Chemical Stability 2

Question 1

Importance of Stability Testing

Answer 1

Measure of drug substance/product quality varying overtime due to enviornmental factors (temp, humidity, light). Evidence for: storage conditions & shelf life

Question 2

Stability Testing Outline

Answer 2

Determines chemical/physical/microbiological stability following application of stress or challenge (microorganism, gravity, ect.). Stress choice dependent on physicochemical properties (gene/protein/small molecule) and conditions it’ll encounter

Question 3

Stability Testing Types

Answer 3

Long Term, Field, Accelerated (used for shelf life, faster and cheaper)

Question 4

Stages Stability is Tested in DLC

Answer 4

Preformulation (aids formulation dev), Early Formulation, Main Formulation & Post-marketing Studies

Question 5

Preformulation Stability Assessments Outline

Answer 5

Evaluation of drug API. Eval what methods of degradation are most likely to have occurred. Biologics higher order structure (tertiary and quaternity)

Question 6

Early Formulation Stability Assessments Outline

Answer 6

Conditions necessary for drug product’s intended use (admin route, bioavailability, packaging, controls). Related to EP dosage forms

Question 7

Main Formulation Stability Assessments Outline

Answer 7

Based on early stage findings. Predefined parameters established by accelerated stability testing (product shelf life). Novel drug substance: 6 months accelerated tests + 6 months of ongoing longterm submitted to dossier

Question 8

Post-Market Stability Assessment Outline

Answer 8

Continuous monitoring of individual or bulk containers to assess acceptance criteria and storage conditions. Differ from pre-MA (eg testing frequency)

Question 9

Stability Qualitative Assessment

Answer 9

Colour, odour, taste, clarity, flocculation degree, dispersibility, microbiological growth, thin layer chromatography

Question 10

Quantitative Stability Assessment Outline

Answer 10

Drug content, degradation product content, sediment vol, tablet dissolution rate, gel yield value, emulsion globule size and antimicrobrial kill rate

Question 11

Monitoring Synthetic Chemical Degradation

Answer 11

High performance liquid chromatography, Gas chromatography, mass spectrometry, nuclear magnetic resonance imaging and infrared

Question 12

Monitoring Biologic Degradation

Answer 12

Chromatography, electrophoresis, mass spectrometry, biophysical methods & biological/binding assay

Question 13

Monitoring Physical Degradation

Answer 13

Differential scanning chromatography, differential thermal analysis, differential thermogravimetry, x-ray diffraction, centrifugation, dissolution testing, hardness and friability

Question 14

Monitoring Microbial Degradation

Answer 14

Plate Count Methods and Membrane Filtration

Question 15

Plate Count Method Outline

Answer 15

Estimates viable microorganism number. Sample diluted and spread on agar. Count colonies grown

Question 16

Membrane Filtration Outline

Answer 16

Captures microorganisms on liquid sample on filter. Filter incubated on agar and colonies grown and counted

Question 17

Longterm Stability Testing Outline

Answer 17

Controlled stresses administered to API/drug product that mimic exact conditions of expected storage conditions (eg room temp of environments)

Question 18

Field Stability Testing Outline

Answer 18

Medicinal products transported to country it’s sold. Stored in pharmacy/warehouse and transported back to manufacturer lab for analysis

Question 19

Accelerated Stability Testing Outline

Answer 19

Drug substance/product challenged by exaggerated stress over a small period of time. Used to predict longterm stability; product dev, shelf-life estimation and quality control

Question 20

Exaggerated Stresses Outline

Answer 20

Temp, humidity, light and oxygen

Question 21

Elevated Temp Tests Outline

Answer 21

Shelf life prediction, temp increase = increased reaction (degradation) risk. Predicts T90. 2 types; Isothermal and Non-Isothermal

Question 22

Isothermal Heat Tests Outline

Answer 22

Reactions from several separate experiments at different temps using Arrhenious plots

Question 23

Non-isothermal Heat Tests Outlines

Answer 23

Single experiment conducted in pre-determined temp-time programme over 1 day. Eliminates temp optimisation

Question 24

Arrhenious Equation Outline

Answer 24

Linear plot. Rate constant (proportional to) 1/T. Experiments ran at no of temps: 40,50,60,70 degrees C. Predicts stability at room temp

Question 25

Arrhenious Deviations

Answer 25

Complex reactions, different degradation mechanisms (not just temp), pH changes, solubility changes, O2 loss, vapourisation

Question 26

High Intensity Light Accelerated Conditions

Answer 26

Tests susceptibility to photodegradation. Artificial lights D65 (standard outside daylight) and ID65 (standard direct daylight)

Question 27

High Partial Pressure Accelerated Conditions

Answer 27

Tests susceptibility to oxidation. Oxidation rate is proportional to partial pressure of gas present predicts storage condition stability

Question 28

High Humidity Accelerated Conditions

Answer 28

Tests susceptibility to hydrolysis. Measures critical relative humidity (when product become hygroscopic). Determines container/packaging

Question 29

Chemical Stability Accelerated Testing

Answer 29

Complex degradation reactions and changes in stability. Order of chain reactions may change

Question 30

Physical Stability Accelerated Testing

Answer 30

Elevated temp (accel. cracking), Centrifugation (accel. sedimentation) and High relative hardness (accel. hardness/friability)

Question 31

Microbiological Stability Accelerated Testing

Answer 31

Inoculum from a highly resistant microorganism

Question 32

International Council of Harmonisation

Answer 32

Founded by EU, US & Japan many grown. Provides guidelines for development of new drug substances and products. Aim: reduce duplicate testing

Question 33

Why are ICH Guidelines Important

Answer 33

Economical use of human, animal & material resources. Increases new medicine availability. Positions patient safety at front

Question 34

Goals of Updating ICH Guidelines

Answer 34

Streamlining single guideline for core stability issues (harmonisation). Stability strategies and innovate tools. Considerations for combination and advanced therapies

Question 35

Accelerated Significant Change Outline

Answer 35

Potency loss from initial batch assay to evaluate if any degradant is exceeding it's specification limit. Eval. if specifications for appearance and physical properties. 2 types: bracketing & matrixing

Question 36

Bracketing Outline

Answer 36

Tests drugs at lowest and highest points of acceptability range for degradation. Intermediate values can be extrapolated

Question 37

Matrixing Outline

Answer 37

Tests subsets of drug population that a selected subset of possible for combinations tested at specified time point