ich guidelines

UNDER THE GUIDENCE OFPROF.B JEEVANA JYOTHI

PRESENTED BYB.N.S.SAI LAKSHMI

Stability testing procedures for pharmaceuticals according to ICH guidelines

Contents

IntroductionOrganizations regulating stability guidelines ICH topicsStability protocol & reportICH stability guidelines

• Stability testing of new drug substances & products• Photo stability testing of new drug

substances & products• Stability testing of dosage forms• Bracketing & matrixing design for

stability testing of new drug substance & products• Evalution of stability data• Stability data package for the

registration applications of the climate zones III & IV

Guideline for Residual SolventsConclusion References

StabilityStability of pharmaceutical product

may be defined as the capability of a particular formulation in a specific container/closure system to remain with its physical, chemical, microbiological, therapeutic and toxicological specification.

Stability studies typesLong term stability studyIntermediate stability studyAccelerated stability study

Factors Affecting Drug Stability

Physical formParticle

size Surface area

D.E ratio

D.E & D.D

interaction

Temperature

RH Light

oxygen

Dru

g &

Excip

ien

ts

Form

ula

tion

En

vir

on

men

t

Need for stability testing

Provide evidence as - how the quality of drug product varies with time.Establish shelf life for the drug productDetermine recommended storage conditionsDetermine container closure system suitability Safety point of view of patient Essential quality attribute

Organizations Regulating Stability Guidelines

The International Conference Of Harmonization of technical requirements for registration of pharmaceuticals for human use.

It is unique in bringing together the regulatory authorities of Europe ,Japan ,US & experts from pharmaceutical industries to discuss the scientific and technical aspects of the product registration

ICH TOPICS

QUALITY(Q)

SAFETY(S)

EFFICACY

(E)

MULTIDISIPLINARY

(M)

Related to mfg. QA

Non clinical pharmacology & toxicology studies

Clinical safety, dose response studies, good clinical practices , clinical evaluation

Medical terminology, electronic standards for transmission of regulatory information etc.

ICH –Quality Quality topic of ICH consist of 6 sub topics as follows:

Q1: Stability testingQ2: Analytical method validationQ3: Impurity testingQ4: Pharmacopoeial harmonizationQ5: Quality of bio technological productsQ6: Specifications for the new drug substances & products

Stability testing guidelines: They include six sub topics,they are

• Stability testing of new drug substances & products

ICHQ1A(R2)• Photo stability testing

of new drug substances & products

ICHQ1B• Stability testing of

dosage formsICHQ1C• Bracketing & matrixing

design for stability testing of new drug substance & products

ICHQ1D

• Evalution of stability dataICHQ1E

• Stability data package for the registration applications of the climate zones III & IV

ICHQ1F

Stability Studies are preformed on ...

Drug Substances (DS)/API:The unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form.

Drug Products (DP)/finished poduct:The dosage form in the final immediate packaging intended for Marketing.---(API & Excipients)

Where and Why?

Zone concept

Temperate zone

KMT- 21⁰cRH-45%

Mediterian zone

KMT-25⁰cRH-60%

Tropical zone

KMT-30⁰cRH-35%

Desert zone

KMT-30⁰cRH-70%

Batches tested General information Container/closure system Literature and supporting data Stability-indicating analytical methods Testing plan Test parameters Test results Other requirements (post-approval

commitments) Conclusions

Result sheets must bear date and responsible person signature / QA approval

Stability Protocol & Report

Q1A(R2)guidelines

Stress testing

Selection of batchesContainer

closure system

specification

Testing frequency

Storage conditions

Stability commitment

Evalution

Q1A (R2) guide lines

Stress testing

Carried out on a single batch and it include the effect of tempratures, humidity where appropriate oxidation & photolysis on DSScope: help to identify degradation products ,degradation pathway & intrinsic stability of the molecule

Selection of batches

Atleast 3 primary batches of the drug substance should be representative to quality of material used for production scale.

Statement&labelling

Q1A(R2)guidelines

Stress testing


closure system

specification

Testing frequency

Storage conditions


Evalution

Container closure system

Stability study conducted on the drug substancePacked in a container closure system i.e, same or stimulate packaging proposed for Storage & distribution.

Specification

These guide lines states the list of test,references to analytical procedure acceptence criteria.

Statement&labelling

Q1A(R2)guidelines

Stress testing


closure system

specification

Testing frequency

Storage conditions


Evaluation

Testing frequencyType of study Testing

frequency

Long term studies

For drug sub. With a proposed re test period of atleast 12 months.1st year……….3months2nd……………..6monthThere after……annualyThrough the proposed re-test period

Accelerated studies

Min. 3 time points(0,3,6 months),from a 6-month study

Intermediate studies

Min. 4 time points (0,6,9,12 months),for a 12month study.

Statement & labelling

Q1A(R2)guidelines

Stress testing


closure system

specification

Testing frequency

Storage conditions


Evalution

Study

Storage condition

Minimum time period covered by data at submission

Long term 25°C ± 2°C / 60% ± 5% R.H or30°C ± 2°C / 65% ± 5% R.H.

12 months

Intermediate 30°C ± 2°C / 65% ± 5% R.H.

6 months

Accelerated 40°C ± 2°C / 75% ± 5% R.H.

6 months

Storage conditions

Statement&labelling

Drug products - General case

Study Storage condition Minimum time period covered by data at submission

Long term 5°C ± 3°C 12 months

Accelerated 25°C ± 2°C / 60% ± 5% R.H. 6 months

Drug substances-intended for storage in refridgerator

Study Storage condition Minimum time period covered by data at submission

Long term -20°C ± 5°C 12 months

Drug substances/Product- intended for storage in Freezer

Q1A(R2)guidelines

Stress testing

Section of batchesContainer

closure system

specification

Testing frequency

Storage conditions


Evalution

Statement&labelling


In case where data submitted for registration do not cover the proposed shelf life , it is necessary to give commitment to continue the stability studies post approval in order to firmly the shelf life.

In addition to long term studies on at first three production batches covering the proposed shelf life, commitment of six month accelerated stability study also is a mostly for new product.

Q1A(R2)guidelines

Stress testing


closure system

specification

Testing frequency

Storage conditions


Evalution

Statement&labelling

Evaluation The purpose of stability is to establish re-test period(DS) & shelf life (DP) for future batches based on evaluation of results obtained from chemical,physical,biological,microbiological tests.A systemic approach should be adopted in the presentation & evaluation of the stability information which covers the physical ,chemical & biological parameter A minimum of 3 batches of drug product was tested.The analyst must found the batch to batch variability & if it is small then only it is accepted & can be done by different statistical tests

Significant change of drug substance or product

A 5% change in assay from its initial value Any degradation product exceeding its acceptance criteriaFailure to meet acceptance criteria for appearance ,physical attributes (colour,phase separation ,hardness), pHFailure to meet acceptance criteria for dissolution for 12 dosage forms

Q1A(R2)guidelines

Stress testing


closure system

specification

Testing frequency

Storage conditions


Evalution

Statement&labelling

Statement & labelling

A storage statement should be established for labeling in relevant national or regional requirements Should be established based on the stability evalution of drug substance

Terms such as “Ambient conditions "or “Room temperature” should be avoided

Retest date for DS & expiry date for DP should be displayed on the container label if appropriate

Photostability testing

Light can effect drugs ,causing chemical changes so evolution of drugs after exposing to light must be carried on single batch of material selected Gives idea about how to store drug Testing carried out on:

Tests on active substance Exposed drug product out side of the immediate pack

Drug product in the immediate pack

Drug product in the marketing pack

Light sources Artificial daylight flourosence lamp combining visible & UV out put , xenon or metal halide lampD65 is for out door day light ID65 is for indoor indirect day light

Procedure

Sample should be exposed to light providing an over all illumination of not less than 1.2 million lux hours & an integrated near UV energy of not less than 200 watt hours /sq.meter

Protected samples (eg., wrapped in aluminium foil)are used as dark controls to evaluate the contribution of thermally induced change to the total observed change.

Stability test for New dosage forms

new dosage forms ……• Same active substance• Different administration route • New specific functionality or delivery

systems• Different dosage forms of same

administration route Stability test parameteres for various types of dosage forms

Dosage form Parameter

Appearance,colour ,odour,assay,disintigration /dissolution,moisture & friability

Appearance,colour ,odour,assay,disintigration /dissolution,moisture &microbial limits

Soft gelatin capsules

Appearance,colour ,odour,assay,disintigration /dissolution,moisture ,microbial limits ,pH,leakage & pellicle formation

Tablets

Hard gelatin capsules

Emulsions

Appearance including phase seperation ,colour ,odour,assay,pH,viscosity,preservative content ,weight loss & microbial limits

Suppositories Appearance,colour ,assay ,particle size ,softening range ,dissolution& microbial limits

Small volume Small volume parentrals

Appearance ,colour,assay,pH, preservative content ,particulate matter , sterlity & pyrogenicity

Large volume Parentrals

Appearance ,colour,assay,pH, preservative content ,particulate matter , sterlity & pyrogenicity

Transdermals

Appearance, assay , leakage,sterility, peel & adhesive forces , drug release rate

Bracketing & matrixing design for stability testing of new drug substance & products

Study design

Full study design

Reduced studydesign

Samples of all designed factors for every combination are tested at all time points

Not Samples of all designed factors for every combination are tested at all time points

Bracketing

Matrixing

Bracketing Bracketing is the design of a Stability schedule such that only samples on the extremes of certain design factors (e.g., strength,container size and/or fill) are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested.

Example of a Bracketing Design

Matrixing Matrixing is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point.

At a subsequent time point, another subset of samples for all factor combinations would be tested. The Design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point.

The parent guideline states that regression analysis is an appropriate approach to analyzing quantitative stability data for retest period or shelf life estimation and recommends that a statistical test for batch poolability be performed using a level of significance of 0.25.

This guideline is intended to provide recommendations on how to use stability data generated in accordance with the principles detailed in the ICH guideline ―Q1A(R) Stability Testing of New Drug Substances and ProductsExtrapolation Extrapolation is the practice of using a known data set to infer information about future data. Extrapolation to extend the retest period or shelf life beyond the period covered by long-term data can be proposed in the application, particularly if no significant change is observed at the accelerated condition.

Evaluation Of The Stability Data

Stability Data Package For Registration In Climatic Zones III and IV

A product’s shelf life should be established according to climatic conditions in which the product is to be marketed. Storage conditions recommended by manufacturers on the basis of stability studies are meant to guarantee the maintenance of quality, safety and efficacy throughout the shelf-life of product. Temperature and humidity determine the storage conditions and so they greatly affect the stability of drug product. Climatic conditions in countries where the product is to be marketed should be carefully considered during drug development phase. So the world has been divided into four climatic zones based on prevalent annual climatic conditions.

ICH Topic Q3C (R4) Guideline for Residual Solvents

Residual solvents in pharmaceuticals are defined here as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products.

The solvents are not completely removed by practical manufacturing techniques.

Appropriate selection of the solvent for the synthesis of drug substance may enhance the yield, or determine characteristics such as crystal form, purity, and solubility.

.

Since there is no therapeutic benefit from residual solvents, all residual solvents should be removed to the extent possible to meet product specifications, good manufacturing practices, or other quality-based requirements.

Drug products should contain no higher levels of residual solvents than can be supported by safety data.

Known human carcinogens, strongly suspected human carcinogens, and environmental hazards.Not be employed in manufacturing bcoz of their unacceptable toxicity or their deleterious environmental effectIf their use is unavoidable – levels should be restricted

Class 1 solvents: Solvents to be avoided

Solvent Conc.limit(ppm)

Concern

Benzene 2 Carcinogen

Ccl4 4 Toxic and environmental hazard

1,2-Dichloroethane

5 Toxic

1,1-Dichloroethane

8 Toxic

Class 2 solvents: Solvents to be limited

Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity.Limited use bcoz of their inherent toxicity.Solvent Conc.

limit(ppm) PDE(mg/day)

Chlorobenzene 360 3.6

Chloroform 60 0.6

1,2-Dichloroethane

1870 18.7

Hexane 290 2.9

Class 3 solvents: Solvents with low toxic potential

Solvents with low toxic potential to man; no health-based exposure limit is needed.Class 3 solvents have PDEs of 50 mg or more per day.Less toxic.No longterm toxicity or carcinogenicityEg : Acetic acid Acetone 1-butanol 2-butanol Heptane

Class 4 solvents: Solvents for which no adequate toxicological data was found

Eg : Isooctane Petroleum ether 1,1diethoxy propane Trichloro acetic acid Methyl tetra hydro furan

Stability studies should be planned on the

basis of pharmaceutical R+D and regulatory requirements.

Forced degradation studies reveal the intrinsic chemical properties of the API, while formal stability studies establish the retest date.

The shelf life (expiry date) of FPPs is derived from formal stability studies.

Variability and time trends of stability data must be evaluated by the manufacturer in order to propose a retest date or expiry date.

Conclusion

2. ICH official web site. www.ich .org

http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html

References





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