Drug Stability. Drug stability It refers to the capacity of a drug substance or product to remain within established specifications of identity, strength,

Drug Stability

Drug stability

It refers to the capacity of a drug substance or product to remain within established specifications of identity strength quality and purity in a specified period of time

Stability is officially defined as the time lapse during which the drug product retains the same properties and characteristics that it possessed at the time of manufacture

The stability of a product is expressed as the expiry period or technically as shelf-life

Objectives of Stability Study

1- Provide an evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such asbull temperaturebull humiditybull and light

2- Establish abull re-test period for the drug substance or abull shelf life for the drug product andbull recommended storage conditions

To gather information during preformulation stage to produce a stable product

- To determine maximum expiration date

- To gate on idea of storage conditions

- To determine the packaging components

- The retest period of pharmaceuticals

- Transport conditions

Purposes of stability studies

bull The purposes of stability studies are to predict and confirm product shelf-life under the climatic conditions expected during trade storage shipping house storage and use

Chemical degradation of active drug may reduce the quality of therapeutic indices like 5-fluorouracil carbamazepine etc have very small therapeutic range slight degradation of drug may produce sub-therapeutic concentration

After degradation a drug may produce more toxic product (s) which may be more toxic than the parent product

Instability of drug product reduce bioavailability This may be caused by physical or chemical instability

Instability of a product may change the physical appearance of the product

Factors affecting drug stability

Storage time

Storage conditions

Type of dosage form

Container and closure system

bull 1- Environmental factors bull - Temperature - Light bull - Oxygen - Moisture bull - Carbon dioxide

bull 2- Drugs or excipients in the dosage form bull Particle size of drug bull pH of the vehicle

bull 3- Microbial contamination bull 4- Trace metal contamination bull 5- Leaching from containers

bull Chemical stability implies - The lack of any decomposition in the chemical moiety that is incorporated in the formulation as the drug preservatives or any other excipients

- This decomposition may influence the physical and chemical stability of the drug

bull Microbiological stability implies that

bull - The formulation has not suffered from any microbiological attack and is meeting the standards with respect to lack of contaminationsterility

bull 1048708 Physical changesbull Appearancebull Melting pointbull Clarity and color of solutionbull Crystal modification (Polymorphism)bull Particle size

1048708 Chemical changesbull Increase in Degradation productsbull Decrease of Assay

1048708 Microbial changesbull Growth of microorganism

Packaging And Stability

bull The immediate container and closure are particularly important in affecting product stability They play an important role in the product shelf-life

bull They may accelerate degradation reactions be an additive to or an absorbent of the drug substance or be ineffective in protecting the contents from environmental conditions

Glass

- Glass is resistant to chemical and physical change and is the most commonly used materials

Limitations overcomes

1 Its alkaline surface may raise the pH of the pharmaceutical and induce chemical reaction

2- Ionic radicals in the drug may precipitate insoluble crystals from the glass such as barium sulfate

3- Permits the transmission of light which may accelerate physical and chemical reactions in the drug

use of Borosilicate glass which contains fewer reactive alkali ions than the other 3 types of USP-recognized glass

Treatment the glass with heat as well as the use of buffers

Amber colored glass reducing light-induced reactions

Plastics

The problems with plastic are

1 Migration of the drug through the plastic into the environment

2 Transfer of environmental moisture oxygen and other elements into the pharmaceutical product

3 Leaching of container ingredients into the drug

4Adsorption or absorption of the active drug or excipients by the plastic

Metals

- Various alloys and aluminum tubes may be utilized as containers for emulsions ointments creams and pastes

- Limitation They may cause corrosion and precipitation in the drug product especially with products at extreme pH values or those containing metallic ions

- Overcome Coating the tubes with polymers may reduce these tendencies

Rubber

- Rubber also has the problems of extraction of drug ingredients and leaching of container ingredients

The use of neoprene butyl or natural rubber in combination with certain epoxy Teflon or vanish coating substantially reduces drug-container interaction

- The pretreatment of rubber vial stoppers and closures with water and steam removes surface blooms and also reduces potential leaching that might affect chemical analysis toxicity or pyrogenicity of the drug formulation

Stability studies at different stages

bull1 Stress- and accelerated Testing with drug substances

2 Stability on pre-formulation batches

3 Stress testing on scale-up Batches

4 Accelerated and long term testing for registration

5 On-going Stability testing

6 Follow-up Stabilities

Stability testing

There shall be a written testing program designed to assess the stability characteristics of drug products The results of such stability shall be used in determining appropriate storage conditions and expiration dates

The written program shall be followed and shall include

1) Sample size and test intervals based on statistical criteria for each attribute examined to assure valid estimates of stability

2) Storage conditions for samples retained for testing3) Reliable meaningful and specific test methods4) Testing of the drug product in the same container-closure system as that in

which the drug product is marketed5) Testing of drug products for reconstitution at the time of dispensing (as

directed in the labeling) as well as after they are reconstituted

bull An adequate number of batches of each drug product shall be tested to determine an appropriate expiration date and a record of such data shall be maintained

bull For homeopathic drug products the requirements of this section are asbull follows

bull (1) There shall be a written assessment of stability based at least on testing or examination of the drug product for compatibility of the ingredients

bull and based on marketing experience with the drug product to indicate that there is no degradation of the product for the normal or expected period of use

bull (2) Evaluation of stability shall be based on the same container-closurebull system in which the drug product is being marketed

bull Before commencement of a stability evaluation the stability protocol should be written and approvedmdashusually by technical services and QA

The key elements of a stability protocol include

1 Product name and packaging details The information should be sufficiently detailed to clearly identify the specific formulation(s) to be evaluated the specific containerclosure types (and sources) the batch size(s)

bull 2- The storage conditionbull 3 Number of batches to be evaluated Normally a minimum of three

batches is required to provide a sufficient basis for shelf-life prediction Development and stability batches may be used provided they are of the same formulations as the commercial product and they were processed in an equivalent manner

bull In general ldquosignificant changerdquo for a drug product is defined as

bull 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

bull 2 Any degradation productrsquos exceeding its acceptance criterion

bull 3 Failure to meet the acceptance criteria for appearance physical attributes andbull functionality test (eg color phase separation resuspendibility caking hardness dose

delivery per actuation) however some changes in physical attributes (eg softening of suppositories melting of creams) may be expected under accelerated conditions and as appropriate for the dosage form

bull 4 Failure to meet the acceptance criterion for pH or

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

bull ICH used the climatic zone conceptbull The key points included

bull bull Stability storage conditions will normally involve long-term studies at 25deg plusmn 2degC with 60 RH plusmn 5 with at least 12 months of data before filing accelerated studies at 40deg plusmn 2degC and 75 RH plusmn 5 with at least 6 months of data

bull bull Where lsquolsquosignificant changersquorsquo occurs during the 40degC accelerated study an additional intermediate station should be used such as 30deg plusmn 2degC 60 RH plusmn 5

bull lsquolsquoSignificant changersquorsquo was defined as a 5 loss of potency any degradant exceeding its specification limit exceeding pH limits dissolution failures using 12 units failures of physical specifications (hardness color etc)

bull 4- Test methodology The stability testing monograph need not include all of the criteria defined in the product release monograph Only those parameters that are potentially susceptible to change during storage and that may impact on quality safety or efficacy need to be evaluated

bull 5 Test frequency should be adequate to demonstrate any degradation and to provide enough data points for statistical evaluation For the scale-up batches and the first three commercial batches testing is expected initially at 3-month intervals during the first year 6-monthly in the second year and yearly thereafter

bull bull For less stable products the storage (and labeling) conditions may be reduced but the accelerated conditions should still be at least 15degC above those used for long-term evaluation

bull For products where water loss may be important such as liquids or semisolids in plastic containers it may be more appropriate to replace the high-RH conditions by lower RH such as 10ndash20

bull The same storage conditions are to be applied for the evaluation of bulk drug substances However retest dates may be used instead of expiration dates

bull For long term studies frequency of testing should be sufficient to establish the stability profile of the drug product For products with a proposed shelf life of at least 12 months the frequency of testing at the long term storage condition should normally be every 3 months over the first year every 6 months over the second year and annually thereafter through the proposed shelf life

bull At the accelerated storage condition a minimum of three time points including the initial and final time points (eg 0 3 and 6 months) from a 6-month study is recommended

bull When testing at the intermediate storage condition is called for as a result of significant

bull change at the accelerated storage condition a minimum of four time points including the

bull initial and final time points (eg 0 6 9 12 months) from a 12-month study is recommended

bull 6 Name andor titles of those responsible for assessing the data Where possible and appropriate the data should be evaluated statistically to obtain the shelf-life

bull Stability studies can be classified into three types

1 Studies usually under accelerated conditions to predict a tentative shelf-life for a new or modified product or process For a new drug substance these studies usually commence with a preformulation evaluation The effect of stress conditions such as temperature humidity light acidity and oxygen can provide much useful information to the formulator The potential interactive effects of the bulk drug and the anticipateddosage form excipients may also be evaluated

bull The accelerated studies at elevated temperature on the dosage form should allow some extrapolation to provide a tentative shelf-life

bull The ICH guidelines allow extrapolation of 6 months data under acceleratedbull conditions with 12 months data at 25degC60 RH to predict a shelf-life of up to 24

months Shelf-life in excess of 24 months should rarely be extrapolated from accelerated data

bull Where there is a change of manufacturing facility for the dosage form but using the same process and similar equipment 3 monthsaccelerated data may suffice again with the commitment to monitor the first three commercial batches

bull 2 Studies under conditions appropriate to the market or those defined in the product labeling are used to provide real-time data for confirmation of the predicted tentative shelf-life These studies are usually performed using controlled environmental cabinets

bull bull A typical warehouse may be an acceptable alternative provided temperature and

humidity are recorded For certain physical parameters such as dissolution tabletbull fragility and parenteral sterility accelerated conditions may not providebull useful data for extrapolation

bull Where such studies demonstrate that the predicted tentative shelf-life was too optimistic it would be necessary to consider recall of released batches

bull Real-time studies are also used to extend the defined shelf-life where the predicted value is found to be too pessimistic

bull 3 Stability studies on current production Once the shelf-life is established it is necessary to evaluate some ongoing batches to confirm that current production is behaving in a similar manner This is to detect the possible impact of any subtle or unknown changes to the components or process In the event that a change is observed it will be necessary to perform a root cause analysis

At this stage there should be a considerable amount of availablestability data that identify the shelf-life limiting factors

Storage conditions for general productsMinimum time period covered by data at submission

Storage conditions Study

12 months 25deg plusmn 2degC with 60 RH plusmn 5 or 30deg plusmn 2degC with 65 RH plusmn 5

Long term

6 months 30deg plusmn 2degC with 65 RH plusmn 5

Intermediate

6 months 40deg plusmn 2degC and 75 RH plusmn 5

Accelerated

It is up to the applicant to decide whether long term stability studies

are performed at 25deg plusmn 2degC with 60 RH plusmn 5 or 30 deg plusmn 2degC with 65 RH plusmn 5

If 30 deg plusmn 2degC with 65 RH plusmn 5 is the long term conditions there is no intermediate conditions

bull The stability requirements for homeopathic products are less demanding than for other drug products The levels of lsquolsquoactive ingredientsrsquorsquo are frequently so low that determination of degradation products or even assay of the active itself may not be practicable The requirements allow examination for compatibility as an alternative to testing

Climatic zones

The four zones in the world that are distinguished by their characteristic prevalent annual climatic conditions

bull Expiration datebull The date placed on the container label of a drug product

designating the time prior to which a batch of the product is expected to remain within the approved shelf life specification if stored under defined conditions and after which it must not be used

bull Shelf life (also referred to as expiration dating period)bull The time period during which a drug product is expected to

remain within the approved shelf-life specification provided that it is stored under the conditions defined on the container label