Upload
sai-lakshmi
View
4.556
Download
17
Embed Size (px)
Citation preview
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
Selection of batchesContainer
closure system
specification
Testing frequency
Storage conditions
Stability commitment
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
Selection of batchesContainer
closure system
specification
Testing frequency
Storage conditions
Stability commitment
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
Selection of batchesContainer
closure system
specification
Testing frequency
Storage conditions
Stability commitment
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
Stability commitment
Evalution
Statement&labelling
Stability commitment
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
Section of batchesContainer
closure system
specification
Testing frequency
Storage conditions
Stability commitment
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
Section of batchesContainer
closure system
specification
Testing frequency
Storage conditions
Stability commitment
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 µbial 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