Pharmaceutical Stability Studies PDF

PHARM 131: PHARMACEUTICS 2 STABILITY STUDIES Professor, RPh | Reviewed: Nov. 19, 2024 | Last Edited: Nov. 19, 2024 properties, including...

PHARM 131: PHARMACEUTICS 2 STABILITY STUDIES Professor, RPh | Reviewed: Nov. 19, 2024 | Last Edited: Nov. 19, 2024 properties, including appearance, palatability, OUTLINE uniformity, dissolution and suspendability, are retained STABILITY STUDIES Microbiological Sterility or resistance to STABILITY microbial growth is retained according to the specified TYPES OF STABILITY requirements. Antimicrobial FACTORS AFFECTING PRODUCT STABILITY agents that are present retain INTERNATIONAL CLIMATIC ZONES effectiveness within the DEFINITION OF TERMS specified limits SHELF-LIFE (EXPIRATION DATING PERIOD OR Therapeutic The therapeutic effect VALIDITY PERIOD) remains unchanged EXPIRY (EXPIRATION) DATE PERIOD Toxicological No significant increase in DATE OF MANUFACTURE toxicity occurs RE-TEST PERIOD (API) *USP 35-NF 30 PROVISIONAL (TENTATIVE) SHELF-LIFE UTILIZATION PERIOD From discussion: IN-USE STABILITY TESTING ○ Chemical PRIMARY BATCH Ex. in a multi constituent drug - each constituent PILOT SCALE BATCH does not change its property PRODUCTION BATCH get the acceptable limits in the USP monographs REAL-TIME TESTING if it is not in the USP go to formulary ACCELERATED TESTING ○ Physical STRESS TESTING Ex. suspensions - it should be redispersible WHY CONDUCT STABILITY STUDY? Ex. emulsions - there should be no instabilities ASEAN GUIDELINE ON STABILITY STUDY OF DRUG like creaming present PRODUCT How do we check for BA? dissolution WHEN DO WE CONDUCT STABILITY STUDIES? STABILITY STUDY DESIGN FACTORS AFFECTING PRODUCT STABILITY PHOTOSTABILITY TESTING Environmental Factors SELECTION OF BATCHES ○ Temperature BRACKETING ○ Light MATRIXING ○ Humidity SPECIFICATION ○ Oxygen GENERAL SPECIFICATIONS ○ Carbon Dioxide TESTING FREQUENCY / STORAGE CONDITION Dosage form factors CONTAINER CLOSURE SYSTEM ○ Particle size STORAGE CONDITIONS ○ pH EVALUATION ○ Solvent system composition STABILITY COMMITMENT ○ Compatibility of anions and cations STATEMENTS OF LABELLING ○ Solution ionic strength ○ Primary container ○ Specific chemical additives STABILITY STUDIES ○ Molecular binding and diffusion of drugs and STABILITY excipients The ability of a drug to retain its chemical, physical, INTERNATIONAL CLIMATIC ZONES microbiological and biopharmaceutical properties within specified limits throughout its shelf-life Climatic Zone Definition Long-term testing conditions TYPES OF STABILITY I Temperature 21°C/45%RH Types of Stability Conditions Maintained Climate Throughout the Shelf Life of II Subtropical and 25°C/60%RH the Drug Product Mediterranean Chemical Each active ingredient retains Climate its chemical integrity and III Hot and Dry 30°C/35%RH labeled potency, within the Climate specified limits IVA Hot and humid 30°C/65%RH Physical The original physical TRANS TEAM MEMBERS 1 bit.ly/TransDatabase  Climate beyond that, di na pwede gamitin maraming sa community naka store sa ref yung IVB Hot and Very 30°C/75%RH mga naka-open na which is wrong Humid Climate *PH is climatic zone 4 IN-USE STABILITY TESTING *US is zone 1 or 2 Established the period of time during which a multidose product can be used while retaining quality within an DEFINITION OF TERMS accepted specification once the container is opened ○ ICH Q1A (2000) SHELF-LIFE (EXPIRATION DATING PERIOD OR VALIDITY liquids that are reconstituted prior to use PERIOD) effervescent tablets in a moisture-proof container The period of time during which a drug product is (eg Al screw-cap tube) expected, if stored correctly, to remain within may mga nasa multi-dose container and specification as determined by stability studies on a everytime na may pumapasok na moisture number of batches of the product. The shelf-life is used to pagkabukas ng container, bumababa ang establish the expiry date of each batch of drug dose product. ophthalmic products (especially with respect to ○ period of time when it is still in specifications preservative efficacy) EXPIRY (EXPIRATION) DATE PERIOD PRIMARY BATCH the date placed on the container label of a drug Batch of drug substance or drug product used in stability product designating the time prior to which a batch of study the product is expected to remain within the approved Should be at least a pilot scale batch but may also be a shelf-life specification if stored under defined conditions production batch expiry vs shelf life ○ expiry - date format PILOT SCALE BATCH ○ shelf life - year/period Batch of a drug substance or drug product manufactured by a procedure fully representative of and simulating that DATE OF MANUFACTURE to be applied to a full production scale batch Date indicating the completion date of the manufacture of For solids: a batch. It is normally expressed by a month and a year. ○ 1/10 of the production scale The date of the release analysis may be taken as a date ○ 100,000 tablets or capsules of manufacture, provided that the period between the beginning of production and the release of the product is PRODUCTION BATCH not longer than one-twentieth of the shelf-life. A batch of a drug substance or drug product RE-TEST PERIOD (API) manufactured at production scale by using production Period of time for which teh API remains within equipment in a production facility as specified in the specification when stored under the recommended application conditions in the proposed bulk storage container ○ Lab scale = 100 grams “After this period, the batch should be retested for compliance with specifications & then used immediately” REAL-TIME TESTING [if in compliance] Stability studies under the recommended storage condition for the retest period or shelf life proposed (or PROVISIONAL (TENTATIVE) SHELF-LIFE approved) for labeling The shelf-life determined by projecting results from accelerated stability studies ACCELERATED TESTING Pre-formulation stability study - 6 months Studies designed to increase the rate of chemical Long term stability study - 2 years degradation or physical change of a drug substance or ○ May new product na re register, ano stability data drug product by using exaggerated storage conditions ipakita sa FDA? - Long Term ang sagot STRESS TESTING UTILIZATION PERIOD Studies undertaken to assess the effect of severe Period of time during which a reconstituted preparation or conditions on the product the finished dosage form in an opened multi-dose Required for analytical method validation container can be used ○ Pharmaceutical formulation ○ beyond this date what do you do? ○ Identify and monitor potential degradants in stability ○ Expiration date doesn’t automatically means last date testing na pwede gamitin yung product ○ Meron ba siyang unwanted chemical entities na ○ Multi-dose containers, for example powder for mapproduce? If meron then unstable reconstitution.. once na maopen, need mo na agad gamitin. WHY CONDUCT STABILITY STUDY? ○ Depende sa storage condition. Kapag ref or room To select the best formulation and container-closure temp. Sometimes they are Antibiotics. Ang utilization system period ay within 7 days after powder reconstitution To determine shelf-life and storage conditions TRANS TEAM MEMBERS 2 bit.ly/TransDatabase  To verify that changes made in the formulation, process, F. Storage Conditions or packaging system do not have any adverse effect on G. Evaluation the stability of the product H. Stability Commitment I. Statements of Labelling ASEAN GUIDELINE ON STABILITY STUDY OF a. what to put in the label after finding out about the shelf-life? DRUG PRODUCT b. hoe about the storage conditions Guideline na sinusundan ng FDA SCOPE disclaimer: medyo binabasa nalang niya ppt haha ○ The drug products covered in this guideline include PHOTOSTABILITY TESTING NCE (new chemical entity), Generics, and Major The intrinsic photostability characteristics of new drug (MaV) and Minor (MiV) Variations, but exclude substances and products should be evaluated to products containing vitamin & mineral preparations demonstrate that, as appropriate, light exposure does not ○ MaV: result in unacceptable change. Change ng route of administration Conducted on at least one primary batch of the drug Change in strength product (if appropriate) Change in indication ICH Q1B: Photostability Testing of New Drug Substances ○ MiV: and Products Changes in packaging Changes in color OBJECTIVES ○ To provide recommendations on the core stability study package required for drug products ○ To propose shelf-life based on the stability data gathered from the study package WHEN DO WE CONDUCT STABILITY STUDIES? New products New packages (ie differing from the prescribed standard) ○ need pa rin kahit pinalitan lang ang sticker and label dahil sa talamak na counterfeiting. You still have to prove na it doesn’t affect the product Change in formula, processing method, or source of raw materials ○ A stability study is needed even if there is only a slight or minor change in the formula, procedure (e.g. wet granulation to dry granulation), or source of raw SELECTION OF BATCHES materials. Same formulation and dosage form in the container Batches released by exception, e.g batches with closure system proposed for marketing properties differing from standard or reworked batches NCE: at least three primary batches of the drug ○ There is a need to conduct stability studies even for products batches with different results from standard batches Generics and Variations: Marketed products to confirm assigned shelf-life ○ For conventional dosage forms/"stable" drug Can be performed last and observed as stability substances: at least two pilot scale batches are commitment wherein you promise to continue the stability acceptable studies even if the products have been released ○ For critical dosage forms/"unstable" drug substances: stability data on three primary batches. Two of the STABILITY STUDY DESIGN three batches should at least be of a pilot scale; the When we design stability studies we need to perform: third batch' may be smaller A. Photostability Testing Stability studies should be performed on each individual a. has separate section strength and container size of the drug product unless b. focus on light resistance bracketing or matrixing is applied B. Selection of Batches ○ gaano kayo katagal magtatabi sa mga pinrepare a. how much is needed? niyong drug products C. Specification dito niyo tinetest yung mga products for recall = a. per type/dosage form: what product magtabi kayo up to 5 years (pati records) para sa characteristics to check for? ganitong instances D. Testing Frequency a. how long is real-time? how about accelerated studies E. Container Closure System TRANS TEAM MEMBERS 3 bit.ly/TransDatabase  BRACKETING ○ Soft gelatin capsules– appearance, colour, and odour of content, assay, degradation products, The design of a stability schedule such that only samples dissolution, microbial content, PH. leakage, and on the extremes of certain design factors, e.g., strength, pellicle formation. Also the fill medium should be package size, are tested at all time points as in a full examined for precipitation and cloudiness. design. 3. Emulsions ○ “performed on each individual strength and container ○ include appearance, odour, degradation products, size” = magastos to pH, viscosity, microbial limits, preservative content, buti nalang daw may bracketing and mean size and distribution of dispersed globules test only yung mga EXTREMES 4. Oral Solutions and Suspensions ○ appearance, colour, odour, assay, degradation products, pH, viscosity, preservative content and microbial limits. Also redispersibility, rheological properties and mean size and distribution of particles 5. Oral Powders for Reconstitution 6. Metered-dose Inhalations and Nasal Aerosols 7. Nasal Sprays : Solutions and Suspensions 8. Topical, Ophthalmic and Otic Preparations 9. Suppositories 10. Large Volume Parenterals (LVPs) MATRIXING 11. Small Volume Parenterals (SVPs) The design of a stability schedule such that a selected 12. Drug Admixture subset of the total number of possible samples for all 13. Transdermal Patches factor combinations is tested at a specified time point. 14. Freeze-dried Products TESTING FREQUENCY / STORAGE CONDITION NCE and Generics - Zone IV Long-term Accelerated Testing Frequency 0, 3, 6, 9, 12, 18, 0, 3 and 6 months 24 months; and annually through the proposed shelf-life Storage Condition 30oC + 2oC 40oC + 2oC 75% RH + 5% RH 75% RH + 5% RH Min. Time period 12 months (6 6 months covered months for generics and variations with stable drug substances) Min. number of 3 3 SPECIFICATION batches (2 for generics and (2 for generics with Testing should cover, as appropriate, the variations stable ○ Physical with stable drug drug substances) substances) ○ Chemical ○ Biological and microbiological attributes ○ Preservative content (e.g. antioxidant, antimicrobial Drug products stored in Refrigerator preservative); and ○ Functionality tests (e.g. for a dose delivery system) Long-term Accelerated Mechanisms of degradation should be considered Testing Frequency 0, 3, 6, 9, 12, 18, 0, 3 and 6 months The analytical procedure should be fully validated and 24 months; stability-indicating and annually through the GENERAL SPECIFICATIONS proposed shelf-life 1. Tablets Storage Condition 5oC ± 3oC 25oC ± 3oC 60% RH + 5% RH ○ appearance, odour, colour, assay, degradation products, dissolution, moisture and hardness/friability Min. Time period 12 months 6 months 2. Capsules covered ○ Hard gelatin capsules– appearance, colour, and Min. number of 3 3 odour of content, assay, degradation products, batches dissolution, moisture and microbial content TRANS TEAM MEMBERS 4 bit.ly/TransDatabase Drug products stored in Freezer ○ Any degradation product exceeding the acceptance criterion; Long-term ○ Failure to meet the acceptance criteria for appearance, physical attributes, and functionality Testing Frequency 0, 3, 6, 9, 12, 18, tests (e.g. colour, phase separation, resuspendability, 24 months; and annually caking, hardness, dose delivery per actuation); through the ○ Failure to meet the acceptance criteria for pH; proposed shelf-life ○ Failure to meet the acceptance criteria for dissolution Storage Condition -20oC ± 5oC for 12 dosage units (capsule or tablet). Extrapolation if: Min. Time period 12 months ○ Long-term data show: (1) little or no change over time covered and (2) little or no variability between batches; Min. number of 3 ○ Accelerated data show: (1) little or no change over batches time and (2) little or no variability between batches; Statistical analysis is normally unnecessary In-use Stability Testing ○ Note: ○ Provides information for the labelling on the Y = up to 2X, but not exceeding X + 12 months preparation, storage conditions and utilization period Y = Proposed shelf life of multidose products after opening reconstitution or X = Period covered by long-term data dilution of a solution General Statistical Approaches ○ Done on primary batches (at least 2) ○ Linear Regression Determining the earliest time at which the 95 CONTAINER CLOSURE SYSTEM percent confidence limit for the mean intersects Stability testing should be conducted on the dosage form the proposed acceptance criterion/ specification packaged in the container closure system proposed for ○ Poolability tests between Batches marketing (including, as appropriate, any secondary Analysis of Covariance (ANCOVA) packaging and container label). ○ Statistical modeling ○ Kasama ba box? Omsim daw Multi-Factor, Full-Design Studies Types of Containers: ○ Moisture-impermeable containers STABILITY COMMITMENT Glass ampoules, aluminum/aluminum blisters, When available Real Time stability data on primary High Density Polyethylene (HDPE) or glass batches do not cover the proposed shelf-life granted at bottles fitted with metal or HDPE closures. the time of approval, a commitment should be made to ○ Moisture-permeable containers continue the stability studies post approval in order to Polyvinyl chloride (PVC) blisters, Low Density firmly establish the shelf-life. Polyethylene (LDPE) bottles, glass or HDPE Where the submission includes Real Time Stability data bottles when fitted with polypropylene closures. on at least the minimum number of production batches required covering the proposed shelf-life, a post approval STORAGE CONDITIONS commitment is considered unnecessary. Type of Container Long-term STATEMENTS OF LABELLING o o Storage temperature: Products in primary 30 C ± 2 C containers 75% ± 5% RH ○ normal storage condition - 30C permeable to ○ under controlled air conditioning - 25C water vapour ○ under refrigeration, no freezing between 2 and 8C Products in primary 30oC ± 2oC ○ under refrigeration - below 8C containers RH not specified ○ freezer - between -5C and 0C impermeable ○ deep freezer - below -18C to water vapour The use of terms such as “ambient conditions” or “room Accelerated studies o o 40 C ± 2 C temperature” is unacceptable. 75% ± 5% RH General precautionary statements, such as “Protect from light” and/or “Store in a dry place”, may be included. If applicable, recommendations should also be made as to EVALUATION the utilization period and storage conditions after opening If there is a “significant change” occurs between 3 and 6 and dilution or reconstitution of a solution. months’ testing at the accelerated storage condition, the Where applicable specific requirements should be stated proposed shelf-life should be based on the real time data particularly for drug products that cannot tolerate available at the Real Time storage condition freezing.+ ALT + 3) “Significant Change” ○ A 5% change in assay from its initial value, or failure to meet the acceptance criteria; TRANS TEAM MEMBERS 5 bit.ly/TransDatabase