Stability testing of drugs and pharmaceuticals factors influencing media effects and pH effects

PRESENTED BY

M. ROHITHA REDDY

ROLE NO:256213886021

M.PHARMACY (PHARMACEUTICS)

UNDER THE GUIDENCE OF

MRS. YASMIN BEGUM

Contents

Drug stability

Criteria for Acceptable Levels of Stability

Applicable guidelines

Role of stability testing

Stability Testing - API

Stability testing - FPP

Factors influencing media effects pH

Climatic zones

Drug stability

Stability of drug also can be defined as the time from the date of manufacture and packaging of the formulation until its chemical or predetermined level of labelled potency and its physical characteristics have not changed appreciably.

Criteria for Acceptable Levels of StabilityType of Stability Conditions Maintained Throughout the Shelf Life of

the Drug ProductChemical Each active ingredient retains its chemical integrity and

labeled potency, within the specified limits.Physical The original physical properties, including appearance,

palatability, uniformity, dissolution and suspend ability are retained.

Microbiological Sterility or resistance to microbial growth is retained according to the specified requirements. Antimicrobial agents that are present retain effectiveness within the specified limits

Therapeutic The therapeutic effect remains unchangedToxicological No significant increase in toxicity occurs.

Applicable guidelines

WHO „Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms”

WHO working document QAS/05.146 - Stability Studies in a Global Environment.

ICH guidelines Q1A-Q1F. Stability testing of new APIs and FPPs has been harmonized at global level.

Selected definitions

Re-test dateThe date after which samples of an API should be examined to ensure that the material is still in compliance with the specification and thus suitable for use in the manufacture of a given FPP. Shelf life (expiration dating period, conformance period)The time period during which an API or a FPP is expected to remain within the approved shelf-life specification, provided that it is stored under the conditions defined on the container label.

Selected definitions

Stress testing – forced degradation (API) Studies undertaken to elucidate the intrinsic stability of the API. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing.

Stress testing – forced degradation (FPP) Studies undertaken to assess the effect of severe conditions on the FPP. Such studies include photo stability testing (see ICH Q1B) and compatibility testing on APIs with each other in FDCs and API(s) with excipients during formulation development.

Selected definitions

Accelerated testing Studies designed to increase the rate of chemical degradation or

physical change by means of exaggerated storage conditions. Intermediate testing

Studies at 30degC/60%RH, intended for extrapolation to long term storage at 25degC [provided that 25degC is appropriate for the market in question]

Stress testing API: Studies which elucidate intrinsic stab of API. Normally

during development. Normally more stressful than ‘accelerated’ testing.

Finished product: Studies of effect of ‘severe’ conditions. Eg freeze/thaw cycling for suspensions & emulsions, low humidity for aqueous liquids in moisture-permeable containers.

In-use stability testing: Establishes the “period of time during which a multidose product

can be used while retaining quality within an accepted specification once the container is opened” For example:

• liquids that are reconstituted prior to use• effervescent tablets in a moisture-proof container (eg Al

screw-cap tube)• ophthalmic products (especially with respect to

preservative efficacy)

Long term stability testing conditions are determined by the climatic condition under which the API is intended to be stored.

Zone I: temperate 21◦C/45%RHZone II: subtropical/mediterranean 25◦C/60%RHZone III: hot/dry 30◦C/35%RHZone VIa: hot/humid (Kenya) 30◦C/65%RHZone VIb: hot/very humid 30◦C/75%RH

Role of stability testing

Provides evidence on how the drug substance or product quality varies with time under environmental conditions during distribution.

Helps to recommend storage conditions including establishment of shelf life, expiry date or retest period.

Key assurance of quality of pharmaceuticals.

Stability Testing - API

Stress testing (forced degradation) Regulatory stability testing

ICH guidelines on stress testing

Q1A (R2) : Stability testing of new drug

substance and new drug product

Q1B : Photo stability testing

Q1C : Stability testing of new dosage forms

Q1D : Bracketing and Matrixing for stability testing

of new drug substance and new drug product

Q1E : Evaluation of stability data

Q1F : Stability data package for the registration

applications of climatic zones

Q5C : Stability testing of

biotechnological/biological products

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 100 C) Humidity

Stress testing

To identify potential degradants (degradation pathways) of the API and assess if they can be formed during manufacture or storage of the FPP (intrinsic stability of the API).

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 the FPP against such effects.

No standard method for testing.

Stress testing (forced degradation)

Degradation factor Conditions

Thermal ≥ 60 oC

Humidity ≥ 75% RH

Acid 0.1N HCl

Base 0.1N NaOH

Oxidative Oxygen gas, or 3% H2O2

Photolytic Metal halide, Hg, Xe lamp, or UV-B fluorescent

Metal ions (optional) 0.05M Fe2+ or Cu2+

Stress testing

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: S1: D1:Total unspecified:

Total impurities:

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

Assay: S1: D1: Total unspecified: Total impurities:

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

Assay: S1: D1: Total unspecified: Total impurities:

Prequalification experience

Results Comments

Deceptive Degradation level is good (<15%) but no relevant degradants are observed

Predictive Degradation level is good (<15%) and at least one or all relevant degradants are

observed

Useless Between 15 and 100% degradation but no relevant degradants observed

Requirements for predictive stress conditions

Recommendations in Supplement 2: Should lead to the degradation of the main compound, but not

more than 5-15%. Should lead to a good predictability of degradation pathways

(i.e., a low probability of "drastic" or "false" degradation) Should be conducted for no longer than three months.

Stress testing of API in solution

Storage conditions Testing period*

pH ± 2, room temperature 2 weeks

pH ± 7, room temperature 2 weeks

pH ± 10-12, room temperature 2 weeks

H2O2, 0.1-2% at neutral pH,

room temperature

24 hours

* Storage times given or 5-15% degradation, whatever comes first

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 FPP 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.

Increase in concentration of API

• During stability studies of Artesunate, the assay results were increasing. The hydrolysis may yield artenimol and succinic acid. The latter can justify the increase in assay. The assay method is”stability indicating” but not specific.

++

Regulatory or formal stability testing

Storage temperature(°C)

Relative humidity

(%)

Minimum time period covered

by data at submission (months)

Accelerated: 40±2 75±5 6

Intermediate: 30±2 65±5 12

Long term: 25±2 60±5 12 (6)

Stress stability testing - Nevirapine

Stress type Conditions Assay (%)

Control 25o C 99.8

36% HCl 80o C, 40 min. 72.0

5N NaOH 80o C, 2h 20’ 98.6

30% w/w H2O2 80o C, 2h 20’ 98.6

Heat 130o C, 49h 101.5

Light 500W/m2, 68h 101.7

Water 25o C, 92% RH, 91h 101.2

Stability Room

1. A special cabinet for each condition

2. Design, construction, qualification, monitoring

3. Costs of operation including R & D failures

4. Time

Stability results

A storage statement should be proposed for the labeling (if applicable), which should be based on the stability evaluation of the API.

A re-test period should be derived from the stability information, and the approved retest date should be displayed on the container label.

An API is considered as stable if it is within the defined/regulatory specifications when stored at 30±2oC and 65±5% RH for 2 years and at 40±2oC and 75±5%RH for 6 months.

Stability testing - FPP

Regulatory stability testing Stress testing (forced degradation)

Potential instability issues of FPPs

Loss/increase in concentration of API Formation of (toxic) degradation products Modification of any attribute of functional relevance Alteration of dissolution time/profile or bioavailability Decline of microbiological status Loss of package integrity Reduction of label quality Loss of pharmaceutical elegance and patient acceptability

Stability-indicating quality parameters

Stability studies should include testing of those attributes of the FPP that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy. For instance, in case of tablets:

♦ appearance ♦ hardness ♦ friability ♦ moisture content ♦ dissolution time ♦ degradants♦ assay ♦ microbial purity

Selection of Batches

At the time of submission data from stability studies should be provided for batches of the same formulation and dosage form in the container closure system proposed for marketing.

Stability data on three primary batches are to be provided. The composition, batch size, batch number and manufacturing date of each of the stability batches should be documented and the certificate of analysis at batch release should be attached.

Where possible, batches of the FPP should be manufactured by using different batches of the API.

Significant Change of FPPs

• 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., color, phase separation, hardness).

• As appropriate for the dosage form, e.g., failure to meet the acceptance criteria for dissolution for 12 dosage units.

Factors influencing media effects and pH

Temperature

Primary factor affecting the drug stability.

To study the effect of temperature on reaction, it is necessary to study decomposition of product at elevated temperature.

Help in predicting stability of product at ordinary temperature.

It catalyses hydrolysis, oxidation and thermal reaction

Method for expressing the influence of temperature on reaction proposed by Arrhenius:

K = A * e-Ea/RT

Where K= specific rate of degradation

A= Frequency factor

Ea = Arrhenius Activation Energy

R= Gas constant

T= Absolute temperature

Logarithmically it can be expressed as:

Log K = log A - Ea/ 2.303 RT

From the graph of K 1/T one can determine Ea from slope and A from intercept.

Limitations of Arrhenius relationship for prediction of stability of products

At higher temperature evaporation of solvent takes place and thus changes in concentration.

At higher temperature change in solubility and humidity (decreases) which cannot be correlated with room temperature.

For disperse systems at higher temperature viscosity decreases which can change physical characteristics resulting in potentially large errors in prediction of stability.

Different degradation mechanisms may predominate at different temperatures thus making stability prediction difficult.

Humidity

Higher humidity may leads to moisture adsorption.

Drugs which are highly sensitive to hydrolysis

Relative humidity Stability increase decrease

Higher humidity increases ageing process through interaction of drugs with excipients.

Effect of solubility

Applicable to drugs in solution form.

Eg:- Penicillin are very unstable in aqueous solution because of hydrolysis of β-lactum ring.

Ways for stabilization

Stabilized by using insoluble salts of API.

Formulate the drug in suspension dosage form.

Effect of ionic strength The rate of reaction can be influenced by the ionic strength of the

solution in accordance with the following equation:

log k = log k0 + 1.02ZA ZB √U

Where,

ZA and ZB = charges carried by the reacting species in solution

U = the ionic strength

K = rate constant at infinite dilution.

Where,

U = ½∑ CZ2

Drugs with

Positive charge:

Undergoes H+ ion catalysis and increase in ionic strength caused by the addition of salt increases rate of reaction.

Neutral charge:

Ionic strength will have no effect.

Negative charge:

Undergoes OH- ion catalysis and increase in ionic strength caused by the addition of salt decreases rate of reaction.

pH

By changing 1 pH unit , there is change in more than 10 fold in rate constant.

Before formulating drug in solution, K vs pH should be studied and optimum pH at lowest value of rate constant is to be found.

Hydrogen ion catalysis occurs at lower pH

Hydroxyl ion occurs at higher pH.

References

1) E.A.Rawlins, Bentley’s Textbook of Pharmaceutics,Bailliere Tindal(2004), 8th edition, page no-140.

2) Jens T. Carstensen, Drug stability, Marcel Dekker, 2ndedition.

3) Patrick J. Sinko, Martin’s Physical Pharmacy & Pharmaceutical sciences, Lippincott Williams & Wilkins, 4th edition, Page No.:397.

4) Leon Lachman,Herbert A.Lieberman,Joseph L. Kanig,The theory & Practice of Industrial Pharmacy, Warghese Publication House(Mumbai),3rd edition, Page No.:171.

5) Gilbert S. Banker & Christopher T. Rhodes, Modern Pharmaceutics, Marcel Dekker(New York), 4th edition.

6) Alfonso R. Gennaro, Remington: The science & Practice of Pharmacy,Vol-1,Lippincott Williams & Wilkins, 20th edition-2000,Ch-41, Page No-780.

7) pharmaceutical preformulation and formulation by Mark Gibson

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