1 The management and technical evaluation requirements of chemical drug substances State Food and Drug Administration Center for Drug Evaluation March.

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The management and technical evaluation requirements of chemical drug substances

State Food and Drug Administration

Center for Drug EvaluationMarch 2010

Huo Xiumin

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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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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.

Preparation Process

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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.

Preparation Process

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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.

Preparation Process

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Structure identification test and reference materials

Chemical name, molecular structure formula (including the three-

dimensional 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.

Structure identification

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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.

Structure identification

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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

Quality Study

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--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.

• For the drug substances for injection (sterile powders-packing), if necessary, examine the bacterial toxins or pyrogens, sterility, etc.

Specification

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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

Specification

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--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

Specification

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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

Specification

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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

Specification

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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

Specification

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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

Specification

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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

Specification

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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

Specification

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Analysis report of three batches of samplesThe 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

Inspection Report

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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

Stability Study

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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)

Stability Study

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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.

Packaging materials and containers

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III. Problems and SolutionsPrinciples: 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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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

Questions and Solutions

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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.

Problems and Solutions

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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.

Problems and Solutions

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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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