GMP in API Drug Development

By: Pharma Tips | Views: 4818 | Date: 20-Nov-2011

GMP in API developmentThe recommendations provided below have been elaborated from the best knowledge of current practice.

GMP in API  Drug Development

 

GMP in API development
The recommendations provided below have been elaborated from the best knowledge of current practice.


GMP in API  Drug Development

 

1. Analytical Matters
1.1. Setting of Specifications
Specifications for raw materials, intermediates and API will be elaborated throughout the development phase, as understanding and knowledge of the process and analytical procedures increase, from Phase I until end of Phase III. It is expected that the final and
full specification for raw materials, intermediates and API will be in place at the end of Phase III and this will be the basis on which the validation of the process is performed at the site of manufacture.

1 According to the information available at the time of the publication of this document. GMP in Api Development November 1999

As a minimum, the API should have defined test procedures for the determination of identity and characterisation of impurities and/or assay. It is recommended that an identity test is performed for Intermediates.A procedure should be in place to document and justify the specification changes to raw materials, intermediates and also to approve API specification changes from Phase I to
Phase III. For additional information on specifications see References section.

1.2. Analytical methods
The analytical methods should be developed in parallel with the development of the process, to control and/or check the appropriate specification at each phase of the development programme. It is expected that the final analytical procedures will be in
place at the end of Phase III and this will be the basis on which the final validation of the process is performed at the site of manufacture.
A procedure should be in place to document and justify the changes to analytical procedures from Phase I to Phase III.

1.3. Validation of analytical methods
Analytical methods must be proven to be appropriate at each phase to give assurance that the data generated is valid and suitable for its intended use. The final validation of the analytical procedures to ICH guideline (Q2a and Q2b) should be done at the end of
Phase III when the specification has been fully developed. Official methods, such as the ones in pharmacopoeias, don't require full validation,
provided that method’s suitability can be demonstrated in the laboratory of the intended user.

1.4. In-Process Checks (IPC)
During development, IPC may be developed to determine the performance of the
process. As the knowledge of the process increases, these IPC may be eliminated or
other checks may be added. Any change should be documented.

1.5. Cleaning process verification
Procedures need to be developed to clean process equipment. In the development phase,
cleaning validation is not usually necessary and thus cleaning verification is used to
assess cleanliness of equipment.

In early development (NC and Phase I) a good starting point can be visual inspection, a
non-specific test (e.g. residue on evaporation) or any other general test which can
determine the level of contamination.

1.6. Calibration
All critical equipment should be calibrated at regular intervals in accordance with a
written procedure.
1.7. Out of specification procedure
As soon as a specification exists, a general written procedure for dealing with Out of
Specification (OOS) results must be available and followed.

OOS results level of investigation should be dependent on the stage of development and
criticality of the specification

1.8. Reference standards and reference substances
These have to be developed in parallel with the development of analytical procedures. At
the end of Phase III, a well characterised and defined Primary Reference Standard should
be in place. If possible reference substances for main impurities should be available,
including degradation products (mixtures of impurities for identification purposes may be
suitable).

1.9. Stability testing
Stability indicating analytical procedures should be developed for use in analysis of
stability samples. These should be able to determine process related impurities and
degradation products.
In the early development phase, accelerated stability studies should be undertaken to
determine the initial stability of the API and from this the retest date and storage
conditions determined.
As the route of the process is fixed then real-time stability studies should be undertaken
in accordance with ICH guidelines Q1a, Q1b and Q6a.

2. Process matters
Chemical process development is done to optimise the chemical process (e.g. solvents,
reagents, reaction conditions) used to manufacture the API. Optimisation would be
carried out to improve quality and yields, enhance operability, reduce costs, and control
any potential health, safety or environmental effects. The objective of chemical process
development is to deliver a validatable process to the manufacturing site, including
procedures for reprocessing, reworking, recovery or cleaning, if applicable.
During development and scale-up studies, batches of API used for the clinical
development programme may be prepared in pilot plants; these are usually dedicated
R&D facilities. The API may need to be produced to different levels of control
dependant upon the intended use and development stage of the API (NC, Phase I, Phase
II or Phase III).

2.1. Chemical/physical characteristics
The composition of the API (e.g. whether a free-base, salt, solvate, hydrate etc.) and its
physical form (e.g. amorphous, crystalline form / polymorphs), controllable by the
process and analytical methodology, should be defined at Phase I. However, there must
be opportunity to change the characteristics of the API in an evolutionary process. These
must be fixed at the end of Phase III. When there are changes, these must be evaluated to
determine if toxicology studies should be repeated and bio-equivalence demonstrated.

2.2. Process description
Process description will develop throughout the development process, as understanding
and knowledge of the process increases. It is expected that the final process instructions
will be in place at the end of Phase III and this will be the basis on which the final
validation of the process is performed at the site of manufacture.

2.3. Definition of chemical synthesis route

At the end of Phase III the chemical synthesis route, as defined by the isolated and nonisolated
chemical intermediates, should be fixed. This route will be described in the
regulatory submission and should identify starting materials as well as intermediates.
However, it should be noted, that the earlier the route is fixed, the fewer problems are
likely to arise. Different routes may be acceptable during development. The impurity
profile changes have to be qualified according to ICH Q3a (e.g. by toxicity studies).
Changes to the impurity profile and/or physical characteristics of the API should be
verified, taking into consideration any impact on bioavailability.

2.4. Stability studies and definition of storage conditions and packaging materials
Stability studies on the API should form the basis for the proposed storage conditions,
packaging materials and retest or shelf life period and so justify operational practices.
Retesting the material prior to use is an acceptable practice.

2.5. Critical process variables
Process variables which need to be controlled in order not to compromise the quality of
the intermediate and/or API, need to be investigated and identified as critical. This study
normally starts in Phase I and should be finished prior to the end of Phase III. These data
are related to PARs.

2.6. Proven Acceptable Ranges (PARs)
PAR apply to critical process parameters and need to be defined during process
development and scale-up. These ranges should be included in the process validation
protocol.

2.7. Process deviations
As soon as process instructions exists, a general written procedure for dealing with
process deviations must be available and followed.
Process deviations level of investigation should be dependent on the stage of
development and criticality of the specification.

2.8. Qualification of production equipment
Production equipment and associated instrumentation, when appropriate, should be
identified and qualified for its intended use. In Phase I an II the use of nonqualified
laboratory equipment is acceptable.

2.9. Calibration and Maintenance
All measuring and control equipment critical to product quality should be calibrated and
maintained at appropriate intervals according to written procedures.

2.10. Cleaning procedures
Cleaning procedures may be either specific (i.e. developed for particular vessels and
chemical stages) or generic and should be developed as integral part of the process in
order to achieve effective cleaning of plant and equipment.
All should be capable of validation when transferred to production sites. The applied
procedures should have associated testing methods and release procedures, if
appropriate.

2.11. Utilities

Utilities in direct contact with the API should be of controlled quality and their systems
should be validated.

2.12. Process validation
Process validation is not required during development, but a process validation strategy
should be available at the end of Phase III.

3. Quality Management Systems, QU, Training and Responsibilities

3.1. Quality Management.
A system for managing quality should be in place. This system should encompass the
organisational structure, general procedures (and specific protocols where required),
processes and resources as well as actions necessary to ensure confidence that the API
for Non-Clinical and Clinical studies will meet its intended (predetermined) specifications
for quality and purity in relation to its intended use.

3.2. Regulatory aspects
The system for managing quality should ensure compliance with the regulatory
submission.
It is recommended a Development Report o equivalent document be compiled, and to be
available at the end of phase III. While it isn't a GMP requirement, it is a regulatory
expectation, which could be reviewed during a Pre-approval Inspection.
This document will resume all background information on the selected route, the
development of the chemical process, the chosen equipment and the development of
analytical methods and specifications. The Development Report needs not contain all
data but refer to more detailed subsidiary reports.

3.3. Documentation of changes
The system for managing quality should ensure that, beginning from an early stage, all
planned changes are documented and justified.

3.4. Selection and documentation of (raw) material suppliers
The system for managing quality should ensure that, at the end of the development,
suppliers of (raw) materials are identified, selected, approved and monitored.
Selected suppliers of (Raw) materials for Phase I and Phase II need to be identified only,
whereas the requirements for Phase III include approval and monitoring of the supplies
by QU.

3.5. Outsourcing and supply
Outsourcing and/or external supply are sometimes needed. Strategic and tactical plans
should be developed concerning to the use of external companies to carry out contract
development and/or supply of materials. The contracted firm must meet appropriate
GMP requirements.
Access to raw data and technology transfer should be agreed and laid down in the formal
contract.
The QU should approve service providers.

3.6. Data integrity review

A procedure should be in place for data integrity checking at milestones, in house or as
defined in the formal contract between the company and the contractor. Responsibility
for such checks should be defined, and could be part of the auditing system of the
company.
It is advisable to conduct a formal review prior to any regulatory submission.

3.6. Training/Competence
Training on tasks to be performed, including GMP, should be given, evaluated, recorded
and kept for further review.

3.7. Labelling
The label should at minimum contain:
- the identification of the compound
- batch number
- storage conditions
- retest date
- safety information, as appropriate, for external transport (a legal requirement, not
a GMP requirement)
Assignment of storage conditions should be based on results of available stability data.

3.8. Documentation and retained samples
To support the GMP-status of work done, documentation and retain samples should be
available. Documentation on production and testing of the API should be kept to allow
for traceability. For the same reason, samples of all pivotal batches are to be retained.
A procedure should be in place to define the storage and retention time of the documents
and samples.

4. Technology transfer
A procedure should be in place describing the transfer of technology (process and
analytical) from R&D to manufacture. This procedure should include responsibilities and
criteria for a successful transfer.
Technology transfer during development should ensure availability and accessibility of
information obtained earlier.

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