (VMP). The VMP should identify the stages which need
to be validated and define acceptance criteria.

• For intra-company transfers, the RU should operate under the same VMP as the
SU. For intercompany transfers, a VMP should be in place at the RU before the
transfer.
• The RU should prepare a validation protocol (VP) for each sequential step.
Successful execution of each VP should be documented in a validation report
(VR).

• Setting up and commissioning of systems at the RU need to be completed before

qualification and validation can be performed at the RU. The steps required for
this purpose have been described in this guideline for buildings, services and
equipment, manufacturing, packaging and cleaning and analytical testing. In
brief, the following basic steps apply equally to each of these areas:

• The SU should provide information on materials, systems and procedures

involved in the manufacturing of the product, process or method to be
transferred;
• The RU should review the information provided by the SU, and audit its current
systems, equipment and processes, including non-process related practices and
support services that impact the process;

• Based on this review, the RU should either accept the information provided or
develop it further to prepare site-specific procedures, SOPs, training program
and protocols which will form the basis of the qualification and validation; and

• Relevant staff, e.g. operators and analysts, should be trained in any new
processes as required.
• Once the required systems and procedures have been commissioned at the RU,
and successful training has been documented, qualification and validation of
facility and equipment should be executed, followed by validation of analytical
test methods, process validation for manufacturing and packaging, and cleaning
validation.

• The RU should review the gap analysis and prepare, where appropriate, VPs for
the facility, services and equipment.

• Both new and existing equipment should satisfy the VPs associated with
purchase and design specifications, factory acceptance tests (FAT) if possible, IQ
and OQ.

• Performance qualification, including a further assessment of operating

parameters with relation to product characteristics, should be established on
Quality Control
• Transfer of analytical methods should accommodate all the
analytical testing required to demonstrate compliance of the product
to be transferred with the registered specification.

• Transfer of analytical methods used to test pharmaceutical products,

their ingredients and leaning (residue) samples, needs to be in place
before process validation studies of manufacturing operations can
be carried out.
• The SU should prepare a protocol defining the steps to be
undertaken for analytical method transfer. The analytical methods
transfer protocol should describe the objective; scope;
responsibilities of the SU and the RU; materials, methods and
equipment; the experimental design and acceptance criteria;
documentation (including information to be supplied with the
results, and report forms to be used if any); deviations; references;
signed approval; and details of reference samples (APIs,
intermediates and finished products).
The SU's responsibilities for the transfer of analytical methods are to:
• Provide method-specific training for analysts and other quality control staff;

• Provide acceptance criteria and validation protocols for any RU training

exercises;

• Assist in analysis of quality control testing results;

• Define and justify all methods to be transferred for testing a given product,
ingredient or cleaning sample;

• Define experimental design, sampling methods and acceptance criteria;

• Provide any validation reports for methods under transfer, and demonstrate
their robustness;

• Provide data for the equipment used and any standard reference samples; and
The RU's responsibilities are to:
• Review analytical methods provided by the SU, and formally agree on
acceptance criteria before execution of the transfer protocol;

• Ensure that the necessary equipment for quality control is available and
qualified at the RU site. Equipment should be replicated where possible,
but it is accepted that different models, e.g. spectrometers and
chromatographs, could already be in place;

• Ensure that adequately trained and experienced personnel is in place for

analytical testing;

• Provide a documentation system capable of recording receipt and testing

of samples.
A suggested analytical training protocol would be as follows:
• SU and RU analysts assay two retained samples from SU;

• SU and RU analysts then assay two sub-potent samples (available

from SU or spiked);

• SU and RU analysts assay samples taken from RU production;

• RU analyst provides sufficient replicate analyses to enable a

significance test (e.g. student’s t) against the established method at
the SU site; and

• A similar exercise should be undertaken for analysis of low levels of

APIs.
Analytical methods Transfer
The analytical methods transfer protocol should cover the following sections:
• Objective;
• Scope;
• Responsibilities of the SU and the RU;
• Materials, methods and equipment;
• The experimental design and acceptance criteria;
• Documentation (including information to be supplied with the results, and
report forms to be used if any);
• Deviations;
• References;
• Signed approval; and
• Details of reference samples (APIs, intermediates and finished products).
• Successful transfer and validation of analytical methods should be documented
in a report.