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ICH HARMONISED TRIPARTITE G - Columbia Pharma

INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICALREQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMANUSEICH HARMONISED TRIPARTITE GUIDELINESTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTSR ecommended for Adoptionat Step 4 of the ICH Processon 27 October 1993by the ICH Steering CommitteeThis Guideline has been developed by the appropriate ICH Expert Working Groupand has been subject to consultation by the regulatory parties, in accordance withthe ICH Process. At Step 4 of the Process the final draft is recommended foradoption to the regulatory bodies of the European Union, Japan and TESTING OF NEW DRUG SUBSTANCES AND PRODUCTSICH HARMONISED TRIPARTITE GuidelineEndorsed by the ICH Steering Committee at Step 4 of the ICH Process27 October 1993 PREAMBLEThe following guideline sets out the stability testing requirement for aRegistration Application within the three areas of the EC, Japan and the USA.

ICH Harmonised Tripartite Guideline Endorsed by the ICH Steering Committee at Step 4 of the ICH Process 27 October 1993 PREAMBLE The following guideline sets out thestability testing requirement for a Registration Application within the three areas of the EC, Japan and the USA. It

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Transcription of ICH HARMONISED TRIPARTITE G - Columbia Pharma

1 INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICALREQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMANUSEICH HARMONISED TRIPARTITE GUIDELINESTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTSR ecommended for Adoptionat Step 4 of the ICH Processon 27 October 1993by the ICH Steering CommitteeThis Guideline has been developed by the appropriate ICH Expert Working Groupand has been subject to consultation by the regulatory parties, in accordance withthe ICH Process. At Step 4 of the Process the final draft is recommended foradoption to the regulatory bodies of the European Union, Japan and TESTING OF NEW DRUG SUBSTANCES AND PRODUCTSICH HARMONISED TRIPARTITE GuidelineEndorsed by the ICH Steering Committee at Step 4 of the ICH Process27 October 1993 PREAMBLEThe following guideline sets out the stability testing requirement for aRegistration Application within the three areas of the EC, Japan and the USA.

2 Itdoes not seek necessarily to cover the testing that may be required for registrationin or export to other areas of the guideline seeks to exemplify the core stability data package required for newdrug substances and products. It is not always necessary to follow this when thereare scientifically justifiable reasons for using alternative guideline provides a general indication on the requirements for stabilitytesting, but leaves sufficient flexibility to encompass the variety of differentpractical situations required for specific scientific situations and characteristics ofthe materials being principle that information on stability generated in any one of the three areasof the EC, Japan and the USA would be mutually acceptable in both of the othertwo areas has been established, provided it meets the appropriate requirements ofthis guideline and the labelling is in accord with national/regional of the specific requirements for sampling, test requirements for particulardosage forms/packaging etc.

3 , are not covered in this purpose of stability testing is to provide evidence on how the quality of a drugsubstance or drug product varies with time under the influence of a variety ofenvironmental factors such as temperature, humidity and light, and enablesrecommended storage conditions, re-test periods and shelf lives to be guideline primarily addresses the information required in RegistrationApplications for new molecular entities and associated drug guideline does not currently seek to cover the information required forabbreviated or abridged applications, variations, clinical trial applications, choice of test conditions defined in this guideline is based on an analysis of theeffects of climatic conditions in the three areas of the EC, Japan and the USA. Themean kinetic temperature in any region of the world can be derived from climaticdata (Grimm, W.)

4 Drugs Made in Germany, 28, 196-202, 1985 and 29, 39-47, 1986).Stability Testing of New Drug Substances and Products2 DRUG SUBSTANCEG eneralInformation on the stability of the drug substance is an integral part of thesystematic approach to stability TestingStress testing helps to determine the intrinsic stability of the molecule byestablishing degradation pathways in order to identify the likely degradationproducts and to validate the stability indicating power of the analytical StudiesPrimary stability studies are intended to show that the drug substance will remainwithin specification during the re-test period if stored under recommended of BatchesStability information from accelerated and long term testing is to be provided on atleast three batches. The long term testing should cover a minimum of 12 monthsduration on at least three batches at the time of batches manufactured to a minimum of pilot plant scale should be by the samesynthetic route and use a method of manufacture and procedure that simulates thefinal process to be used on a manufacturing overall quality of the batches of drug substance placed on stability should berepresentative of both the quality of the material used in pre-clinical and clinicalstudies and the quality of material to be made on a manufacturing information may be provided using stability data on batches of drugsubstance made on a laboratory first three production batches of drug substance manufactured post approval,if not submitted in the original Registration Application.

5 Should be placed on longterm stability studies using the same stability protocol as in the approved Procedures and Test CriteriaThe testing should cover those features susceptible to change during storage andlikely to influence quality, safety and/or efficacy. Stability information should coveras necessary the physical, chemical and microbiological test stability-indicating testing methods must be applied. The need for theextent of replication will depend on the results of validation of acceptability should be derived from the profile of the material as used inthe pre-clinical and clinical batches. It will need to include individual and totalupper limits for impurities and degradation products, the justification for whichStability Testing of New Drug Substances and Products3should be influenced by the levels observed in material used in pre-clinical studiesand clinical ConditionsThe length of the studies and the storage conditions should be sufficient to coverstorage, shipment and subsequent use.

6 Application of the same storage conditionsas applied to the drug product will facilitate comparative review and storage conditions are allowable if justified. In particular, temperaturesensitive drug substances should be stored under an alternative, lowertemperature condition which will then become the designated long term testingstorage temperature. The six months accelerated testing should then be carriedout at a temperature at least 15 C above this designated long term storagetemperature (together with the appropriate relative humidity conditions for thattemperature). The designated long term testing conditions will be reflected in thelabelling and re-test TimePeriod at SubmissionLong term testing25 C 2 C/ 60% RH 5%12 MonthsAccelerated Testing40 C 2 C/75% RH 5% 6 MonthsWhere 'significant change' occurs during six months storage under conditions ofaccelerated testing at 40 C 2 C/75 percent RH 5 percent, additional testing atan intermediate condition (such as 30 C 2 C/60 percent RH 5 percent) should beconducted for drug substances to be used in the manufacture of dosage formstested long term at 25 C/60 percent RH and this information included in theRegistration Application.

7 The initial Registration Application should include aminimum of 6 months data from a 12 months study.'Significant change' at 40 C/75 percent RH or 30 C/60 percent RH is defined asfailure to meet the long term testing will be continued for a sufficient period of time beyond 12months to cover all appropriate re-test periods, and the further accumulated datacan be submitted to the Authorities during the assessment period of theRegistration data (from accelerated testing or from testing at an intermediate condition)may be used to evaluate the impact of short term excursions outside the labelstorage conditions such as might occur during FrequencyFrequency of testing should be sufficient to establish the stability characteristics ofthe drug substance. Testing under the defined long term conditions will normallybe every three months, over the first year, every six months over the second yearand then Testing of New Drug Substances and Products4 Packaging/ContainersThe containers to be used in the long term, real time stability evaluation should bethe same as or simulate the actual packaging used for storage and design of the stability study is to establish, based on testing a minimum ofthree batches of the drug substance and evaluating the stability information(covering as necessary the physical, chemical and microbiological testcharacteristics), a retest period applicable to all future batches of the bulk drugsubstance manufactured under similar circumstances.

8 The degree of variability ofindividual batches affects the confidence that a future production batch will remainwithin specification until the retest acceptable approach for quantitative characteristics that are expected todecrease with time is to determine the time at which the 95% one-sided confidencelimit for the mean degradation curve intersects the acceptable lower specificationlimit. If analysis shows that the batch to batch variability is small, it isadvantageous to combine the data into one overall estimate and this can be done byfirst applying appropriate statistical tests (for example, p values for level ofsignificance of rejection of more than ) to the slopes of the regression lines andzero time intercepts for the individual batches. If it is inappropriate to combinedata from several batches, the overall retest period may depend on the minimumtime a batch may be expected to remain within acceptable and justified nature of any degradation relationship will determine the need fortransformation of the data for linear regression analysis.

9 Usually the relationshipcan be represented by a linear, quadratic or cubic function on an arithmetic orlogarithmic scale. Statistical methods should be employed to test the goodness offit of the data on all batches and combined batches (where appropriate) to theassumed degradation line or data may show so little degradation and so little variability that it is apparentfrom looking at the data that the requested retest period will be granted. Underthe circumstances, it is normally unnecessary to go through the formal statisticalanalysis but merely to provide a full justification for the extrapolation of the real time data beyond the observed range to extendexpiration dating at approval time, particularly where the accelerated datasupports this, may be undertaken. However, this assumes that the samedegradation relationship will continue to apply beyond the observed data andhence the use of extrapolation must be justified in each application in terms ofwhat is known about the mechanism of degradation, the goodness of fit of anymathematical model, batch size, existence of supportive data evaluation should cover not only the assay, but the levels of degradationproducts and other appropriate LabellingA storage temperature range may be used in accordance with relevantnational/regional requirements.

10 The range should be based on the stabilityStability Testing of New Drug Substances and Products5evaluation of the drug substance. Where applicable, specific requirements shouldbe stated, particularly for drug substances that cannot tolerate freezing. The use ofterms such as 'ambient conditions' or 'room temperature' is re-test period should be derived from the stability PRODUCTG eneralThe design of the stability programme for the finished product should be based onthe knowledge of the behavior and properties of the drug substance and theexperience gained from clinical formulation studies and from the stability studieson the drug substance. The likely changes on storage and the rationale for theselection of product variables to include in the testing programme should of BatchesStability information from accelerated and long term testing is to be provided onthree batches of the same formulation and dosage form in the containers andclosure proposed for marketing.


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