Stability Studies and Shelf Life Prediction of Pharmaceuticals-origina

Views:
 
Category: Entertainment
     
 

Presentation Description

No description available.

Comments

Presentation Transcript

Stability Studies and Shelf Life Prediction of Formulations.:

Stability Studies and Shelf Life Prediction of Formulations. Presented By: Dept: of Pharmaceutical Analysis, [email protected]

Stability:

Stability USP defines stability as the extend to which a product retains, within specified limits and throughout its period of storage and use. Applies to: Chemical stability Physical stability Microbiological stability Pharmacological and Toxicological stability. 2

Shelf Life:

Shelf Life The shelf life is the period of time for which the drug product is assured to maintain its identity, strength, quality, and purity when stored at the conditions specified on the labeling. Short term stability studies. Long term stability studies. Stability of batch calculated using regression technique. 3

Stability Testing Guidelines.:

Stability Testing Guidelines. ICH guidelines and WHO guidelines are developed to harmonize the stability data of drug for the authorities in the associated countries. ICH guidelines is adopted by the 17 countries of the US, EU and Japan. WHO guidelines is adopted by the 170 member states. 4

Factors affecting stability of drugs and drug products:

Factors affecting stability of drugs and drug products Moisture, hydrolysis and pH Oxygen and oxidation Light Temperature Microbes API’s and excipients Physicochemical properties like hygroscopic nature, crystalline or amorphous state, polymorphism, vapor pressure etc. 5

PowerPoint Presentation:

Test conditions ICH Guidelines WHO Guidelines -Accelerated 40 °C±2°C, 75% RH ± 5% for 6 months. 40 °C±2 °C, 75% RH ± 5% for 6 months for zone 4 countries. 40 °C±2 °C, 75% RH ± 5% for 3 months for zone 2 countries. -Real time 25 °C±2°C, 60% RH ± 5% for 12 months, assurance to be provided for continuity of the test up to the end of expected shelf life 30 °C±2°C, 60% RH ± 5% for zone 4 countries. 25 °C±2°C, 60% RH ± 5% for zone 2 countries. Data for 6 months minimum shall be provided at the time of registration. 6

PowerPoint Presentation:

Storage Conditions for Stability Evaluation of APIs 7

PowerPoint Presentation:

Storage Conditions for Stability Evaluation of Drug Products 8

PowerPoint Presentation:

Climate Zones for World Wide Stability Testing Climate zone Measured data in open air Measured data in storage room °C %RH °C %RH Zone1 10.9 75 18.7 46 Zone2 17.0 70 21.1 52 Zone3 24.4 39 26.0 54 Zone4 26.5 77 28.4 70 Calculated Data Derived storage conditions (for real time studies) °C °C(MKT) %RH °C %RH Zone1 20.0 20.0 42 21 45 Zone2 21.6 22.0 52 25 60 Zone3 26.4 27.0 35 30 35 Zone4 26.7 27.4 76 30 70 Zone1:Temperate Zone2:Sub-tropical Zone3:Hot/Dry Zone4:Hot/Humid 9

Climate zones:

Climate zones 10

Shelf Life:

Shelf Life Shelf life is defined as the time taken for a drug to reduce to 90% of its initial concentration. May be calculated from the appropriate kinetic equation. For first order decay, it may be given as t 10% = -(ln 0.90)/K = 0.105/K If compound is sufficiently stable, then liquid formulation development may commence 11

Solid State Stability:

Solid State Stability Samples are exposed to a range of temperature, humidities and lighht intensities upto 12 weeks. Three 5-10mg samples for HPLC analysis and 10-50mg of sample for polymorphic evaluation by DSC and/or IR. Surface oxidation analysed by storing the samples in vials of injection, headspace filled with dry oxygen. 12

PowerPoint Presentation:

Through these tests, the decay process order is ascertained and the same order is used to analyze the data at each temperature. Humidity not a factor means that Arrhenius plot may be constructed and if found linear may be extrapolated to predict shelf life. If humidity is a factor, then concentration of water in atmosphere may be determined using psychometric charts. 13

PowerPoint Presentation:

Stability data obtained at various humidities may be linearized with respect to moisture using the decay rate constant. K H = [gpl] K O - where, gpl is the grams of water per litre of dry air and K O is the decay rate constnt at zero humidity. 14

Accelerated Stability Analysis:

Accelerated Stability Analysis Based on Chemical kinetics. Arrhenius equation k=A.e −E/(RT) Decomposition rate constants of drug solution at elevated temperatures obtained by plotting function of conc: against time. From this log of specific rate of decomposition is plotted against reciprocal of absolute temperature, thenm extrapolating to room temperature. 15

PowerPoint Presentation:

16

PowerPoint Presentation:

Or, the fractional life period is plotted against reciprocal temperatures, And shelf life is obtained from a second graph in which log time to 90% is plotted against 1/T and the time at 25 °C is found out. This methods helps in the calculation of overages that must be added. 17

PowerPoint Presentation:

18

PowerPoint Presentation:

19

Degradation Data Evaluation at Accelerated Conditions:

Degradation Data Evaluation at Accelerated Conditions 20

PowerPoint Presentation:

21

PowerPoint Presentation:

The analysis can be done assuming that the reaction is first order (this is usually the case in real life) or zero order (simpler analysis with no significant error for degradation of less than 10%). Both cases are presented here. For first – order kinetics the first step is to obtain the natural logarithm of the concentrations, which is done in Table 29 . 22

PowerPoint Presentation:

Then, these values are graphed as a function of time where straight lines should be obtained as shown in Figure 2 . The slope of each line corresponds to the value of k 1 , which is shown in the bottom part of Table 29 . Next, a plot of ln ( k 1 ) versus 1/ T is prepared with the three values of k 1 , one for each temperature as shown in Figure 3 23

PowerPoint Presentation:

Note that absolute temperature should be used here. From Equation (64) , the value of k 1 can be extrapolated to T = 25 ° C (1/ T = 0.003354 K −1 ) to then predict the drug product assay as a function of time. The values of slope and intercept are shown in the inset of Figure 3 ; the calculation is ln k 25 =-8237.4 *0.003354+21.639 = −5.990 k 25 = 0.00250 month −1 24

PowerPoint Presentation:

This value can be substituted in the equation ln(C/C 0 ) = -k 1 t 25

PowerPoint Presentation:

26

By Non-Isothermal Kinetics::

By Non-Isothermal Kinetics: Activation energy, reaction rates and stability predictions are obtained. Done by a single experiment in which temperature change at a predetermined rate. Temperature and time may be related as 1/T = 1/T O + α t Where T O is initial temperature and α is the reciprocal of heating rate constant. 27

PowerPoint Presentation:

Arrhenius equation between time zero and time t may be given as, lnK t = lnK o – (E α /R)(1/T t -1/T 0 ) Or on rearrangement, lnK t = lnK o – (E α /R)( α t) Since temperature is a function of time t, a measure of stability K t is directly obtained over a range of temperatures. 28

PowerPoint Presentation:

Testing methods based on arrhenius law valid only when the breakdown is a thermal phenomenon with activational energy of 10-30 kcal/mol. Temperature study can’t be used if degradation rate is affected by freezing, microbes, excessive agitation transport. For products with methyl cellulose, or proteins or for ointments or suppositories. 29

PowerPoint Presentation:

If autocatalysis is a factor. Order of rection changes gradually from zero order to first order, to second order, and to fractional order due to several factors. Change in the activational energy. 30

Photo Stability Studies:

Photo Stability Studies To demonstrate that an appropiate light exposure do not result in an unacceptable change. Systematic Approach: On drug substance On exposed drug product outside immediate pack On drug product inside immediate pack On drug product in marketting pack. 31

PowerPoint Presentation:

Light source with an overall illumination of 1.2million lux.hours and integrated UV energy not less than 200 watt hours/m 2 . Designed to produce output similar to day light, xenon or metal halide lamp may be used. Conditions monitored using caliberated lux meters, and validated actinometric systems 32

Drug Substance:

Drug Substance Forced degradation testing and confirmatory testing conducted. Former one employes a variety of exposure conditions, and decomposition products obtained if any are monitored that are unlikely to be formed in confirmatory studies. Confirmatory studies help provide information necessary for packaging, labelling and handling. 33

PowerPoint Presentation:

Presented by taking account of the physical characteristics of the drug. Interactions between sample and containers for storage must be eliminated. Drug substance Solid Liquid Exposed in a petridish, spread to give a thickness nmt 3 mm Exposed in chemically inert, transparent containers At the end of time, examined for physical properties like appearance, clarity, color, performed assay and other suitable tests 34

Results interpretation:

Results interpretation Degradation studies Capable of resolving and detecting photolytic degradents that appear in confirmatory studies. Confirmatory studies Should identify precautionary measure needed in the manufacturing and formulation of drug, or if light resistant pack is needed. 35

Drug product:

Drug product Testing conducted till results demonstrate that drug product is adequately protected from light. If pack is totally impenetrable to light, tests must be conducted on exposed product. Analytical methods must be suitably validated. Special labelling or packaging instructions may be provided as required. 36

PowerPoint Presentation:

37

Stability Tests Specific to Dosage Forms :

Stability Tests Specific to Dosage Forms Tablets: Dissolution (or disintegration, if justified), water content, hardness/ friability. Hard Gelatin Capsules: Brittleness, dissolution (or disintegration, if justified), water content, and microbial bio burden. Soft Gelatin Capsules: Dissolution (or disintegration, if justified), microbial bio burden, pH, leakage, and pellicle formation. 38

PowerPoint Presentation:

Emulsions: Phase separation, pH, viscosity, microbial bioburden, mean size and distribution of dispersed globules. Oral Solutions and Suspensions: Formation of precipitate, clarity for solutions, pH, viscosity, microbial bio burden, extractable, and polymorphic conversion when applicable. Additional tests for suspensions include redispersability, rheological properties, mean size, and distribution of particles. 39

PowerPoint Presentation:

Powders for Oral Solutions and Suspensions: Water content, reconstitution time, and reconstituted solutions and suspensions should be tested as above for oral solutions and suspensions. Topical, Ophthalmic and Otic Preparations: Clarity, homogeneity, pH, resuspendability (for lotions), consistency, viscosity, microbial bioburden, and water loss should be tested. For ophthalmic and otic products additional attributes should include sterility, particulate matter, and extractables. 40

PowerPoint Presentation:

Suppositories: Softening range, dissolution at 37 ° C. Transdermal Patches: In vitro release rates, leakage, microbial bioburden/ sterility, and peel and adhesive forces. Metered - Dose Inhalers and Nasal Aerosols Content uniformity, aerodynamic particle size distribution, microscopic evaluation, water content, leak rate, microbial bioburden, valve delivery, extractable, leachable from plastic and elastomeric components. 41

PowerPoint Presentation:

Nasal Sprays Clarity: microbial bioburden, pH, particulate matter, unit spray medication content uniformity, droplet and/or particle size distribution, weight loss, pump delivery, microscopic evaluation of suspensions, particulate matter, extractables, leachables from plastic and elastomeric components of container closure and pump. Large - Volume Parenterals Color, clarity, particulate matter, pH, sterility, endotoxin/ pyrogen, and volume. 42

PowerPoint Presentation:

Small - Volume Parenterals Color, clarity of solutions, particulate matter, pH, sterility, endotoxins. Powders for injection solutions include clarity, color, reconstitution time and water content, pH, sterility, endotoxins/pyrogens, and particulate matter. Suspensions for injection should include additional particle size distribution, redispersability, and rheological properties. Emulsion for injection should include phase separation, viscosity, mean size, and distribution of dispersed globules. 43

Reference::

Reference: ICH Q1A(R2) stability testing of new drug substances and products. Guidance for Industry Q1B Photostability Testing of New Drug Substances and Products, USFDA. Alfred Martin; Physical Pharmacy; 4 TH edition; page-317, 319. Pharmaceutical Manufacturing Handbook, Regulations and Quality by Shayne Cox Gad, PhD, D.A.B.T. page 625-632 44 [email protected]

PowerPoint Presentation:

Thank You 45 [email protected]

authorStream Live Help