ICH GUIDELINES FOR STABILITY STUDIES 1

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ICH GUIDELINES FOR STABILITY STUDIES:

ICH GUIDELINES FOR STABILITY STUDIES BY O.PRIYANKA M pharm 1st yr.

ICH GUIDELINES FOR STABILITY STUDIES::

ICH GUIDELINES FOR STABILITY STUDIES: Q1A(R2)- Stability Testing of New Drug Substances and Products Q1B- Stability Testing : Photostability Testing of New Drug Substances and Products Q1C- Stability Testing for New Dosage Forms Q1D- Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products Q1E- Evaluation of Stability Data Q1F- Stability Data Package for Registration Applications in Climatic Zones III and IV 7/28/2012 2 O.priyanka,department of pharmaceutics,GPRCP

ICH guideline Q1-A(stability studies):

ICH guideline Q1-A (stability studies) OBJECTIVE OF THE GUIDELINE: It defines stability of drug substance and drug product for registration of application of NCE or associated drug, within three regions of ICH i . e; EU, Japan, USA . NOTE: It does not cover testing for registration of drug substance or product intended for import or export to other areas of the world. 7/28/2012 3 O.priyanka,department of pharmaceutics,GPRCP

PRINCIPLES OF THE GUIDELINE :

PRINCIPLES OF THE GUIDELINE 1. Purpose of stability testing is to provide evidence how quality varies with time under influence of - temperature - humidity - light 2. establish re-test period for drug substances RETEST PERIOD: the period after which samples of the drug substance should be examined to ensure that the material is still in compliance with the specification, and thus suitable for use in manufacturing. A retest period should be proposed on the basis of stability results and may be extended to five years (e.g., Ethambutol 2HC l , or Isoniazid) 3. establish shelf life for drug products SHELF LIFE: (EXPIRY DATE/EXPIRATION DATING PERIOD) The period of time during which a pharmaceutical product, if stored correctly, is expected to comply with the specification as determined by stability studies on a number of batches of the product. The shelf-life is used to establish the expiry date of each batch . 7/28/2012 4 O.priyanka,department of pharmaceutics,GPRCP

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4. recommends storage conditions 5.Gives Test conditions based on analysis of effects of climatic conditions in the three regions of the EU, Japan, USA. 6. Gives mean kinetic temperature which is derived from climatic data 7.divided world into four climatic zone I-IV - This guideline addresses climatic zones I and II 8. And the Stability information generated in one of the three regions is mutually acceptable to the other two provided: - information is consistent with this guideline, - labelling is in accord with national/ regional requirements. 7/28/2012 5 O.priyanka,department of pharmaceutics,GPRCP

CLIMATIC ZONES::

CLIMATIC ZONES: CLIMATIC ZONE DEFINITION STORAGE CONDITIONS I TEMPERATE CLIMATE 21 0 C/45 % R.H II SUBTROPICAL AND MEDITERRANEAN CLIMATE 25 0 C/60 % R.H III HOT , DRY CLIMATE 30 0 C/35 % R.H IV HOT , HUMID CLIMATE 30 0 C / 70% R.H 7/28/2012 6 O.priyanka,department of pharmaceutics,GPRCP

STEPS IN STABILITY TESTING OF DRUG SUBSTANCE OR PRODUCT:

STEPS IN STABILITY TESTING OF DRUG SUBSTANCE OR PRODUCT Drug Substance Drug Product Stress Testing Photostability Testing Selection of Batches Selection of Batches Container Closure System Container Closure System Specification Specification Testing frequency Testing frequency Storage Conditions Storage Conditions Stability Commitment Stability Commitment Evaluation Evaluation Statements/ Labelling Statements/ Labelling 7/28/2012 7 O.priyanka,department of pharmaceutics,GPRCP

What is the use of stress testing::

What is the use of stress testing: To validate the stability indicating power of the analytical procedures . To identify stability-affecting factors such as ambient temperature, humidity and light and to select packing materials which protect s the formulation against such effects. To identify potential degradants of the API and assess if they can be formed during manufacture or storage of the formulation. To select manufacturing process for particular drug substance. 7/28/2012 8 O.priyanka,department of pharmaceutics,GPRCP

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Test parameter proceedure observations Temperature A thin layer of the API is wetted with water and is kept at 80°C for 4 weeks in a Petri dish (open system) with sampling once a week Assay: Humidity A thin layer of the API is wetted with water and kept at 40°C / 100% RH for 4 weeks in a Petri dish (open system) with sampling once a fortnight “ Oxidation Oxygen is bubbled slowly through the oxygen-saturated aqueous solution/suspension (under constant mixing) of the API for 24 hours with sampling every eight (8) hours “ 7/28/2012 9 O.priyanka,department of pharmaceutics,GPRCP

ASSAY of certain compounds is difficult::

ASSAY of certain compounds is difficult: Example: artesunate Reason: increase in concentration of API During stability studies of Artesunate , the assay results were increasing. The hydrolysis yields artenimol and succinic acid. The formation of succinic acid justifies the increase in assay. The assay method is „stability indicating” but not specific. 7/28/2012 10 O.priyanka,department of pharmaceutics,GPRCP

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+ 7/28/2012 11 O.priyanka,department of pharmaceutics,GPRCP

STRESS TESTING: (forced degradation):

STRESS TESTING: (forced degradation) Degradation factor Conditions Thermal ≥ 60 o C Humidity ≥ 75% RH Acid 0.1N HCl Base 0.1N NaOH Oxidative Oxygen gas, or 3% H 2 O 2 Photolytic Metal halide, Hg, Xe lamp, or UV-B fluorescent Metal ions (optional) 0.05M Fe 2+ or Cu 2+ 7/28/2012 12 O.priyanka,department of pharmaceutics,GPRCP

STRESS STABILITY TESTING::

STRESS STABILITY TESTING: An optimal degradation pattern generated during stress testing would show only those degradation products observed at the end of shelf life in regulatory stability studies and those that might appear if the API or formulation if not manufactured, handled or packed properly. Chromatograms thus obtained will be representative and not too complicated to evaluate, which may be the case if drastic conditions are applied and many second- and third-generation degradation products are formed. 7/28/2012 13 O.priyanka,department of pharmaceutics,GPRCP

Stress stability testing - Nevirapine:

Stress stability testing - Nevirapine STRESS TYPE CONDITIONS ASSAY(%) control 25 o C 99.8 36% HCl 80 o C, 40 min. 72.0 5N NaOH 80 o C, 2h 20 ’ 98.6 30% w/w H 2 O 2 80 o C, 2h 20 ’ 98.6 Heat 130 o C, 49h 101.5 light 500W/m 2 , 68h 101.7 Water 25 o C, 92% RH, 91h 101.2 7/28/2012 14 O.priyanka,department of pharmaceutics,GPRCP

Selection of Batches:

Selection of Batches Data from formal stability studies should be provided at least three primary batches are selected. From batches manufactured to a minimum of pilot scale from batches having same synthetic route From a batch where method of manufacture and procedure simulates final process. Other supporting data can be provided 7/28/2012 15 O.priyanka,department of pharmaceutics,GPRCP

Container Closure System:

Container Closure System Container closure system same or simulates packaging proposed for storage and distribution Specification: specification: • list of tests, • reference to analytical procedure, • proposed acceptance criteria Test Attributes • attributes that are susceptible to changed storage, • influence quality, safety and/or efficacy • Should cover physical, chemical, biological and microbiological attributes 7/28/2012 16 O.priyanka,department of pharmaceutics,GPRCP

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Analytical procedures • validated stability indicating • replication depending on result s from validation studies The following requirements for replication can be fixed: RSD ≤ 1% single analysis RSD > 1% 3fold analysis The initial assay at time point 0 should be always analysed 3fold 7/28/2012 17 O.priyanka,department of pharmaceutics,GPRCP

Testing Frequency:

Testing Frequency General : every 3 months first year, every 6 months second year, then annually through proposed re-test period: e.g. 0, 3, 6, 9, 12, 18, 24, 36, 48, 60 months ˆ Accelerated storage condition: 0, 3, 6 months. Where expectation to approach significant change, increasing testing necessary : adding samples at final time point or forth time point in study design: 0, 3, 2x 6 or 0, 1, 3, 6 months 7/28/2012 18 O.priyanka,department of pharmaceutics,GPRCP

Storage Conditions::

Storage Conditions: Long term testing should cover a minimum of 12 months duration on at least three primary batches at time of submission and should be continued sufficient to cover the proposed re-test period. GENERAL: Study Storage condition Duration Long term* 25°C ± 2°C/60% ± 5% or 30°C ± 2°C/65% ± 5% 12 months Intermediate** 30°C ± 2°C/65% ± 5% 6 months Accelerated 40°C ± 2°C/75% ± 5% 6 months NOTE: *It is up to the applicant, to decide whether long term stability is performed at 25°C ± 2°C/60% ± 5% or 30°C ± 2°C/65% ± 5%. ** If 30°C ± 2°C/65% ± 5% is the long-term condition, there is no intermediate condition 7/28/2012 19 O.priyanka,department of pharmaceutics,GPRCP

Drug substance intended for storage in a refrigerator:

Drug substance intended for storage in a refrigerator Study Storage condition Minimum time period at submission Long term 5°C ± 3°C 12 months Accelerated 25°C ± 2°C/60% ± 5% 6 months If significant change between 3 and 6 months at accelerated testing propose re-test data based on real time data. If significant change within 3 months discussion should address excursions outside label storage. Single batch shorter than 3 months with more frequent testing. 7/28/2012 20 O.priyanka,department of pharmaceutics,GPRCP

Drug substance intended for storage in a freezer :

Drug substance intended for storage in a freezer Study Storage condition Minimum time period at submission Long term - 20 °C ± 5°C 12 months Re-test period based on real time data at long term storage condition. In absence of accelerated storage condition testing on a single batch at an elevated temperature e.g. 5°C ± 3°C address short term excursions 7/28/2012 21 O.priyanka,department of pharmaceutics,GPRCP

Stability Commitment:

Stability Commitment When Re-test period not covered or not mentioned long term stability data do not cover proposed re-test period granted at time of approval, commitment should be made to continue post approval to establish re-test period Not required for Submission which includes data from 3 production batches, commitment to continue through proposed re-test period. Fewer than three production batches commitment continue with these studies through proposed re-test period and place additional production batches to a total of three on long term stability through proposed re-test period No Production batches commitment to place first three production batches on long term stability studies through proposed re-test period. 7/28/2012 22 O.priyanka,department of pharmaceutics,GPRCP

Evaluation :

Evaluation Re-test period Purpose of stability studies is to establish a re-test period applicable to all further batches of the drug substance manufactured under similar circumstances. It is based on results of physical, chemical, biological and microbiological tests from three batches. 1) No formal statistical analyses needed for The data may show so little degradation and so little variability requested re-test period will be granted. Under these circumstances normally unnecessary to go through the formal statistical analyses; Providing a justification for the omission should be sufficient. 2) Statistical evaluation For the Data that changes with time statistical evaluation is required. 7/28/2012 23 O.priyanka,department of pharmaceutics,GPRCP

Compliance alert::

Compliance alert: 7/28/2012 24 O.priyanka,department of pharmaceutics,GPRCP

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Extrapolation Limited extrapolation of the real time data beyond the observed range to extend the re-test period can be undertaken at approval time, if justified. Justification should be based on • Knowledge on mechanism of degradation • results of accelerated testing, • goodness of fit of mathematical model • existence of supporting data and batch size 7/28/2012 25 O.priyanka,department of pharmaceutics,GPRCP

Statements/Labelling:

Statements/ Labelling Storage Statement Storage statement established for labelling should be in accordance with national/regional requirements. Statement based on stability evaluation ˆ Re-test date Re-test date derived from stability information. The re-test date should be displayed on the container label 7/28/2012 26 O.priyanka,department of pharmaceutics,GPRCP

Significant change of drug substance or product::

Significant change of drug substance or product: A 5% change in assay from its initial value . Any degradation product exceeding its acceptance criterion . Failure to meet the acceptance criteria for appearance , physical attributes, and functionality test (e.g., colour, phase separation, hardness). A s appropriate for the dosage form , e.g., failure to meet the acceptance criteria for dissolution for 12 dosage units . 7/28/2012 27 O.priyanka,department of pharmaceutics,GPRCP

Photostability testing: Q1-B:

Photostability testing: Q1-B A systematic approach to photostability testing is recommended covering, as appropriate, studies such as : i ) Tests on the active substance; ii) Tests on the exposed product outside of the immediate pack, and if necessary ; iii) Tests on the product in the immediate pack; and if necessary ; iv) Tests on the product in the marketing pack. 7/28/2012 28 O.priyanka,department of pharmaceutics,GPRCP

Light sources::

Light sources: D65/ID65 emission standard such as an artificial daylight fluorescent lamp combining visible and ultraviolet (UV) outputs, xenon, or metal halide lamp. D65 is the internationally recognised standard for outdoor daylight as defined in ISO 10977 (1993). ID65 is the equivalent indoor indirect daylight standard. For a light source emitting significant radiation below 320 nm, an appropriate filter(s) may be fitted to eliminate such radiation. 7/28/2012 29 O.priyanka,department of pharmaceutics,GPRCP

NEW DOSAGE FORMS-Q1 C:

NEW DOSAGE FORMS-Q1 C definition: A new dosage form is defined as a medicinal product which is a different pharmaceutical product type, but containing the same active substance as included in an existing product approved by the pertinent regulatory authority. Include: products of a different route of administration (e.g., oral to parenteral ) , new specific functionality/delivery systems (e.g., immediate release tablet to modified release tablet) and different dosage forms of the same route of administration ( e.g., capsule to tablet, solution to suspension). Stability protocols for new dosage forms should follow the guidance in the parent stability guideline in principle. However, a reduced stability database at submission time may be acceptable with proper justification. e.g., 6 months accelerated and 6 months long term data from ongoing studies may be acceptable in certain justified cases. 7/28/2012 30 O.priyanka,department of pharmaceutics,GPRCP

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STABILITY TEST PARAMETERS FOR VARIOUS TYPES OF PRODUCTS Tablets – Appearance, colour , odour , assay, disintegration/dissolution, moisture and friability or hardness testing. Hard gelatin capsules - Appearance, colour , odour of contents, assay, disintegration/dissolution, moisture and microbial limits Soft gelatin capsules - Appearance, colour , odour of contents, assay, disintegration/dissolution, moisture, microbial limits, ph , leakage and pellicle formation. Emulsions – Appearance including phase separation , colour , odour , assay, pH, viscosity , preservative content, weight loss and microbial limits. 7/28/2012 31 O.priyanka,department of pharmaceutics,GPRCP

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Suppositories – Appearance, colour , assay, particle size , softening range , appearance, dissolution and microbial limits. Small volume parenteral : Drug injection – Appearance, colour , assay, ph, preservative, content, particulate matter, sterility and pyrogenicity . Large volume parenteral - Appearance, colour , assay, ph, preservative content, particulate matter, sterility and pyrogenicity Transdermals – Appearance, assay, leakage, microbial limit/sterility, peel and adhesive forces , drug release rate. 7/28/2012 32 O.priyanka,department of pharmaceutics,GPRCP

Q1D- Bracketing and Matrixing Designs for Stability Testing : :

Q1D- Bracketing and Matrixing Designs for Stability Testing : guideline Recommends for application of bracketing and matrixing Applicability of Reduced Designs Applicable to formal stability studies of most types of drug products Drug substances: matrixing limited, bracketing generally not applicable Whether bracketing or matrixing depends on circumstances Any reduced design should be justified. Type and level of justification depends on avaiable supporting data. Careful consideration and scientific justification, if bracketing and matrixing in one design. 7/28/2012 33 O.priyanka,department of pharmaceutics,GPRCP

BRACKETING: :

BRACKETING: • Bracketing is the design of a stability schedule such that only the extremes of certain design factors are tested at all time points. - different strengths - different container size and/or fill Stability of intermediate levels represented by stability or tested extremes. Bracketing design not appropriate, if tested samples are not the extremes. 7/28/2012 34 O.priyanka,department of pharmaceutics,GPRCP

DESIGN EXAMPLE: :

DESIGN EXAMPLE: Three strengths and three container sizes: Container size 15 ml 100 ml 500 ml 1 2 3 1 2 3 1 2 3 T T T T T T T T T T T T 7/28/2012 35 O.priyanka,department of pharmaceutics,GPRCP

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MATRIXING: Matrixing is t he statistical design of a stability schedule . Each storage condition should be treated separately under its own matrixing design A t a given time point (other than the initial or final ones) not every batch on stability needs to be tested Full testing must be performed at the maximum storage period at the time of submission 7/28/2012 36 O.priyanka,department of pharmaceutics,GPRCP

Design example: :

Design example: Type Storage period in months(time points) Total number 0 3 6 9 12 18 24 36 48 60 A × × ­ ­ × ­ ­ × ­ × 5 B × ­ × ­ × × ­ ­ × × 6 C × ­ ­ × × ­ × ­ ­ × 5 7/28/2012 37 O.priyanka,department of pharmaceutics,GPRCP

Bracketing or matrixing? :

Bracketing or matrixing ? Stage of development Preferable procedure Predevelopment bracketing Clinical phases I-III bracketing Accelerated and long term testing with registration batches bracketing / matrixing On-going stability testing matrixing Follow-up stability testing matrixing 7/28/2012 38 O.priyanka,department of pharmaceutics,GPRCP

EVALUATION OF STABILITY DATA- Q 1 E :

EVALUATION OF STABILITY DATA- Q 1 E Objectives of the Guideline : It describes: How to propose a retest period for drug substances and a shelf life for drug products in the registration application When and how a extrapolation beyond available data can be considered. Q1F- Stability Data Package for Registration Applications in Climatic Zones III and IV Objectives of the Guideline Application of ICH Q1A(R) in countries of Climatic zones III and IV 7/28/2012 39 O.priyanka,department of pharmaceutics,GPRCP

References: :

References: www. ich .org/products/ guidelines /quality.html www.ema.europa.eu/pdfs/human/ ich /273699en.pdf www. ich .org/fileadmin/.../ ICH .../ Guidelines /.../Q1B_ Guideline .pdf apps.who.int/ prequal / trainingresources / pq .../ stabilitystudies . ppt Jens T cartensen , C.T Rhodes Drug stability Principles and Practices, Third Edition N K Jain Pharmaceutical Product Development 7/28/2012 O.priyanka,department of pharmaceutics,GPRCP 40

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By O.priyanka m pharm 1 st year department of pharmaceutics GPRCP 7/28/2012 41 O.priyanka,department of pharmaceutics,GPRCP

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