Documents to be published This document recommends acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. It recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents. Read together with the annexes on specifications for class 1 and class 2 residual solvents in active substances and residues of solvents used in the manufacture of finished products. In , ICH was notified by an external party of a discrepancy between Summary Table 2 of the guideline and the monograph for EG listed in Appendix 5. The PDE indicated in the monograph was 3. This issue was presented to the Q3C EWG for discussion and given the lack of any additional information or awareness of a supporting rationale for the value listed in Summary Table 2, the EWG considered the discrepancy to be a transcription error in the Summary Table 2.

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Parametric release can be used as an operational alternative to routine release testing for the drug product in certain cases, when approved by the regulatory authority. Sterility testing for terminally sterilized drug products is one example. In this case, the release of each batch is based on satisfactory results from monitoring specific parameters, e.

These parameters can generally be more accurately controlled and measured, so they are more reliable in predicting sterility assurance than is end-product sterility testing. Appropriate laboratory tests e. It is important to note that the sterilization process should be adequately validated before parametric release is proposed, and maintenance of a validated state should be demonstrated by revalidation at established intervals.

When parametric release is performed, the attribute that is indirectly controlled e. Alternative procedures are those that may be used to measure an attribute when such procedures control the quality of the drug substance or drug product to an extent that is comparable or superior to the official procedure.

Example: For tablets that have been shown not to degrade during manufacture, it may be permissible to use a spectrophotometric procedure for release as opposed to the official procedure, which is chromatographic. However, the chromatographic procedure should still be used to demonstrate compliance with the acceptance criteria during the shelf life of the product.

Wherever they are appropriate, pharmacopeial procedures should be used. The full utility of this guidance is dependent on the successful completion of harmonization of pharmacopeial procedures for several attributes commonly considered in the specification for new drug substances or new drug products. Where harmonization has been achieved, an appropriate reference to the harmonized procedure and acceptance criteria is considered acceptable for a specification in all three regions.

For example, after harmonization, sterility data generated using the JP procedure, as well as the JP procedure itself and its acceptance criteria, will be considered acceptable for registration in all three regions. To signify the harmonized status of these procedures, the pharmacopeias have agreed to include a statement in their respective texts that indicates that the procedures and acceptance criteria from all three pharmacopeias are considered equivalent and are, therefore, interchangeable.

Since the overall value of this guidance is linked to the extent of harmonization of the analytical procedures and acceptance criteria of the pharmacopeias, it is agreed by the members of the Q6A expert working group that none of the three pharmacopeias should change a harmonized monograph unilaterally.

Such technologies should be used when they are considered to offer additional assurance of quality, or are otherwise justified. Example: It is normally not considered necessary to test the drug product for synthesis impurities that are controlled in the drug substance and are not degradation products. It should have a quality appropriate to its use. It is often characterized and evaluated for its intended purpose by additional procedures other than those used in routine testing.

Guidance 3. It establishes the set of criteria to which a new drug substance or new drug product should conform to be considered acceptable for its intended use. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval.

It is possible that, in addition to release tests, a specification may list in-process tests as defined in section 2. In such cases the applicant should specify which tests are routinely conducted batch by batch, and which tests are not, with an indication and justification of the actual testing frequency. It should be noted that changes in the specification after approval of the application may need prior approval by the regulatory authority. The justification should refer to relevant development data, pharmacopeial standards, test data for drug substances and drug products used in toxicology and clinical studies, and results from accelerated and long-term stability studies, as appropriate.

Additionally, a reasonable range of expected analytical and manufacturing variability should be considered. It is important to consider all of this information. Approaches other than those set forth in this guidance may be applicable and acceptable. The applicant should justify alternative approaches. This justification may consider theoretical tolerances for a given procedure or acceptance criterion, but the actual results obtained should form the primary basis for whatever approach is taken.

If multiple manufacturing sites are planned, it may be valuable to consider data from these sites in establishing the initial tests and acceptance criteria. This is particularly true when there is limited initial experience with the manufacture of the drug substance or drug product at any particular site. If data from a single representative manufacturing site are used in setting tests and acceptance criteria, product manufactured at all sites should still comply with these criteria.

Presentation of test results in graphic format may be helpful in justifying individual acceptance criteria, particularly for assay values and impurity levels. Data from development work should be included in such a presentation, along with stability data available for new drug substance or new drug product batches manufactured by the proposed commercial processes.

Justification for proposing exclusion of a test from the specification should be based on development data and on process validation data where appropriate. If any of these characteristics change during storage, this change should be investigated and appropriate action taken. Identification tests should be specific for the new drug substance, e. Identification solely by a single chromatographic retention time, for example, is not regarded as being specific.

If the new drug substance is a salt, identification testing should be specific for the individual ions. An identification test that is specific for the salt itself should suffice.

New drug substances that are optically active may also need specific identification testing or performance of a chiral assay.

Please refer to section 3. In many cases it is possible to employ the same procedure e. In cases where use of a nonspecific assay is justified, other supporting analytical procedures should be used to achieve overall specificity. For example, where titration is adopted to assay the drug substance, the combination of the assay and a suitable test for impurities should be used.

Decision Tree 1 addresses the extrapolation of meaningful limits on impurities from the body of data generated during development.

At the time of filing it is unlikely that sufficient data will be available to assess process consistency. Therefore it is considered inappropriate to establish acceptance criteria that tightly encompass the batch data at the time of filing see section 2. If any of these characteristics change during manufacture or storage, this change should be investigated and appropriate action taken. The acceptance criteria should include the final acceptable appearance. If color changes during storage, a quantitative procedure may be appropriate.

Identity tests should be specific for the new drug substance, e. Results of content uniformity testing for new drug products can be used for quantitation of drug product strength, if the methods used for content uniformity are also appropriate as assays. For example, where titration is adopted to assay the drug substance for release, the combination of the assay and a suitable test for impurities can be used.

A specific procedure should be used when there is evidence of excipient interference with the nonspecific assay. Organic impurities arising from degradation of the new drug substance and impurities that arise during the manufacturing process for the drug product should be monitored in the new drug product. Acceptance limits should be stated for individual specified degradation products, which may include both identified and unidentified degradation products, as appropriate, and total degradation products.

Process impurities from the new drug substance synthesis are normally controlled during drug substance testing, and therefore are not included in the total impurities limit. However, when a synthesis impurity is also a degradation product, its level should be monitored and included in the total degradation product limit. When it has been conclusively demonstrated via appropriate analytical methodology that the drug substance does not degrade in the specific formulation, and under the specific storage conditions proposed in the new drug application, degradation product testing may be reduced or eliminated upon approval by the regulatory authorities.

Decision Tree 2 addresses the extrapolation of meaningful limits on degradation products from the body of data generated during development. Tests other than those listed below may be needed in particular situations or as new information becomes available.

The procedures used for the measurement of these properties are usually unique and do not need much elaboration, e. The tests performed in this category should be determined by the physical nature of the new drug substance and by its intended use.

In such instances, testing for particle size distribution should be carried out using an appropriate procedure, and acceptance criteria should be provided.

Decision Tree 3 provides additional guidance on when particle size testing should be considered. Polymorphism may also include solvation or hydration products also known as pseudopolymorphs and amorphous forms. Differences in these forms could, in some cases, affect the quality or performance of the new drug products. In cases where differences exist that have been shown to affect drug product performance, bioavailability, or stability, then the appropriate solid state should be specified.

Physicochemical measurements and techniques are commonly used to determine whether multiple forms exist. Examples of these procedures are: Melting point including hot-stage microscopy , solid state IR, X- ray powder diffraction, thermal analysis procedures like DSC differential scanning calorimetry , TGA thermogravimetric analysis and DTA differential thermal analysis , Raman spectroscopy, optical microscopy, and solid state NMR nuclear magnetic resonance spectroscopy.

Decision Trees 4 1 through 4 3 provide additional guidance on when, and how, polymorphic forms should be monitored and controlled. Note: These decision trees should be followed sequentially. Trees 4 1 and 4 2 consider whether polymorphism is exhibited by the drug substance, and whether the different polymorphic forms can affect performance of the drug product.

Tree 4 3 should only be applied when polymorphism has been demonstrated for the drug substance, and shown to affect these properties. Tree 4 3 considers the potential for change in polymorphic forms in the drug product and whether such a change has any effect on product performance. It is generally technically very difficult to measure polymorphic changes in drug products.

A surrogate test e. However, that impurity in the chiral new drug substance and the resulting new drug product s should otherwise be treated according to the principles established in those guidances. Decision Tree 5 summarizes when and if chiral identity tests, impurity tests, and assays may be needed for both new drug substances and new drug products, according to the following concepts: Drug Substance: Impurities.

For chiral drug substances that are developed as a single enantiomer, control of the other enantiomer should be considered in the same manner as for other impurities. However, technical limitations may preclude the same limits of quantification or qualification from being applied. Assurance of control also could be given by appropriate testing of a starting material or intermediate, with suitable justification.

An enantioselective determination of the drug substance should be part of the specification. It is considered acceptable for this to be achieved either through use of a chiral assay procedure or by the combination of an achiral assay together with appropriate methods of controlling the enantiomeric impurity.

For a drug substance developed as a single enantiomer, the identity test s should be capable of distinguishing both enantiomers and the racemic mixture. Drug Product: Degradation products. Control of the other enantiomer in a drug product is considered necessary unless racemization has been shown to be insignificant during manufacture of the dosage form and on storage.

An achiral assay may be sufficient where racemization has been shown to be insignificant during manufacture of the dosage form and on storage. Otherwise a chiral assay should be used. Alternatively, the combination of an achiral assay plus a validated [Page ] procedure to control the presence of the opposite enantiomer may be used. A stereospecific identity test is not generally needed in the drug product release specification. When racemization is insignificant during manufacture of the dosage form and on storage, stereospecific identity testing is more appropriately addressed as part of the drug substance specification.

When racemization in the dosage form is a concern, chiral assay or enantiomeric impurity testing of the drug product will serve to verify identity. The acceptance criteria may be justified with data on the effects of hydration or moisture absorption.

In some cases, a loss on drying procedure may be considered adequate; however, a detection procedure that is specific for water e.


ICH Q3C (R6) Residual solvents



U.S. Food and Drug Administration






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