ByS.SANATH KUMAR

M. Pharm(Pharmaceutics), 1st semester, JAYAMUKHI COLLGE OF PHARMACY

Contents

Introduction ICH guidelines over view Stability protocols for drug products(ICH

Q1A guidelines) Test parameters for different dosage forms Reference

What is ICH guidelines ? International Conference on

Harmonization of Technical Requirements for Registration of Pharmaceuticals for human use

ICH is a joint initiative involving both regulators and industry as equal partners in the scientific and technical discussions of the testing procedures

There are six parties directly involved in the decision making processEU : European commission – European union EFPIA : European Federation of

Pharmaceutical Industries and AssociationsMHLC : Ministry of Health ,Labor and

Welfare, JapanJPMA : Japan Pharmaceutical Manufacturers

AssociationsFDA : US Food and Drug AdministrationPhRMA : Pharmaceutical Research and

Manufacturers of America

Why the ICH guidelines?

Harmonization of registration applications with in the three regions of the EU , Japan and the United states

ICH aims to produce a single set of technical requirements for the registration of drug products and hence the development process

To ensure and assess the safety, quality and efficacy of medicines.

What and Why the stability ? Defined as the capability of a particular

formulation in a specific container to remain within it’s physical, chemical, microbiological specifications throughout its shelf life

Evidence of Quality of the drug substance or drug product

And provides how Quality of the drug substance or product varies with time under the influence of a variety of environmental factors such asTemperature Humiditylight

In addition, product-related factors influence the stability, e.g. the chemical and physical properties of the active substance and the pharmaceutical excipients, the dosage form and its composition, the manufacturing process, the nature of the container-closure system etc.

Establish re test period for drug substances Establish shelf life for drug products Recommend storage conditions Test conditions based on analysis of effects of

climatic conditions in three regions of the EC, Japan and USA

World can thereby divided in to four climatic zones I-IV

Countries of climatic zone I&II:-• Europe: all countries• America: Argentina, Bolivia, Canada, Usa• Asia: Armenia, China, Iran, Japan, Korea, Nepal• Africa: Egypt, Libya, Namibia, Zambia,

southafrica• Australia: Australia&Newzeland Countries of climatic zone III&IV:-• America: Bahamas, Belize, Brasilia, Costa rica,

Colombia • Asia: India, Bangladesh, Iraq, Kuwait,

Thailand, UAE• Africa: Angola, Ethiopia, Benin, Botswana

The Four Climatic Zones

Climatic Climatic ZoneZone

DefinitionDefinition Storage Storage conditionsconditions

II

IIII

IIIIII

IV IV

Temperature Temperature climateclimate

Subtropical Subtropical and and MediterraneaMediterranean climaten climate

Hot, dry Hot, dry climateclimate

Hot, humid Hot, humid climateclimate

212100c/c/45%r.h.45%r.h.

252500c/c/60%r.h.60%r.h.

303000c/c/35%r.h.35%r.h.

303000c/c/70%r.h.70%r.h.

ICH guidelines over view In 1980

Harmonization of regulatory requirements was pioneered by the European community, as the European union moved towards the development of a single market for pharmaceuticals

At the same time there were bilateral discussions between Europe, Japan and the US on possibilities for harmonization.

In 1989 At the WHO conference of Drug

Regulatory Authorities (ICDRA), in Paris, specific plans for action began to materialize.

In 1990The birth of ICH took place at meeting

in April 1990 in Brussels where Representatives of the regulatory agencies of Europe, Japan and the USA.

Scope: ICH produces guidelines which covers: “Q” – Quality Guidelines

Concerned with stability, specifications and analytical method validation

“S” – Safety GuidelinesIn-vitro and In-vivo pre-clinical studiesCovering Carcinogenicity Testing,

Genotoxicity Testing, Toxicokinetics and pharmacokinetics

“E” – Efficacy GuidelinesClinical studies in human subject

Covering clinical safety, Dose response Studies, Good clinical practices, Clinical evolutions.

“M” – Multidisciplinary Guidelines Covering medical Terminology,

Electronic standards for Transmission of Regulatory information.

ICH Q – Guidelines (Quality)

• Q1A - stability testing for drug substances or drug products• Q1B – photo stability testing• Q1C – stability testing for new dosage forms• Q1D – Bracketing and Matrixing designs • Q1E – Evaluation of stability data• Q1F – stability testing in climatic zone III & IV• Q2 – validation of Analytical procedures• Q3 – Impurities• Q4 – pharmacopiel harmonization• Q5 – Biotechnological products• Q6 - Specifications

Stability protocols for drug products:

1. General2. Photo stability testing3. Selection of batches4. Container closure system5. Specifications6. Testing frequency7. Storage conditions8. Stability commitment9. Evaluation10. labeling

1.General: The design of stability studies should be

based on knowledge of the Behavior and Properties of the drug substance

The manufacturer of the pharmaceutical product confirms that the active substance complies with the pharmacopoeial monograph immediately prior to the manufacture of the pharmaceutical product. In this case no stability studies on the active substance are required.

2.Photo stability testing:

Testing should be conducted on at least one batch

Photo stability characteristics of drug products should be evaluated to demonstrate that light exposure does not result in unacceptable change

ProcedureTests on the exposed drug product out side

of the immediate pack

Tests on the drug products in the immediate pack

Tests on the drug product in the marketing pack

By using an integrated near ultraviolet energy of not less than 200 watt hours/square meter

3. Selection of batches:

At least three primary batches of the drug product are requiredSame formulation and in same container

closure system as proposed for marketingThe manufacturing process used for primary

batches should simulate that to be applied to production batches

Same quality and meeting specifications as that intended for marketing

That at least the first two production scale batches manufactured should be long-term stability studies.

Two of three batches at least pilot scale third can be smaller

Drug products should be manufactured by using different batches of the drug substances

Stability studies should be performed on each individual strength and container size of the drug product unless bracketing or matrixing is applied.

4.Container closure system:

the testing should be carried out in the final packaging proposed for marketing

Additional testing of unprotected finished product can form a useful part of the stress testing

Or other packaging materials can form a useful part of the stress testing of the dosage form

• The non-pharmacopoeial products should be derived from acceptable and justifiable derivations from release specifications based on the stability evaluation and changes observed on storage.

• attributes susceptible to change during storage

• may influence quality, safety and/or efficacy

• should cover physical, chemical, biological, microbiological attributes.

5.Specifications:

It is based on all available stability informationWhere necessary the justification for the limits

proposed for certain other tests as particle size or dissolution rate will require reference to the results observed in bioequivalence or clinical studies.

Any differences between the release and shelf life specifications for antimicrobial preservative should be supported by preservative effectiveness testing

Single primary batch should be tested for antimicrobial preservative effectiveness at proposed shelf life

6. Testing frequency:

• Long term studieso first year every three months. 0, 3, 6, 9,

12o second year every six months: 12, 18, 24o third year and longer annually: 24, 36,

48, 60• Accelerated studieso general minimum three time points: 0,3,6 monthso expectation of significant change increases testing adding samples at final time point or forth time point: 0, 1, 3, 6 months

o reduced designs, (matrixing or bracketing) where the testing frequency is reduced or certain factor combinations are not tested at all, can be applied

• Intermediate storage condition studies

o minimum four time points, including initial and final e.g.: 0,6,9,12 months, at time of submission 0,6 months

• Reduced design

7. Storage conditions:

o Storage should be evaluated under storage conditions that test thermal stability and, if applicable, sensitive to moisture

o The storage conditions and the lengths of studies chosen should be sufficient to cover storage, shipment, and subsequent use

o The long term testing should be cover a minimum of 12 months’ duration on at least three primary batches

o Should be continued to cover proposed shelf life

o Data from the accelerated storage condition and, if appropriate, from the intermediate storage condition can be used to evaluate the effect of short term excursions out side the label storage condition

o A significant change in water loss alone during 6 months accelerated testing does not necessitate storage at inter- mediate condition, but no significant water loss at25°C/40%.o A significant change is a 5% water loss after 3 months accelerated testing

o For small containers (1 ml or less) more than 5% loss after 3 months may be appropriate

o Storage under general storage conditions and calculate water loss determining permeation coefficient or using calculated ratio of water loss.

StudyStudy Storage Storage conditioncondition

Minimum time Minimum time period covered period covered by data at by data at submissionsubmission

Long termLong term 252500c c ++2200c/60%r.hc/60%r.h

OrOr

303000c c ++2200c/65%r.hc/65%r.h

12 months12 months

intermediaintermediatete

303000c c ++2200c/65%r.hc/65%r.h

6 months6 months

AccelerateAcceleratedd

404000c c ++2200c/75%r.hc/75%r.h

6 months6 months

Drug products - In Drug products - In general casegeneral case

Drug products – packed in semi permeable containerStudyStudy Storage Storage

conditionconditionMinimum time Minimum time period covered period covered by data at by data at submissionsubmission

Long termLong term 252500c c ++2200c/40%r.hc/40%r.h

OrOr

303000c c ++2200c/35%r.hc/35%r.h

12 months12 months

intermediaintermediatete

303000c c ++2200c/65%r.hc/65%r.h

6 months6 months

AccelerateAcceleratedd

404000c c ++2200c/25%r.hc/25%r.h

6 months6 months

Drug products – intended for storage in a refrigerator

StudyStudy Storage Storage conditioncondition

Minimum time Minimum time period covered period covered by data at by data at submissionsubmission

Long termLong term 5500c c ++ 3 300cc 12 months12 months

accelerateacceleratedd

252500c c ++ 2 200cc 6 months6 months

Drug products – intended for storage in a freezer

StudyStudy Storage Storage conditioncondition

Minimum time Minimum time period covered period covered by data at by data at submissionsubmission

Long Long termterm

202000c c ++ 5 500cc 12 months12 months

8. Stability commitment

• Proposed shelf life not covered When long term stability data do not proposed shelf life granted at time of approval, a commitment should be made to continue the stability studies post approval to establish the shelf life• Commitment not necessary Submission includes data on three production batches covering proposed shelf life

• Commitment required Submission does not includes data from three production batches, commitment to continue through proposed shelf life

o Fewer than three production batches commitment continue with these studies through proposed shelf life and place additional batches to a total of three on long term and accelerated stability testing through proposed shelf life.

o The stability protocol used for studies on commitment batches should be the same as that for the primary batches

9. Evaluation

o To establish shelf life and storage instructions applicable for all further batches manufactured and packed under similar circumstances.

o Systematic approach in presentation and evaluation of stability information.

o Should include results from physical, chemical, biological and microbiological tests.

o The batch to batch variability is if small, it is advantageous to combine the data in to one overall estimate

o If it is inappropriate to combine data from several batches, the overall shelf life should be based on the minimum time a batch can be expected to remain with in acceptance criteria

o Any evolution should cover not only the assay, but also the levels of degradation products and other appropriate attributes.

10. labeling A storage statement for labeling in accordance with

national/regional requirements Statement based on the stability evaluation of the

drug product A minimum temperature range or maximum

temperature range of storage must be specified(in degree Celsius) the use of terms such as “room temp” is unacceptable.

An expiration date should be displayed on container label.

Some specific requirements like “protect from light” & “protect from freezing” should be stated where applicable.

TEST PARAMETERS FOR DIFFERENT DOSAGE FORMS:

TABLETS: appearance, color, odour, assay, weight variation test, disintegration or dissolution, friabillity or hardness testing.

CAPSULE: appearance, color, odour ,assay, disintegration or dissolution , microbial growth.

ORAL POWDERS: appearance, color, odour, moisture and re constitution time

SUPPOSITORY: appearance, color, particle size, assay, dissolution, microbial growth.

EMULSION: appearance, color, odour, assay , viscosity, microbial growth.

SUSPENSION: particle size, appearance, color, odour, preservative content, microbial growth, re-dispersbility.

SOLUTIONS: appearance, color, odour, pH, viscosity, microbial growth, sterility.

PARENTERALS: appearance, color, assay, sterility (pyrogenicity or bacterial endotoxin), impurities.

IMPLANTS: total drug substance content,

in-vitro drug release rate, sterility.

TRANSDERMAL: appearance, assay, leakage, microbial growth, drug release rate.

REFERENCE Guidelines on cGMP and quality of

pharmaceutical products by S.Iyer. Futscher, N.; Schumacher ,P.; Pharm. Ind. 34,

479 - 483 (1972) Grimm, W.; Krummen, K.; Stability Testing in

the EC, Japan and the USA, Wissenschaftiche Verlagsgesellschaft mbH,

Stuttgart (1993) Grimm, W.; Drugs made in Germany 28, 196 -

202 (1985) and 29, 39 - 47 ( 1986) Dietz, R.; Feilner, K., Gerst, F.; Grimm, W.;

Drugs made in Germany 36, 99 - 103,(1993) Haynes, J.D.; J. Pharm. Sci. 60, 927 - 929 (1971) www.ich.org

Thank you !...........