Transcript 幻灯片 1

The management and technical
evaluation requirements of
chemical drug substances
Huo Xiumin
State Food and Drug Administration
Center for Drug Evaluation
March 2010
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Main Contents
I. Drug substance management of SFDA
II. The information requirements and the
main points of evaluation of CMC
III. Problems and Solutions
IV. Summary
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I. Drug substance management of
SFDA
Article 25 of Drug Registration Regulation: When an application is only made
for registration of drug products, the drug substances used for investigation
must have a Drug Approval Number, Import Drug Certificate or Pharmaceutical
Product Registration Certificate, and must have been obtained from legal
channels. Any investigative drug substance which does not have a Drug
Approval Number, Import Drug Certificate or Pharmaceutical Product
Registration Certificate must be approved by the SFDA.
-----Drug substances will be approved by the SFDA.
-----Production and sales can be conducted only after
having obtained the registration certificate.
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Article 95 of Drug Registration Regulation:
For an imported drug products
application, ......For drug substances and
excipients that have not yet been approved by
SFDA, standardized study information of
relevant production processes, specification,
and test methods should be submitted.
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II. The information requirements and the main
points of evaluation of CMC
Principles: The consistent requirements between import and
domestic research drugs
 Synthetic process study and reference materials
 Structure identification test and reference materials
 Quality study test and reference materials
 Specification and its drafting instructions, the source and purity of standards or
the reference substances
 Certificate of Analysis of three batches of samples
 Stability test materials
 The selection basis and specification of primary packaging materials and
containers
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Preparation Process
 Synthetic process study and reference materials
 Basis for design of process route
 Complete process (chemical reaction equation, the starting materials, the
various step reaction type, reaction conditions and reaction intermediates, final
product purification / purification methods, etc).
 Key synthetic steps and critical process parameters affecting the quality
 It should be described that if the special reagents, solvents, catalysts, or special
reaction conditions are used.
 The major items and limits are included in the internal control standards of the
key starting materials and key intermediates. For the chiral materials and chiral
intermediates, the chirality control indicator should be included.
 Process control methods (HPLC method or TLC method controlling reaction
process)，the qualitative identification of each of reaction intermediates
(melting / boiling point, optical rotation, IR method, NMR method, mass
spectrometry), and the comparison with reference data.
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Preparation Process
Focus on: The processes of pilot scaling up and the
preparation of clinical samples, including the manufacture site,
batch and batch size, the quality control indicators of starting
materials, reagents, solvents and intermediates, the process
parameter scope of the key steps, the use conditions of organic
solvents, the studies of impurities and analysis method validation,
etc.
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Preparation Process
 Production process and its validation
Focus on: the presence or absence of changes of the process
routes of the production scale, as well as small scale and pilot scale,
starting materials, reaction reagents, solvent level (from AR to a
chemical pure or industrial pure), process parameters, etc
Production process validation protocol and validation report
(validation batches, scale, key process parameters of validation, and
outcome evaluation, etc.)
Evaluation: the feasibility of the proposed process for commercial
production and whether the products meeting the specification can
be produced stably by using the specified raw materials and
equipment and according to the proposed process.
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Structure identification
 Structure identification test and reference materials
 Chemical name, molecular structure formula (including the threedimensional configuration), molecular formula, molecular weight
 Purification methods and purity of test samples (purity determination
method)
 With the generic drugs, the reference substances can be available, and
the source, purity and other information of reference substances can
be provided
 Test methods (elemental analysis, UV, IR, MS, NMR, thermal analysis,
powder X-ray diffraction, etc.), and the instruments and testing
conditions used, including the tests for the three-dimensional
conformation, crystal solvent (or the crystal water) and the crystal
forms, etc.
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Structure identification
Focus on: whether the method used is
in line with its structural test requirements,
and the test results of the planar structure,
three-dimensional configuration, crystal
forms, crystal solvent and crystal water are
consistent with the target product or the
product by imitated.
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Quality Study
Quality study and reference materials
 Quality study tests include the determination of study items
and methodology study.
--Determination of study items
--Methodology study includes the method selection and method
validation
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Specification
--Determination of the study items
Based on product characteristics, preparation process and
stability study results, the quality study items are determined
•
Study items include: description (appearance, color, smell, taste,
crystallinity, hygroscopicity, etc.), physical and chemical properties
(melting point, optical rotation, solubility, absorption coefficient,
etc.), identification, examination (General impurities: chloride,
sulfate, heavy metals, arsenic salt, residue on ignition, etc.
Impurity: the starting materials, intermediates, polymers, vice
reaction products, isomers introduced during the production
process, as well as degradation products occurred during storage,
residual solvents, crystal form, particle size, dry weight loss, or
moisture, solution clarity and color, pH, etc.) and assay.
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For the drug substances for injection (sterile powders-packing),
if necessary, examine the bacterial toxins or pyrogens, sterility, etc.
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Specification
Focus on: Whether the quality study items are comprehensive
(it is necessary to consider the general requirements, but also
targeted requirements), and can fully reflect the circumstances of
product characteristics and quality changes
The effects of starting materials and reagents, reaction
intermediates and side reaction products, as well as organic
solvents on the quality of final products should be considered
during the preparation process
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Specification
--Method selection and method validation
The selection of analysis methods should be aimed at selected research
items and the experimental purpose
The method selection should have the basis, including the basis of
references and tests
Pharmacopoeia methods can be used for the conventional items
The comparison study with two or more methods will be used for the
examination of impurities and assay to compare the pros and cons of
methods and choose the best of them
The method validation should be conducted for the analytical methods
used
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Specification
Focus on: The specificity of identifying item
methods, the specificity of examination item
methods, sensitivity and accuracy, the accuracy
and repeatability of assay methods, and the
method validation results can confirm the
feasibility of methods
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Specification
 Specification and the drafting instructions, the source and
purity of standards or reference substances
----Specification is consist of three aspects, including the test
items, analysis methods and the limits
----The analytical method should only be confirmed to
become a specification method by the method validation
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Specification
 Determination of specification items and limits
--Item settings have both universal and also targeted (for the characteristics of the
product itself), and can sensitively reflect the changes in product quality
--Limit determination at the first should be based on drug safety and efficacy
considerations, and analytical methods errors. Under the premise of ensuring safe
and effective products, the actual situation of production process can be
considered, as well as taking into account the influences of the circulation and the
use
R & D staff should pay attention to the scale of industrial production of products
and carry out the safe, effective study of the quality consistency of the samples
----In other words, commercial production can not be lower than the quality of the
products used for safe, effective test samples, otherwise they will be re-evaluated
the safety and effectiveness
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Specification
Focus on: Whether the items of specification to control
the product quality can reflect the characteristics and
quality changes of the product, the feasibility of
methods and ease of operation, as well as the science
and rationality of limits, and whether the specification
can effectively control the consistency between batches
of product quality
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Specification
The drafting instructions of specification
The drafting instructions of specification are
the comment of specification, R & D staff will
describe in detail the various items settings and
the basis of limit determination in the
specification drafting instructions (the relevant
research data, measured data and literature data
should be noted to list), and some reasons why
several research items can not listed in the
specification
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Specification
 The source and purity of Standard or reference
substances
The standardized test materials must be provided in the case of
self-production standards or reference substances
Focus on: the legality of the source of standards or reference
substances, or the scientific nature of the standardized
testing methods and the reliability of test results
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Inspection Report
Analysis report of three batches of samples
The analysis report of three continuous batches of
samples with full review should be provided according
to requirements of specification and with the signature
of department leader
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Stability Study
 Stability test materials
 The batch, lot number, size, packing cases of stability test
samples
 Stability protocol (impact factor tests, accelerated tests
and long-term tests, and their observation indicators of
quality)
 Test methods used
 Test results and analysis and evaluation of results
 post-marketing stability protocol and commitments
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Stability Study
Focus on: Whether the stability research samples are representative,
and the study contents are comprehensive (impact factor tests,
accelerated tests and long-term tests), the observation indicators of
quality are reasonable and can reflect the changes in the quality of
the sample, the setting conditions and observation time are
reasonable, and the requirements of detection methods and limits
are reasonable
Whether the stability protocol design, implementation, and
observation can support the packaging, storage conditions and
expiry period (retest period)
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Packaging materials and containers
 The selection basis and specification of primary packaging materials
and containers
Based on China’s current drug management regulation, as an
important component of pharmaceutical drugs ----- primary
packaging materials and containers must be approved by SFDA, the
pharmaceutical packaging material registration certificate and
specification should be provided.
Focus on: whether the registration certificate for
pharmaceutical packaging material and containers can be available,
as well as the applicability for medicine storage and transportation,
etc.
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III. Problems and Solutions
Principles: import and domestic research drugs have a consistent requirement
 The application registration for Domestic drug substances should in accordance with
the requirements of submitting the application materials according to the Annex 2 of
Drug Registration Management Regulation of SFDA
 Also, the application registration for imports drug substances should in accordance
with the requirements of submitting the application materials according to the Annex
2 of Drug Registration Management Regulation of SFDA
 For the application registration for drug products, there is a larger gap between the
study materials of quality control for drug substances used and the requirements of
the Annex 2 of Drug Registration Management Regulation of SFDA.
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Questions and Solutions
 The format of application materials
 SFDA "Drug Registration Management Regulation" Annex 2 format√
 CTD format √
 Application for an import registration of drug products
 Registration application for imports preparations of self-produced drug substances
The application material requirements of drug substances should be consistent with the
registration requirements of the domestic drug substances √
 Import registration application for outsourcing preparations of drug substances
The application material requirements of both drug substances and drug products should
be consistent with the registration requirements of the domestic drug substances
----Technological security
----Main body of responsibility
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Problems and Solutions
For the registration applications of import preparations of drug
substances, the specification and analysis report of drug
substances, simple chemical reaction equations and the structure
test pattern, or DMF registration number, CEP numbers should
usually be submitted. Without a detailed production process,
structure identification, the specification and stability research
materials, the reasonableness of specification and controllability of
product quality can not be determined.
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Problems and Solutions
 Solutions
 According to the relevant provisions of the "Drug Registration Regulation” of
SFDA
 In accordance with the API Management and Assessment Model of U.S. FDA and
the EU EDQM
-----the relevant study data are required to submit for API suppliers and drug
products manufacturers respectively, and the RP part of the review process can
be started only based on the written authorization of permission of API suppliers
An AP copy of DMF will be included in the application information submitted
by the applicant of drug products. This AP part can be determined through the
review the adequacy of the AP content, if not fully, the DMF holder will be
requested to provide the supplementary RP content.
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IV Summary
 Drug substances quality control evaluation is a prerequisite for quality
evaluation of drug products
 Submitting drug substances quality control information for imported
drug products is the management requirements of SFDA
 AP part of the DMF used in drug substances can be provided by the
certificate holder of drug products
 RP part of the DMF can be submitted directly to SFDA by drug
substances suppliers (DMF holder)
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