Presentation of PHARMACEUTICAL PRODUCT DEVELOPMENT

TOPICS:-

ICH guidelines of stability testing &

Protocols

PRESENTED BY

V.GOUTHAMI

Dpt.of Pharmaceutics

MALLA REDDY COLLEGE OF PHARMACY

ICH PARTNERS EFPIA[European Federation of pharmaceutical

Industries and Associations]

JPMA[Japan Pharmaceutical Manufactures Association]

PhRMA[Pharmaceutical Research and Manufactures Of America]

MHLW[Ministry Of Health Labor Welfare]Japan

USFDA

EU regulators

ICH GUIDELINESQUALITY :-

Q1:-Stability testing Q2:-Analytical validation Q3:-Impurities Q4:-Pharmacopoeias Q5:-Biotechnological products Q6:-Test procedures acceptance criteria Q7:-Good manufacturing practices Q8:-Pharmaceutical development Q9:-Quality risk management Q10:-Pharmaceutical quality system

SAFETY:- S1A:-Guidelines for carcinogenicity studies of

pharmaceuticals

S1B:-Testing for carcinogenicity of pharmaceuticals

S1C:-Dose selection

S2A:-Guidence on genotoxicity tests for pharmaceuticals

S3A:-Guidence on toxicokinetic studies

•S3B:-Guidance for repeated dose tissue distribution studies•S4 :-Chronic toxicity testing in animals(rodents and non rodent toxicity testing•S5 :-Detection of toxicity to reproduction for medicinal products•S6 :-Preclinical safety evaluation of biotechnology derived products•S7A:-Safety pharmacology studies for human pharmaceuticals•S7B:-Non clinical evaluation of the potential for dalayedventricular repolarisation (QT interval prolongation)by human pharmaceuticals•S8 :-Immuno toxicity studies for human pharmaceuticals•S9 :-Non clinical evaluation for anti cancer drugs

EFFICACY E1 :-Clinical safety for drugs intended for long term

treatment

E2A:-Definitions and standards for expedited reporting

E2B:-Data elements for transmission of individual case safety reports

E2C:-Periodic safety up date reports for marketed drugs

E2D:-Definitions and standards for expedited reports

•E2E:-Pharmacovigilance planning•E3 :-Structure and content of clinical study reports•E4 :-Dose-response information to support drug registration•E5 :-Ethinic factors in the acceptability of foreign clinical data•E6 :-Good clinical practice •E7 :-Studies in support of special populations •E8 :-General considerations for clinical trials•E9 :-Statistically principles for clinical trials•E10:-Choice of control group and related tissues in clinical trials•E11:-Clinical investigations of medicinal products

•E12:-Principles for clinical evaluation of new antihypertensive agent•E14:-The clinical evaluation of QT interval prolongation and pro arryhthmic potential for non-anti arrhythmic drugs•E15:-Definitions for pharmacogenomics, pharmacogenetics, genomic data and sample coding categories•E16:-Genomic biomarkers related to drug responds-context structure and format of qualification submission

Q1 Q1A:-Stability testing of new API $ FPP

Q1B:-Photo stability testing of new API $ FPP

Q1C:-Stability testing of new dosage forms

Q1D:-Bracketing and matrixing designs for stability testing of API $ FPP

Q1E:-Evaluation of stability data

Q1F:-Stability data package for registration in climatic zones III & IV

Q1A:-STABILITY TESTING OF NEW API$FPP Stress testing

Selection of batches

Container and closure systems

Storage conditions

Stress testing of API in solutionStorage 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

Stress testing of FPPs in solid stateStorage conditions Testing period*

40°C, 75 % RH; open storage** 3 months

50-60 °C, ambient RH; open

storage

3 months

** For API1-API2, or API-excipient, or FPP without packing material,

typically a thin layer of material is spread in a Petri dish. Open storage is

recommended, if possible.

3.11.3 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.

Illustrative data of API stability batches

Batch number

Date of manufacture

Site of manufacture

Batch size (kg)

Primary packing materials

Date of initial analysis

.

Batch number

Date of manufacture

Site of manufacture

Batch size (kg)

Primary packing materials

Date of initial analysis

Illustrative data of capsule/tablet stability batches

Batch number

Date of manufacture

Site of manufacture

Batch size (kg)

Batch size (number of

units)

Primary packing materials

Date of initial analysis

Batch number of the API

photo stability testingA systematic approach to photostability testing is recommended covering, as appropriate, studies such as: i) Tests on the drug substance; ii) Tests on the exposed drug product outside of the immediate pack; and if necessary ; iii) Tests on the drug product in the immediate pack; and if necessary ; iv) Tests on the drug product in the marketing Pack

Bracketing and matrixing designsBracketing:-As defined in the glossary to the parent guideline, bracketing is the design of a stabilityschedule 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.

MatrixingAs defined in the glossary of the parent guideline, 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 differences in the samples for the same drug product should be identified as, for example, covering different batches, different strengths, different sizes of the same container closure system etc

STABILITY PROTOCOL AND REPORT1. Batches tested2. General information3. Container/closure system 4. Literature and supporting data 5. Stability-indicating analytical methods 6. Testing plan 7. Test parameters8. Test results9. Other requirements (post-approval commitments)10. ConclusionsResult sheets must bear date and responsible person

signature / QA approval

Stability results A storage statement should be proposed for the

labeling (if applicable), which should be based on thestability 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 thedefined/regulatory specifications when stored at30±2oC and 65±5% RH for 2 years and at 40±2oCand 75±5%RH for 6 months.

REFERENCES

•Drug Stability: Principles and Practices, 3rd Edition, edited by Jens T.Carstensen and C. T. Rhodes (Marcel Dekker, Inc., New York, 2000)

•Silke Klick and others: Toward a Generic approach for Stress Testing of Drug Substances and Drug Products (Pharmaceutical Technology, February 2005)

•Raphael Bar: Statistical Evaluation of Stability Data: Criteria for Change-over-time and Data Variability (PDA Journal of Pharmaceutical Science and Technology, Vol. 57. No.5, Sept./Oct. 2003, pp. 369-377)

•WWW.USFDA.COM