ICH Guidelines of Stability Studies & Accelerated Stability Studies

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ICH Guidelines of Stability Studies & Accelerated Stability Studies Presented By: Mr. Sachin S. Patil M. Pharm-I (Pharmaceutics) Yahsoda Technical Campus, Faculty of Pharmacy, Satara . 1 12-11-2011

DRUG STABILITY:

DRUG STABILITY Stability of pharmaceutical product may be defined as the capability of a particular formulation in a specific container/closure system to remain within its physical, chemical, microbiological therapeutic and toxicological specification . Assurance that the packed product will be stable for its anticipated shelf life must come from an accumulation of valid data on the drug in its commercial package. These stability data involves selected parameters that taken together from the stability profile . Pharmaceutical products are expected to meet their specification for identifying purity, quality and strength throughout their defined storage period at specific storage condition. 2 12-11-2011

DRUG STABILITY:

DRUG STABILITY The stability of pharmaceutical product is investigated throughout the various stages of the development process . The stability of the drug substance is first assessed in the preformulation stage . Stability/ compatibility with various solvents, buffered solutions, and excipients considered for formulation developments 3 12-11-2011

WHY STABILITY…:

WHY STABILITY… Provide an evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as….. temperature, Humidity and light. Establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions. Because physical, chemical or microbiological changes might impact the efficiency and security of the final product. 4 12-11-2011

Where and Why?:

Where and Why? Stability Studies are preformed on ... Drug Substances (DS)  The unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form. Drug Products (DP)  The dosage form in the final immediate packaging intended for marketing……. controlled and documented determination of acceptable changes of the drug substance or drug product 5 12-11-2011

What are changes? :

What are changes? Physical changes • Appearance • Melting point • Clarity and color of solution • moisture • Crystal modification (Polymorphism) • Particle size Chemical changes • Increase in Degradation • Decrease of Assay Microbial changes 6 12-11-2011

ICH:

ICH ICH stands for I nternational C onference on H armonization of Technical Requirements for Registration of Pharmaceuticals for Human use Objectives of ICH • Harmonization of registration applications within the three regions of the EU, Japan and the United States. • ICH is a joint initiative involving both regulators and industry as equal partners in the scientific and technical discussions of the testing procedures which are required to ensure and assess the safety, quality and efficacy of medicines. Tripartite guideline on stability testing of new drug substances and products (Q1A) in 1993, has become standard for stability evaluation in Japan, US, Europe. 7 12-11-2011

ICH Guidelines:

ICH Guidelines • Quality Guidelines “ Q ” (chemical and pharmaceutical QA) – details see next slide • Safety Guidelines “ S ” (in vitro and in vivo pre-clinical studies) – covering Carcinogenicity Testing, Genotoxicity Testing, Toxicokinetics and Pharmacokinetics ….. etc. • Efficacy Guidelines “ E ” (clinical studies in human subject) – Covering clinical safety, Dose Response Studies, Good Clinical Practices, Clinical evaluation …. etc. • Multidisciplinary Guidelines “ M ” – Covering Medical Terminology, Electronic Standards for Transmission of Regulatory Information …… etc. – Important for Stability ! » Guideline M4 : The Common Technical Document (CTD) 8 12-11-2011

TYPE, SIZE, NUMBER OF BATCHES:

TYPE, SIZE, NUMBER OF BATCHES ICH/ WHO GUIDELINES- At least 3 primary batches of drug product, should be of the same formulation, packaged in same container as proposed for marketing 2 out of 3 batches should be pilot scale batches. Stability to be performed on each strength, container size. 9 12-11-2011

LONG TERM STABILITY STUDIES:

LONG TERM STABILITY STUDIES Study is performed at 25 0 C/60% or 30 0 C/ 65%. Ideally 12 months data is to be generated but 6 months data is also acceptable in circumstances for submission of registration dossier, continued till end of shelf life. For parentrals stability has to carried out at 2-8 0 C for drugs to be stored in freezer testing should be done at -20 0 C 10 12-11-2011

ACCELERATED STABILITY STUDIES:

ACCELERATED STABILITY STUDIES Storage condition of 40 0 C and relative humidity of 75% has been recommended for all the four zones for drug substances and drug products. Studies carried out for 6 months. Accelerated storage conditions must be at least 15 0 C above the expected actual storage temperature and appropriate relative humidity 11 12-11-2011

PowerPoint Presentation:

Study Storage condition Minimum time period covered by data at submission Long term 25°C ± 2°C / 60% ± 5% r.h or 30°C ± 2°C / 65% ± 5% r.h . 12 months Intermediate 30°C ± 2°C / 65% ± 5% r.h. 6 months Accelerated 40°C ± 2°C / 75% ± 5% r.h. 6 months Drug substances - intended for storage in a Refrigerator Study Storage condition Minimum time period covered by data at submission Long term 5°C ± 3°C 12 months Accelerated 25°C ± 2°C / 60% ± 5% r.h. 6 months Climatic Zones / Storage conditions 12 12-11-2011

PowerPoint Presentation:

Drug substances/Product- intended for storage in Freezer Study Storage condition Minimum time period covered by data at submission Long term -20°C ± 5°C 12 months Drug products - General case Study Storage condition Minimum time period covered by data at submission Long term 25°C ± 2°C / 60% ± 5% r.h . or 30°C ± 2°C / 65% ± 5% r.h . 12 months Intermediate 30°C ± 2°C / 65% ± 5% r.h. 6 months Accelerated 40°C ± 2°C / 75% ± 5% r.h . 6 months Climatic Zones / Storage conditions 13 12-11-2011

PowerPoint Presentation:

Drug products - packaged in Semi-permeable containers Study Storage condition Minimum time period covered by data at submission Long term 25°C ± 2°C / 40% ± 5% r.h . or 30°C ± 2°C / 35% ± 5% r.h . 12 months Intermediate 30°C ± 2°C / 65% ± 5% r.h. 6 months Accelerated 30°C ± 2°C / 65% ± 5% r.h. 6 months 14 12-11-2011

PROTECTION AGAINST HYDROLYSIS:

PROTECTION AGAINST HYDROLYSIS Good packaging practices like moisture resistant packs. Eg - strip packs stored in controlled humidity and temperature conditions, even using desiccant such as silica gel. Buffering agents for pH control Alteration of dielectric constant Addition of complexing agents like caffeine Use of Surfactants ,Good Refrigeration 15 12-11-2011

PROTECTION AGAINST OXIDATION:

PROTECTION AGAINST OXIDATION Incorporation of antioxidants such as BHA, BHT, Propyl gallate , Tocopherol Chelation using EDTA, Citric acid, Tartaric acid Use of inert gas like Nitrogen Protection from light by use of amber colored container Storage at low temperature 16 12-11-2011

Testing scope for Solid dosage:

Testing scope for Solid dosage Physical-chemical properties – Appearance – Elasticity – Moisture – Hardness – Disintegration – Dissolution Chemical properties – Assay – Degradation Microbial properties Container closure system properties – Functionality tests (e.g. extraction from blister) 17 12-11-2011

Testing scope for LIQUID FORMS for inj. and PARENTRAL:

Testing scope for LIQUID FORMS for inj. and PARENTRAL Physical-chemical properties – pH – Loss on weight – Color & clarity of solution - Sterility Tests Chemical properties – Assay – Degradation products – Degradation preservatives – Content antioxidants Microbial properties - Pyrogen Testing Container closure system properties – Functionality tests - Leakage test 18 12-11-2011

Testing scope for Oral liquid form :

Testing scope for Oral liquid form Physical-chemical properties – pH – Color & clarity of solution – Viscosity – Particle size distribution (for oral suspensions only) Chemical properties – Assay – Degradation products – Degradation preservatives – Content antioxidants Microbial properties Container closure system properties – Functionality tests 19 12-11-2011

Testing scope for SEMI LIQUID FORMS:

Testing scope for SEMI LIQUID FORMS Physical-chemical properties – Appearance, odor, homogeneity, consistency – Loss on weight, Viscosity – Content uniformity (within the container) Chemical properties – Assay – Degradation products & preservatives – Content preservatives – Degradation– Content antioxidants Microbial properties Container closure system properties – Functionality tests 20 12-11-2011

Recent development in ICH Guidelines:

Recent development in ICH Guidelines In February this year two new ICH Guidelines on the topic of stability testing were published. They can now be commented. Q1E Draft Consensus Guideline Evaluation of Stability Data Q1F Draft Consensus Guideline Stability Data Package for Registration in Climatic Zones III and IV Both new Drafts refer to the revised ICH Guideline Q1A(R) – "Stability Testing of New Drug Substances and Products.“ 21 12-11-2011

Recent development in ICH Guidelines:

Recent development in ICH Guidelines The Guideline "Evaluation of Stability Data" describes when and how an extrapolation of the data can be undertaken in order to establish the re-test period for a drug substance or the shelf life for a drug product beyond the observed range itself, based on the data resulting from the long-term stability testing. The Guideline on stability testing for Climatic Zone III and IV takes up a proposal made by WHO and now defines not only storage conditions for stability testing relevant for the ICH tripartite regions (Europe, USA, Japan), but also completes the recommendations for the standardization of the storage conditions for the Climatic Zones III (dry-hot) and IV (very hot/humid). 22 12-11-2011

Recent development in ICH Guidelines:

Recent development in ICH Guidelines For these Climatic Zones, the following standard conditions are recommended: Long-term testing: 30°C / 65% RH Accelerated conditions: 40°C / 75% RH This means that the "accelerated conditions" remain the same as in the Q1A(R) Guideline and only the "long-term storage conditions" have to be modified. 23 12-11-2011

Accelerated stability studies :

Accelerated stability studies 24 12-11-2011

Salient features:

Salient features Gross picture on the stability Properties of degradation Mechanism of chemical reaction Establish an analytical method for estimation of drug & degraded product The temperature effect on the chemical degradation is estimated To establish efficacy, safety and toxicity Objective To predict the shelf life of a product by accelerating the rate of decomposition, preferably by increasing the temperature 25 12-11-2011

Forced degradation studies:

Forced degradation studies Acidic & Basic conditions. Dry heat exposure UV radiation exposure Influence of pH Influence of temperature Influence of ionic strength 26 12-11-2011

STABILITY:

STABILITY Ideally any commercial pharmaceutical product should have a shelf life of 5 yrs and should not fall below 90-95% potency under recommended storage. In designing a solid dosage form it is necessary to know the inherent stability of the drug substance, excipients to be used, formulation procedure. 27 12-11-2011

CHEMICAL DEGRADATION STUDY :

CHEMICAL DEGRADATION STUDY Hydrolysis- usually drugs such as esters, amides and lactams undergo hydrolysis. Oxidation Reduction- loss of electrons, gain of electrons. Auto oxidation also is responsible. Eg - tetracyclines , vit A, vit D, morphine. Photolysis - Compounds such as ascorbic acid, riboflavin, cyanacobalamine , folic acid undergo degradation on exposure to light. Sometimes coupled with thermal reactions. Isomerisation -Compounds get converted into a less effective form. Eg -Adrenaline solutions at low pH lose activity since its levo form is more stable than dextro form 28 12-11-2011

ELEVATED TEMPERATURE STUDIES:

ELEVATED TEMPERATURE STUDIES Tests are usually performed at 40 ,50 ,60 0 C in conjuction with ambient humidity. Higher temperatures are also used, samples kept at highest temperature examined for chemical and physical changes at weekly intervals- if no change is seen after 30 days at 60 0 C Stability prognosis is excellent. Arrhenius Treatment is used to determine the degradation rate at lower temperature. 29 12-11-2011

STABILITY UNDER HIGH HUMIDITY CONDITIONS:

STABILITY UNDER HIGH HUMIDITY CONDITIONS In presence of moisture, many drug substances hydrolyze react with other excipients or oxidize. These tests are performed by exposing the drugs to different relative humidity conditions Preformulation data of this type is helpful in determining if the material should be protected and stored in a controlled low-humidity environment or if aqueous based granulation should be avoided. 30 12-11-2011

PHOTOLYTIC STABILITY :

PHOTOLYTIC STABILITY Many drugs fade or darken on exposure to light and this leads to an aesthetic problem which can be controlled by using 1 Amber Glass Container 2 Opaque Container 3 Incorporating a Dye 31 12-11-2011

STABILITY TO OXIDATION:

STABILITY TO OXIDATION Stability to oxygen must be evaluated to establish that the final product should be packaged under inert atmosphere or it requires an antioxidant. A 40% oxygen atmosphere allows for rapid evaluation The samples are kept in dessicators . Process is repeated 3-4 times to assure 100% of desired atmosphere. 32 12-11-2011

EFFECT OF pH:

EFFECT OF pH Most of the drugs are stable at pH 4 – 8. Weakly acidic and basic drugs are most soluble in ionized form and instability is likely as they are charged. This dilemma that potent drugs being poorly soluble, pH ionisation being best solution. Inclusion of a water miscible solvent increases stability thus suppressing ionization 33 12-11-2011

STRESS TESTING :

STRESS TESTING Helps to identify the likely degradation products and establish degradation pathways and intrinsic stability of molecule. Carried out on single batch. Effect of temperature ( every 10 0 C) Humidity 34 12-11-2011

SHELF LIFE:

SHELF LIFE Self life (referred to as expiration dating period) is the time period during which a drug product is expected to remain within the approved specification for use, provided that it is stored under the conditions defined on the container label. 35 12-11-2011

SHELF LIFE:

SHELF LIFE 36 12-11-2011

Limitations:

Limitations temperature energy of activation is about 1 to 30 kcal/mole degradation due to a . Diffusion b . Microbial contamination c . Photochemical reaction d . Excessive agitation higher temp. e.g.(i) coagulation of suspending agent (ii) denaturation of proteins (iii) breaking of emulsion (iv) loss of consistency of ointment 37 12-11-2011

PowerPoint Presentation:

Summary Stability studies should be planned on the basis of pharmaceutical R+D and regulatory requirements . Forced degradation studies reveal the intrinsic chemical properties of the API , while formal stability studies establish the retest date . The shelf life (expiry date) of FPPs is derived from formal stability studies. Variability and time trends of stability data must be evaluated by the manufacturer in order to propose a retest date or expiry date . 38 12-11-2011

PowerPoint Presentation:

References: http:// www.ich.org/products/guidelines/quality/article/quality-guidelines.html Aulton’s Pharmaceutics The Design & Manufacture of Medicines, Edited By Michael E. Aulton , Third Edition, Published by Churchill Livingstone Elsevier, Page No. 661 to 665 Essentials of Physical Pharmacy By C. V. S. Subrahmanyam , Page no. 51-65 Futscher , N.; Schumacher ,P.; Pharm. Ind. 34, 479 - 483 (1972) Grimm , W.; Krummen , K.; Stability Testing in the EC, Japan and the USA Wissenschaftiche Verlagsgesellschaft mbH, Stuttgart (1993) Grimm , W.; Drugs made in Germany 28, 196 - 202 (1985) and 29, 39 - 47 ( 1986) Dietz , R.; Feilner, K., Gerst, F.; Grimm, W.; Drugs made in Germany 36, 99 - 103, (1993) Haynes , J.D.; J. Pharm. Sci. 60, 927 - 929 (1971 ) 39 12-11-2011

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Thank you! 40 12-11-2011

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