Stability Of Drugs:Stability Programmes And Stability Testing

From Pharmpedia

1 Introduction
2 Stability programme for a new drug
3 A Brief History of ICH
4 Steps in ICH Process
5 Climatic Zones and Conditions
6 Quality Guidelines Stability=
7 Q 1 A (R2)
8 Stability Testing for Established Drug Substances
9 Main Objectives of Stability Testing
10 Shelf ÃÂÃÂ¢ÃÂÃÂÃÂÃÂ Life and Recommended Storage Conditions
11 Shelf Life Determination Based on Arrhenius Plot
12 Shelf Life Determination Based on Real Time Testing

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Introduction

Stability Of Drugs

Introduction
Physical Stability
Chemical Stability
Microbiological Stability
Mechanisms
Photolysis
Rate Kinetics
Effect Of Temperature/pH
Factors Affecting
Packaging And Stability
Stability Programmes
Author

When a manufacturer plans to design, manufacture and market a drug product it is his responsibility to provide to the regulatory authorities assurance that the drug product meets with all the labelled claims and is stable in all senses till the expiry date is over. This responsibility implies that he/she undertake stability testing studies in a systematic way right from the Phase-I studies level. Upto the seventies these studies were undertaken by different companies in different manner. But today ICH guidelines help the manufacturers adopt a stability programme that is suitable for them. The final draft the ICH Harmoised Tripartite Guideline ÃÂÃÂ¢ÃÂÃÂÃÂÃÂStability Testing of New Drug Substances and Products was issued by the International Conference on Harmonization (ICH) Expert Working Group of the ICH on technical requirements for the registration of pharmaceuticals for human use in October 1993. J.T. Cartensen in his book ÃÂÃÂ¢ÃÂÃÂÃÂÃÂDrug Stability, Principles and PracticesÃÂÃÂ¢ÃÂÃÂÃÂÃÂ discussed these guidelines in great detail.

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Stability programme for a new drug

These guidelines divide the world into four zones and specify the temperature and relative humidity conditions to be maintained by each zone for stability studies. For example, if a manufacturer plans to sell his products in Zone III he has to submit stability data of his batches of products maintained at the temperature and relative humidity suggested by ICH for Zone III.

I will introduce the spirit and the text of the guidelines to you in a very brief manner.

Stability testing is done in five different occasion when an NDA is being contemplated.

1. Preformulation and compatibility

2. Preclinical formulation

3. Clinical and NDA formulation

4. Commitment and product monitoring

5. Post NDA change of formulation

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Preformulation and compatibility

In the early stage of drug designing studies are done to find out what sort of decomposition is possible, what is the mechanism, sensitivity to moisture and oxygen interaction probabilities (compatibilities) optimum pH and polymorphic information. Drug excipient interactions physical as well as chemical are extensively studied.

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Preclinical formulation

Keeping the data from the preformulation studies in mind formulations are designed and manufactured for use in Phase-I trails. More than the one or two formulations being used in Phase-I studies are manufactured and started on stability studies. This is because even a supposedly stable formulation may while in Phase-I use fail with respect to some stability issue, then you must have something to fall back upon.

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Clinical formulation

When a product has passed Phase-I, its dosage level, interactions and stability profile are known to some degree and armed with this knowledge the ÃÂÃÂ¢ÃÂÃÂÃÂÃÂClinical manufacturing groupÃÂÃÂ¢ÃÂÃÂÃÂÃÂ of the company manufactures several batches of the product and keeps some products from every batch for stability. The required stability aspects of clinical are simply to ascertain that each batch is within specifications during the length of the trail.

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Late Clinical and First Pilot Batch

The ICH stability guidelines require that three substantial batches, made in the same type production equipment intended for the final product, be made and that at least 12 months stability be in place at the time of NDA submittal.

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Marketed product stability

At the time the NDA is filed, the large clinical and scate-up batches are only about a year old, and the stability data on them is not yet complete. So at this time, the company asks for an expiry date based on extrapolation of the existing stability data. The FDI will take all facts into consideration and grant an expiry date based on a commitment form the company that the company will continue to do stability studies on different batches.

The storage requirements and the sampling times are very clearly specified by the ICH guidelines.

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A Brief History of ICH

Prior to 1960s there were not many controls over introduction of new drugs and also over the assurance of the quality by the manufacturer over his established drug products. Some stray tragic incidents in some countries like USA and India triggered the introduction of exacting drug laws to ensure the quality, safety and efficacy of the drug. Around 1970s the pharmaceutical industry started getting global but the registration of medicines remained a national responsibility. Although the laws of all the countries were based on the same fundamental obligations to evaluate the quality, safety and efficacy the detailed technical requirements differed from country to country. So the companies had to duplicate many time consuming and expensive test procedures, in order to market new products, internationally. All this resulted in unnecessary expenses and long delays in introducing new drugs.

So a necessity to harmonise or make uniform, the testing procedures and regulatory requirements of different countries was felt and the result is the birth of ICH in April 1990.

The birth of ICH took place at a meeting in April 1990, hosted by the EFPIA in Brussels. Representatives of the regulatory agencies and industry associations of Europe, Japan and the USA met primarily to plan an International Conference but the meeting also discussed the wider implications and terms of reference of ICH. The ICH steering committee which was established at that meeting has since met at least twice a year, with the location rotating between the three regions.

The topics first chosen for harmonization were ÃÂÃÂ¢ÃÂÃÂÃÂÃÂsafety, quality and efficacy and Expert Working Groups were set up to discuss scientific and technical aspects of each harmonization topic.

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Steps in ICH Process

The ICH process envisages harmonisatin in 5 steps.

Step-1: Concept paper, guideline development through EWG scientific consensus.

Step-2: EWG and steering committee guideline ÃÂÃÂ¢ÃÂÃÂÃÂÃÂsign offÃÂÃÂ¢ÃÂÃÂÃÂÃÂ.

Step-3: Public comments requested and reviewed, drafts revised by regulators.

Step-4: Regulatory parties EWG and steering committee of ÃÂÃÂ¢ÃÂÃÂÃÂÃÂsign offÃÂÃÂ¢ÃÂÃÂÃÂÃÂ finalized ICH guidelines.

Step-5: Implementation in three regions.

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Climatic Zones and Conditions

WHO has issued guidelines, where it is stated that the world is divided into four zones based on the prevailing annual climatic conditions for the purpose of stability testing.

Zone I : temperate

Zone II : subtropical with possible high humidity

Zone III : hot/dry

Zone IV : hot/humid

Tables 1 and 2 gives some interesting data. Table 1 gives the temperatures and relative humidities as recorded in different zones.

Table ÃÂÃÂ¢ÃÂÃÂÃÂÃÂ 1: Mean climatic conditions: measured data in the open air and in the storage room ¹

Climatic Zone

Measured data in the open air

Measured data in storage room

^oC

%RH

^oC

%RH

III

10.9

17.0

24.4

26.5

18.7

21.1

26.0

28.4

¹RH = relative humidity.

ClimaticZone

Calculated data

Derived storage conditions(for real-time studies)

^oC

^oC MKT³

%RH

^oC

%RH

III

20.0

21.6

26.4

26.7

20.0

22.0

27.9

27.4

¹Based on: Grimm W. Storage conditions for stability testing in the EC, Japan and USA; the most important market for drug products. Drug

development and industrial pharmacy, 1993, 19:2705-2830.

² Calculated temperatures are derived from measured temperatures, but all measured temperatures of less than 19^oC were set equal to 19 ^oC.

³ MKT = mean kinetic temperature

⁴ RH = relative humidity

Table 2 gives the calculated values of temperature, mean kinetic temperature and relative humidity and also gives derived storage conditions for real time studies. So for example if a manufacturer plans to sell his products in zone-III he/she should do real time studies at 30oc and 35%RH.

What has ICH done so far regarding stability?

It has issued guidelines in six important areas, all of them regarding stability testing of new drugs or dosage forms.

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Quality Guidelines Stability=

Q1A (R2) Stability Testing of New Drug Substances and products (Second Revision)

Q1B Stability Testing: Photostability Testing of New Drug Substances and Products.

Q1C Stability Testing for New Dosage Forms

Q1D Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Products.

Q1E Evaluation of Stability Data

Q1F Stability Data Package for Registration Application in Climatic Zones III and IV.

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Q 1 A (R2)

I will try to briefly summarize Q1A(R2) for you.

If a manufacturer wants to apply for the registration of a new drug, i.e. if he is applying for a (1) Investigative New Drug Application (IND) or (2) New Drug Application (NDA) or (3) New Drug Application (ANDA) then he has to assure the FDA regarding the drugÃÂÃÂ¢ÃÂÃÂÃÂÃÂs/drug productÃÂÃÂ¢ÃÂÃÂÃÂÃÂs safety, quality and efficacy. For this he has to carry out stability tests and submit stability data. How he should do this is specified by Q1A (R2).

Selection of Batches

Data from formal stability studies should be provided on at least three primary batches of the drug substance. These batches should be made to a minimum of pilot scale by the same synthetic route as that of the production batches.

Specifications which include testing methods and acceptance criteria should be fixed.

Testing frequency:

___________Months________

Long term : 0, 3, 6, 9, 12, 18, 24

Accelerated storage: 0, 3, 6

Storage conditions recommended

General case

Study	Storage condition	Minimum time period covered by data at submission
Long term*	25 ^oC + 2 ^oC/60% RH + 5% RH or 30 ^oC + 2 ^oC/65% RH + 5% RH	12 months
Intermediate**	30 ^oC + 2 ^oC/65% RH + 5% RH	6 months
Accelerated	40 ^oC + 2 ^oC/75% RH + 5% RH	6 months

It is up to the applicant to decide whether long term stability studies are performed at 25 + 2^oC/60% RH + 5% RH or 30 oC + 2^oC/65% RH + 5% RH.

- If 30^oC + 2^oC/65% RH + 5% RH is the long-term condition, there is no intermediate condition.

If long-term studies are conducted at 25^oC+ 2^oC/60% RH + 5% RH and ÃÂÃÂ¢ÃÂÃÂÃÂÃÂsignificant changeÃÂÃÂ¢ÃÂÃÂÃÂÃÂ occurs at any time during 6 monthsÃÂÃÂ¢ÃÂÃÂÃÂÃÂ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria.

ÃÂÃÂ¢ÃÂÃÂÃÂÃÂSignificant changeÃÂÃÂ¢ÃÂÃÂÃÂÃÂ for a drug substance is defined as failure to meet is specification.

Drug substances intended for storage in a refrigerator

Study	Storage condition	Minimum time period covered by data at submission
Long term	5 ^oC + 3 ^oC	12 months
Accelerated	25 ^oC + 2 ^oC/60% RH + 5% RH	6 months

Drug substances intended for storage in a freezer

Study	Storage condition	Minimum time period covered by data at submission
Long term	-20^oC + 5 ^oC	12 months

On the basis of the testing of all these stored products and analysing them for various stability parameters data is obtained and this data is analysed statistically and a storage statement is made on the label.

Almost all conditions are similar for new drug and new drug product.

Significant change for a drug substance is defined as failure to meet its specification.

Significant change for a drug product is defined as

1. A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures;

2. Any degradation productÃÂÃÂ¢ÃÂÃÂÃÂÃÂs exceeding its acceptance criterion;

3. Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g.: color, phase separation, resuspendibility, caking, hardness, dose delivery per actuation); however, some changes in physical attributes (e.g.: softening of suppositories, melting of creams) may be expected under accelerated conditions; and, as appropriate for the dosage form:

4. Failure to meet the acceptance criterion for pH; or

5. Failure to meet the acceptance criteria for dissolution for 12 dosage units

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Stability Testing for Established Drug Substances

WHO has issued guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms. The stability of finished pharmaceutical products depends on environmental factors and on product related factors. So stability considerations should be given, the highest priority in the design and formulation of a product. The shelf life should be established with due regard to the climatic zones. To ensure both patient safety and the rational management of drug supplies, it is important that the expiry date and storage conditions are properly indicated on the label.

Let us look at a few definitions here.

Accelerated stability testing

These are the studies designed to increase the rate of chemical degradation and physical change of a drug by using exaggerated storage conditions as part of the formal stability testing programme. The data thus obtained, in addition to those derived from real ÃÂÃÂ¢ÃÂÃÂÃÂÃÂ time stability studies, may be used to assess longer ÃÂÃÂ¢ÃÂÃÂÃÂÃÂ term chemical effects under non-accelerated conditions and to evaluate the impact of short-term excursions outside the label storage conditions, as might occur during shipping. The results of accelerated testing studies are not always predictive of physical changes. These are also known as stress testing studies.

Expiry date

The date given on the individual container of a drug product up to and including which the product is expected to remain within specifications if stored correctly. It is established for each batch by adding the shelf-life period to the date of manufacture.

Mean Kinetic Temperature

The single test temperature for a drug product corresponding to the effects on chemical reaction kinetics of a given temperature ÃÂÃÂ¢ÃÂÃÂÃÂÃÂ time distribution. A mean kinetic temperature is calculated for each of the four world climatic zones according to the formula developed by a scientist known as Hayanes. It is normally higher than the arithmetic mean temperature.

Real time (Long term) stability studies

Experiments on the physical, chemical, biological, biopharmaceutical and microbiological characteristics of a drug, during and beyond the expected shelf life and storage periods of samples under the storage conditions expected in the intended market. The results are used to establish the shelf life, to confirm the projected shelf life and to recommend storage conditions.

Stability tests

A series of tests designed to obtain information on the stability of a pharmaceutical product in order to define its shelf-life and utilization period under specified packging and storage conditions.

The following table gives the main objectives and uses the different types of stability testing

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Main Objectives of Stability Testing

Objective	Type of study	Use
To select adequate (from the viewpoint of stability) formulations and container-closure systems	Accelerated	Development of the product
To determine shelf-life and storage conditions	Accelerated and real-time	Development of the product and of the registration dossier
To substantiate the claimed shelf-life	Real-time	Registration dossier
To verify that no changes have been introduced in the formulation or manufacturing process that can adversely affect the stability of the product	Accelerated and real- time	Quality assurance in general, including quality control.

Test Samples

For established products the following schedule is suggested by WHO:

- one batch every other year for formulations considered to be stable, otherwise one batch per year.

- One batch every 3 ÃÂÃÂ¢ÃÂÃÂÃÂÃÂ 5 years for formulations for which the stability profile has been established, unless a major change has been made, eg: in the formulation or the method of manufacture.

Test Conditions

Example of conditions for accelerated stability testing of products containing relatively stable active ingredients

Storage temperature (^oC)	Relative humidity (%)	Duration of studies (months)
40 + 2	Zone IV ÃÂÃÂ¢ÃÂÃÂÃÂÃÂ For hot climatic zones or global market
	75 + 5	6
40 + 2	Zone II ÃÂÃÂ¢ÃÂÃÂÃÂÃÂ For temperate and subtropical climatic zones:	3
	75 + 5

Alternative storage conditions may be observed, in particular, storage for 6 months at a temperature of at least 15oC above the expected actual storage temperature (together with the appropriate relative humidity conditions). Storage at higher temperatures may also be recommended, e.g.3 months at 45 ÃÂÃÂ¢ÃÂÃÂÃÂÃÂ 50oC and 75% relative humidity (RH) for zone IV

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Shelf ÃÂÃÂ¢ÃÂÃÂÃÂÃÂ Life and Recommended Storage Conditions

The results of stability studies are evaluated with the objective of establishing a tentative shelf life Statistical methods are often used for the interpretation of these results. A tentative shelf ÃÂÃÂ¢ÃÂÃÂÃÂÃÂ life of 24 months may be established provided the active ingredient is known to be stable.

Products containing less stable active ingredients and formulations not suitable for experimental studies at elevated temperature (eg: suppositories) will need more extensive real time stability studies. The proposed shelf-life should then not exceed twice the period covered by the real time studies.

After the stability of the product has been evaluated, one of the following recommendations as to storage conditions can be prominently indicated on the label.

- store under normal storage contisions1;

- store between 2 and 8^oC (under refrigeration, no freezing);

- store below 8 ^oC (under refrigeration);

- store between -5 and -20^oC(in a freezer);

- store below -18^oC(in a deep freezer).

Normal storage conditions have been defined by WHO (3) as: ÃÂÃÂ¢ÃÂÃÂÃÂÃÂstorage in dry, well-ventilated premises at temperatures of 15-25 ^oC or, depending on climatic conditions, upto 30^oC. Extraneous odours, contamination, and intense light have to be excluded.

Recommended storage conditions must be determined in the light of the conditions prevailing within the country of designated use.

General precautionary statements, such as ÃÂÃÂ¢ÃÂÃÂÃÂÃÂprotect from lightÃÂÃÂ¢ÃÂÃÂÃÂÃÂ and/or ÃÂÃÂ¢ÃÂÃÂÃÂÃÂstore in a dry placeÃÂÃÂ¢ÃÂÃÂÃÂÃÂ, may be included, but should not be used to conceal stability problems.

WHO guidelines give a list of essential drugs for which they seek reports from people regarding stability problems. The list consists of 25 drugs and we find it is headed by acetylsalicylic acid and also contains the names of ampicillin, ibuprofen, isosorbide dinitrate, propranolol, spironolactone and warfarin. The stability problems to be reported include pharmacopoeial non-compliance, organoleptic changes and microbial changes.

Thus the WHO guidelines help us in carrying out stability studies on established drug substances in conventional dosage forms

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Shelf Life Determination Based on Arrhenius Plot

How do we determine the shelf life based on an Arrhenius Plot?

1. We keep several samples of the drug product at atleast three temperatures, such as 40^oC, 50 ^oC and 60 ^oC.

2. We determine the dug content at all three storage points by taking a number of samples and take the mean drug content. We do this for a few weeks.

3. At each temperature we plot a graph between time and log percent drug remaining. If the decomposition is first order this gives a straight line. If it is zero order, percent drug remaining versus time will give a straight line.

4. Next we take the logK or log of reaction constant on Y axis and 1/T x 10-3 on X axis and draw a best fit line. This line is the Arrhenius Plot. We extrapolate this line to get k at 25 ^oC and from this we calculate the shelf-life.

If the reaction is following zero-order

Expiration date at 25 ^oC (tx)

Initial potency ÃÂÃÂ¢ÃÂÃÂÃÂÃÂ minimum potency / reaction rate at 25 oc

tx =

Yo - Yx/ Ko

If the reaction is following first order

Expiration date at 25 ^oC (tx)

= Log initial potency ÃÂÃÂ¢ÃÂÃÂÃÂÃÂ log minimum potency/reaction rate at 25 oc

tx =

log Yo ÃÂÃÂ¢ÃÂÃÂÃÂÃÂ log Yx / K1

Where Yo = initial potency

Yx = final potency

Ko = zero order constant

K1 = first order constant

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Shelf Life Determination Based on Real Time Testing

Let me tell you another method which involves real time testing and statistical analysis, followed for determinng shelf life.

1. Keep three batches for stability study at least for 1 year at one fixed temperature.

2. Test them at 0, 1, 3, 6, 9, and 12 months for drug content. At each testing time test a number of samples, so that you have a mean and a standard deviation value of the result.

3. Now plot the graph of % drug content on Y axis and time on X axis along with confidence intervals. Where the lower 95% confidence curve intersects minimum potency, there you fix the shelf life.

As an example we can see the data and figure given in Tablets, Volume 3, page 355 by Hebet A Lieberman and Leon Lachman.

Vitamin Tablets Stability Confidence Intervals at 40^oC

Fig: Plot of In potency against time showing 95% confidence limit line

Table: Vitamin Tablets Stability Confidence Intervals at 40^oC

Time (Months)

Results

(mg/tablet)

Lower

limit

Upper

Limit

100.0

91.2

83.1

75.8

69.1

63.0

95.2

88.7

79.3

69.8

61.2

53.6

104.9

93.8

87.3

82.5

78.2

74.0

Where estimate of the standard error of regression(s)

y1 = predicted value at t1

n = sample size

Sy = standard error of the line

ÃÂÃÂÃÂÃÂ± = 0.1 two-sided

0.05 one-sided

This method also helps formulation scientists in fixing the amount of overages to be added to vitamin products.

So this then is the story of how we estimate the shelf-life.

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Stability Of Drugs:Stability Programmes And Stability Testing

Contents

Introduction

Stability programme for a new drug

Preformulation and compatibility

Preclinical formulation

Clinical formulation

Late Clinical and First Pilot Batch

Marketed product stability

A Brief History of ICH

Steps in ICH Process

Climatic Zones and Conditions

Quality Guidelines Stability=

Q 1 A (R2)

Stability Testing for Established Drug Substances

Main Objectives of Stability Testing

Shelf ÃÂÃÂ¢ÃÂÃÂÃÂÃÂ Life and Recommended Storage Conditions

Shelf Life Determination Based on Arrhenius Plot

Shelf Life Determination Based on Real Time Testing

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Stability Of Drugs:Stability Programmes And Stability Testing

Contents

Introduction

Stability programme for a new drug

Preformulation and compatibility

Preclinical formulation

Clinical formulation

Late Clinical and First Pilot Batch

Marketed product stability

A Brief History of ICH

Steps in ICH Process

Climatic Zones and Conditions

Quality Guidelines Stability=

Q 1 A (R2)

Stability Testing for Established Drug Substances

Main Objectives of Stability Testing

Shelf ÃÂÃÂ¢ÃÂÃÂÃÂÃÂ Life and Recommended Storage Conditions

Shelf Life Determination Based on Arrhenius Plot

Shelf Life Determination Based on Real Time Testing

Find

Browse

Edit

This page

Context

My pages

Special pages

Shelf ÃÂÃÂ¢ÃÂÃÂÃÂÃÂ Life and Recommended Storage Conditions