Stability testing protocol

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Stability testing protocol

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STABILITY TESTING PROTOCOL: INDIAN REGULATORY PERSPECTIVE BY CH.AVINASH Y11MPH443 I/II M.PHARMACY INDUSTRIAL PHARMACY CHALAPATHI INSTITUTE OF PHARMACEUTICAL SCIENCES

SUBJECTS FOR DISCUSSION:

SUBJECTS FOR DISCUSSION OBJECTIVE ABBREVIATIONS ESSENTIAL ICH DEFINITION S STABILITY TESTING OF APIS STABILITY TESTING OF FPPS PHOTOSTABILITY TESTING BRACKETING & MATRIXING RECOMMENDED LABELLING STATEMENTS REFERENCE DOCUMENTS 2

OBJECTIVE OF STABILITY TESTING:  :

OBJECTIVE OF STABILITY TESTING: “……To provide 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 as temperature, humidity & light, & enables recommended storage conditions, re-test periods & shelf lives to be established” (ICH) 2003 3

PowerPoint Presentation:

Stability studies play a central role in drug development Permit understanding of the molecule Essential for developing analytical methods Essential for selecting packaging for drug substance and drug product Essential for choosing storage conditions for drug substance and drug product 4 Why Stability studies are necessary ?

ABBREVIATIONS:

5 ABBREVIATIONS DRA Drug Regulatory Authority ICH International Conference on Harmonizatio n GMP Good Manufacturing Practices API Active Pharmaceutical Ingredient FPP Finished Pharmaceutical Product

SELECTED DEFINITIONS:

SELECTED DEFINITIONS Shelf life (also referred to as expiration dating period): 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. Re-test date: The date after which samples of the drug substance should be examined to ensure that the material is still in compliance with the specification and thus suitable for use in the manufacture of a given drug product. Re-test period: The period of time during which the drug substance is expected to remain within its specification and, therefore, can be used in the manufacture of a given drug product, provided that the drug substance has been stored under the defined conditions. 6

SELECTED DEFINITIONS:

SELECTED DEFINITIONS Accelerated testing: Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies. Intermediate testing: Studies conducted at 30°C/65% RH and designed to moderately increase the rate of chemical degradation or physical changes for a drug substance or drug product intended to be stored long term at 25°C. Long term testing: Stability studies under the recommended storage condition for the re-test period or shelf life proposed (or approved) for labeling. 7

SELECTED DEFINITIONS:

SELECTED DEFINITIONS Stress testing (drug substance): Studies undertaken to elucidate the intrinsic stability of the drug substance. It is normally carried out under more severe conditions than those used for accelerated testing. Stress testing (drug product): Studies undertaken to assess the effect of severe conditions on the drug product. Such studies include photostability testing and specific testing on certain products, (e.g., metered dose inhalers, creams, emulsions, refrigerated aqueous liquid products). 8

SELECTED DEFINITIONS:

SELECTED DEFINITIONS Container closure system: The sum of packaging components that together contain and protect the dosage form. Formal stability studies: Long term and accelerated (and intermediate) studies undertaken on primary and/or commitment batches according to a prescribed stability protocol to establish or confirm the re-test period of a drug substance or the shelf life of a drug product. Commitment batches: Production batches of a drug substance or drug product for which the stability studies are initiated or completed post approval through a commitment made in the registration application. 9

SELECTED DEFINITIONS:

SELECTED DEFINITIONS Primary batch: A batch of a drug substance or drug product used in a formal stability study, from which stability data are submitted in a registration application for the purpose of establishing a re-test period or shelf life. Pilot scale batch: A batch of a drug substance or drug product manufactured by a procedure fully representative of production scale batch. Production batch: A batch of a drug substance or drug product manufactured at production scale by using production equipment in a production facility as specified in the application 10

SELECTED DEFINITIONS:

SELECTED DEFINITIONS Specification – Release: The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug product at the time of its release. Specification - Shelf life: The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug substance throughout its re-test period, or that a drug product should meet throughout its shelf life. 11

SELECTED DEFINITIONS:

SELECTED DEFINITIONS Impermeable containers: Containers that provide a permanent barrier to the passage of gases or solvents, e.g., sealed aluminum tubes for semi-solids, sealed glass ampoules for solutions. Semi-permeable containers: Containers that allow the passage of solvent, usually water, while preventing solute loss. Examples of semi-permeable containers : low-density polyethylene (LDPE) pouches for large volume parenterals (LVPs) and LDPE ampoules, bottles, and vials. 12

Worldwide zones and the temperature and humidity conditions :

ZONE TEMPERATURE YEARLY AVERAGE HUMIDITY (%RH) Zone I ( Moderate) 21 ̊C 45 Zone II (Mediterranean) 25 ̊C 60 Zone III (Hot, dry) 30 ̊C 35 Zone IV (Very hot, moist) 30̊ C 70 Worldwide zones and the temperature and humidity conditions

Countries belonging to various zones :

REGIONS ZONE I &II ZONE III&IV EUROPE All countries AMERICA Argentina, Bolivia, Canada, Mexico, US Brazil, Columbia, Cuba, Jamaica ASIA Afghanistan, China, Iran, Nepal, Turkey INDIA, Bahrain , Hong Kong, Oman , Pakistan, Srilanka , UAE AFRICA Egypt, Algeria, South Africa, Libya Angola, Benin, Congo, Uganda, Sudan, Somalia, Senegal Countries belonging to various zones

PowerPoint Presentation:

General Stress Testing Selection of Batches Container Closure System Specification Testing Frequency Storage Conditions Stability Commitment Evaluation Statements/Labelling 15 STABILITY TESTING OF API S

General::

General: For active substances not described in an official pharmacopoeial monograph, stability studies are required. For active substances described in an official pharmacopoeial monograph, for which suitable limits have been set but a re-test period is not defined, two options are acceptable: 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. The manufacturer establishes a re-test period based on the results of long term testing stability studies conducted on the active substance. 16

Stress Testing::

Stress Testing: For an API the following approaches may be used: When available, it is acceptable to provide relevant data published in the scientific literature to support the identified degradation pathways and products. When no data is available, stress testing should be performed. The nature of the stress testing will depend on the individual active substance and the type of pharmaceutical product involved. 17

The Role of Stress Testing::

The Role of Stress Testing: Stress testing of the active substance can help in Identification of degradants Identification of degradation pathways Determination of which type(s) of stress affect the molecule: Photostability High Temperature Low Temperature Oxidation pH extremes Water 18

PowerPoint Presentation:

Oxidation: Typically done by placing the drug substance in aqueous solution of hydrogen peroxide. Goal is significant degradation (typically 10-30% of API) Can identify degradants Determine whether protective packaging is required Determine if an antioxidant should be considered for the drug product formulation. pH: Typically done by adding drug substance to buffered aqueous solutions at pH values from 1-10 Decide if the molecule will survive passage through the stomach Is enteric coating necessary? Should the drug be given by injection? 19

Typical Stress conditions::

Typical Stress conditions: 20 Stress factor Conditions Heat 10°C increments Humidity 75%RH or greater Acid 0.1N Hcl Base 0.1N NaOH Oxidative 3%H 2 O 2 Photolytic Xenon,Metal hailde lamp or Near UV,White florescent lamp

Selection of Batches::

Selection of Batches: Data from formal stability studies should be provided on at least three primary batches of the active substance. The batches should be manufactured to a minimum of pilot scale by the same synthetic route as, and using a method of manufacture and procedure that simulates the final process to be used for, production batches. 21

Container Closure System::

Container Closure System: The stability studies should be conducted on the active substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution. 22

Specification::

Specification: Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes. e.g. appearance, assay, degradation. 23

Testing Frequency::

Testing Frequency: For long term studies: Year 1: every 3 months Year 2: every 6 months Subsequent years: annually At accelerated storage conditions: (6 month study) Minimum three points including t 0 and t final , e.g. 0 3 6 (initial) (final) At intermediate storage conditions : (12 month study) Four points including t 0 and t final , e.g. 0 6 9 12 (initial) (final) 24

Storage Conditions::

Storage Conditions: In general, a drug substance should be evaluated under storage conditions that test its thermal stability and, if applicable, its sensitivity to moisture. The long-term testing should cover a minimum of 12 months’ duration on at least three primary batches at the time of submission and should be continued for a period of time sufficient to cover the proposed re-test period. 25

PowerPoint Presentation:

If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and “significant change” occurs at any time during six months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria. significant change – failure to meet its specification 26 Study Storage condition Minimum time period covered by data at submission Long Term * (Ambient) 25 º C ± 2º C 60%RH ± 5% 12 months Intermediate ** (controlled) 30 º C ± 2 º C 65%RH ± 5% 6 months Accelerated 40 º C ± 2 º C 75%RH ± 5% 6 months General case:

:

Drug substances intended for storage in a refrigerator: 27 Study Storage condition Minimum time period covered by data at submission Long Term 5 º C ± 3º C 12 months Accelerated 25 º C ± 2º C 60%RH ± 5% 6 months If significant change occurs between three and six months’ testing at the accelerated storage condition, the proposed re-test period should be based on the real time data available at the long term storage condition.

PowerPoint Presentation:

In the absence of an accelerated storage condition for active substances intended to be stored in a freezer, testing on a single batch at an elevated temperature (e.g. 5°C ± 3°C or 25°C ± 2°C or 30°C ± 2°C) for an appropriate time period should be conducted to address the effect of short term excursions outside the proposed label storage condition. e.g., during shipping or handling 28 Study Storage condition Minimum time period covered by data at submission Long Term -20º C ± 5º C 12 months Drug substances intended for storage in a freezer:

Stability Commitment::

Stability Commitment: When available long-term stability data does not cover the proposed re-test period, a commitment should be made to continue stability studies in order to firmly establish the re-test period. Where the data submitted is from fewer than 3 production batches, a commitment should be made to continue the long-term studies with additional production batches, to a total of at least 3. If the submission does not include stability data on production batches, a commitment should be made to place the first 3 production batches on long-term studies through the proposed re-test period. 29

Evaluation::

Evaluation: A systematic approach should be adopted in the presentation and evaluation of the stability information . Minimum of 3 batches of drug product was tested The analyst must found the batch to batch variability & if it is small than only it is accepted & it can be done by different statistical test's ( P value for level of significance for rejection). Where the data show so little degradation and so little variability then it is normally unnecessary to go through the formal statistical analysis; providing a justification for the omission should be sufficient. The stability of the drug product after reconstitution or diluting according to labeling, should be addressed to provide appropriate and supportive information. 30

Statements/Labelling::

Statements/ Labelling : A storage statement should be established for the labelling based on the stability evaluation of the active substance. Where applicable, specific instructions should be provided, particularly for active substances that cannot tolerate freezing. Terms such as “ambient conditions” or “room temperature” must be avoided. 31

STABILITY TESTING OF FPPS:

STABILITY TESTING OF FPP S General Selection of Batches Container Closure System Specification Testing Frequency Storage Conditions Stability Commitment Evaluation Statements/Labelling On-going Stability Studies 32

General::

General : The design of the formal stability studies for the pharmaceutical product should be based on knowledge of -the behaviour and properties of the active substance, -from stability studies on the active substance, -on experience gained from pre-formulation studies and investigational pharmaceutical products. 33

Selection of Batches::

Selection of Batches: Data from stability studies should be provided on at least three primary batches of the pharmaceutical product. The primary batches should be of the same formulation and packaged in the same container closure system as proposed for marketing. Two of the three batches should be at least pilot scale batches and the third one can be smaller, if justified. Where possible, batches of the pharmaceutical product should be manufactured by using different batches of the active substance. 34

Container Closure System::

Container Closure System: Stability testing should be conducted on the dosage form packaged in the container closure system proposed for marketing (including, as appropriate, any secondary packaging and container label). The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content (e.g. antioxidant, antimicrobial preservative). Analytical procedures should be fully validated, and stability indicating. 35 Specification:

Testing Frequency::

Testing Frequency: For long term studies: Year 1: every 3 months Year 2: every 6 months Subsequent years: annually At accelerated storage conditions: (6 month study) Minimum three points including t 0 and t final , e.g. 0 3 6 (initial) (final) At intermediate storage conditions : (12 month study) Four points including t 0 and t final , e.g. 0 6 9 12 (initial) (final) 36

Storage Conditions::

Storage Conditions: In general, a pharmaceutical product should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and, if applicable, its sensitivity to moisture or potential for solvent loss. The storage conditions and the lengths of studies chosen should be sufficient to cover storage, shipment, and subsequent use with due regard to the climatic zone(s) in which the product is intended to be marketed. Photostability testing should be conducted on at least one primary batch of the pharmaceutical product if appropriate. 37

PowerPoint Presentation:

If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and “significant change” occurs at any time during 6 months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria 38 Study Storage condition Minimum time period covered by data at submission Long Term * (Ambient) 25 º C ± 2º C 60%RH ± 5% 12 months Intermediate ** (controlled) 30 º C ± 2 º C 65%RH ± 5% 6 months Accelerated 40 º C ± 2 º C 75%RH ± 5% 6 months General case:

PowerPoint Presentation:

In general, “significant change” for a drug product is defined as: 1. A 5% change in assay from its initial value; 2. Any degradation product’s exceeding its acceptance criterion; 3. Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, resuspendibility , caking, hardness, dose delivery per actuation); however, some changes in physical attributes (e.g., softening of suppositories, melting of creams) may be expected under accelerated conditions; and, as appropriate for the dosage form: 4. Failure to meet the acceptance criterion for pH; or 5. Failure to meet the acceptance criteria for dissolution for 12 dosage units. 39

PowerPoint Presentation:

Drug products packaged in impermeable containers: Sensitivity to moisture or potential for solvent loss is not a concern for drug products packaged in impermeable containers that provide a permanent barrier to passage of moisture or solvent. Thus, stability studies can be conducted under any controlled or ambient humidity condition. Drug products packaged in semi-permeable containers: Aqueous-based products packaged in semi-permeable containers should be evaluated for potential water loss in addition to physical, chemical, biological, and microbiological stability. This evaluation can be carried out under conditions of low relative humidity. 40

PowerPoint Presentation:

A 5% loss in water from its initial value is considered a significant change for a product packaged in a semi-permeable container after an equivalent of 3 months’ storage at 40°C/NMT 25% RH. 41 Study Storage condition Minium time period covered by data at submission Long Term * (Ambient) 25 º C ± 2º C 40%RH ± 5% 12 months Intermediate ** (controlled) 30 º C ± 2 º C 65%RH ± 5% 6 months Accelerated 40 º C ± 2 º C NMT25%RH 6 months

PowerPoint Presentation:

If significant change occurs between 3 and 6 months’ testing at the accelerated storage condition, the proposed shelf life should be based on the real time data available from the long term storage condition. 42 Study Storage condition Minimum time period covered by data at submission Long Term 5 º C ± 3º C 12 months Accelerated 25 º C ± 2º C 60%RH ± 5% 6 months Drug products intended for storage in a refrigerator:

PowerPoint Presentation:

For drug products intended for storage in a freezer, the shelf life should be based on the real time data obtained at the long term storage condition. 43 Drug products intended for storage in a freezer: Study Storage condition Minimum time period covered by data at submission Long Term -20º C ± 5º C 12 months

Stability Commitment::

Stability Commitment: When available long-term stability data does not cover the proposed re-test period, a commitment should be made to continue stability studies in order to firmly establish the re-test period. Where the data submitted is from fewer than 3 production batches, a commitment should be made to continue the long-term studies with additional production batches, to a total of at least 3 If the submission does not include data on production batches, a commitment should be made to place the first 3 production batches on long-term studies through the proposed re-test period 44

Evaluation::

Evaluation: A systematic approach should be adopted in the presentation and evaluation of the stability information . Minimum of 3 batches of drug product was tested The analyst must found the batch to batch variability & if it is small than only it is accepted & it can be done by different statistical test's ( P value for level of significance for rejection). Where the data show so little degradation and so little variability then it is normally unnecessary to go through the formal statistical analysis; providing a justification for the omission should be sufficient. The stability of the drug product after reconstitution or diluting according to labeling, should be addressed to provide appropriate and supportive information. 45

Ongoing Stability Studies::

Ongoing Stability Studies: Purpose: to monitor and determine that API/FPP remains within specifications under the storage conditions, within the re-test period/shelf life in all future batches. The programme should be described in a written protocol. The programme should include at least one production batch per year, tested at least annually. An ongoing study should be conducted after any significant change to the synthetic route/manufacturing process or container which may impact stability.

Stability-indicating quality parameters:

Stability-indicating quality parameters Stability studies should include testing of those attributes of the FPP that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy. For instance, in case of tablets: ♦ appearance ♦ hardness ♦ friability ♦ moisture content ♦ dissolution time ♦ degradants ♦ assay ♦ microbial purity 47

DOSAGE FORM CONSIDERATION:

48 Dosage form Evaluation Tablets Appearance,colour,odour,assay , degradation products, dissolution,moisture and friability. Hard gelatin capsules Appearance,colour,odour,assay,degradation products,dissolution,moisture and microbial limits Soft gelatin capsules Appearance,colour,odour,assay,degradation products,dissolution,moisture and microbial limits,pH,leakage . Emulsions Appearance,colour,odour,assay , degradation products, microbial limits,PH,viscosity,preservative content and distribution of dispersed phase globules. DOSAGE FORM CONSIDERATION

PowerPoint Presentation:

49 Dosage form Evaluation Oral solutions Appearance,colour,odour,assay,degradation products, PH,microbial limits, preservative content. Oral suspensions Appearance,colour,odour,assay,degradation products, PH,microbial limits, preservative content,redispersibility,rheological properties, mean size and distribution of particle. Oral powders Appearance,colour,moisture,and reconstitution time. Inhalations and nasal sprays Appearance,colour,odour,assay,degradation products, dose content uniformity, microscopic evalution,water content, leak rate, microbial limits.

PowerPoint Presentation:

50 Dosage form Evaluation Topical,opthalamic,ointments ,creams, lotions,pastes,gels,solutions . Appearance,clarity,colour , homgeneity,odour,pH,resuspendibility,viscosity,particle size distribution, assay, degradation products,preservatives , microbial limits, weight loss Small volume parenterals Appearance,colour,clarity , assay,presarvative content, degradation products, particulate matter, sterility, Large volume parenterals Appearance,colour,clarity , assay,presarvative content,degradation products,particulate matter,sterility,pH,pyrogenicity , volume.

PowerPoint Presentation:

51 Accelerated Stability This stability study run under more stressful conditions than expected for long term storage to account for any changes outside the label storage conditions e.g. during shipping or handling. Acc Storage condition should be guided by intended climatic condition in which API/FPP will be stored. The goal is to get a quick understanding of what may be expected from a long term study. Long-term conditions Accelerated Conditions Room temperature (25-30°C) 40°C ± 2°C/75% RH ± 5% Refrigerated (5°  3°C) 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% Freezer (-20°C  5°C ) Can range from 5°C ± 3°C or 25°C ± 2°C or 30°C ± 2°C

PHOTOSTABILITY TESTING :

PHOTOSTABILITY TESTING Photostability testing studies include: Test on drug substance. Test on exposed drug product outside the immediate pack. Test on drug product in the immediate pack. Test on drug product in the marketing pack. Light source Option 1: Artificial daylight lamp combining both visible & UV output similar to D65 & ID65. Option 2: Cool white fluorescent & near UV lamp( 320 - 400nm ) 52 output similar to that specified in ISO 10977 max. energy emission between 350-370 nm

Procedure::

Procedure: 53 determine the absorbances of the sample (AT) and the control ( Ao ) at 400 nm using a 1 centimeter (cm) path length Eg: Quinine chemical actinometry: 2%w/v aq.solution of quinine monohydrochloride dihydrate 10ml of sol. in a 20 ml colorless ampoule wraped in aluminum foil (CONTROL) 10ml of sol. in a 20 ml colorless ampoule (SAMPLE) Expose to the light source Change in absorbance calculated by Δ A = AT - Ao .

PowerPoint Presentation:

To Evaluate the photosensitivity In elucidating degradation pathway In validating analytical procedures Information necessary for handling, packaging and labeling To study, identify precautionary measures needed in manufacturing or in formulation 54

PowerPoint Presentation:

55 Large stability chambers

BRACKETING:

BRACKETING It is the design of a stability schedule such that only samples on the extremes of certain design factors, e.g., strength, package size, 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. Where a range of strengths is to be tested, bracketing is applicable if the strengths are identical or very closely related in composition. e.g: for a tablet range made with different compression weights of a similar basic granulation. Bracketing can be applied to different container sizes or different fills in the same container closure system. 56

BRACKETING DESIGN:

57 BRACKETING DESIGN Pack type Label strength and batch numbers (X,Y,Z) 10 mg 20mg 30mg X Y Z X Y Z X Y Z Alu/Alu blister cards of 10 tablets + + + - - - + + + HDPE pack of 30 tablets + + + - - - + + + HDPE pack of 100 tablets - - - - - - - - - HDPE pack of 1000 tablets + + + - - - + + + + indicates- Sample tested

MATRIXING:

58 MATRIXING It is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations is tested at a specified time point . At a subsequent time point, another subset of samples for all factor combinations is tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point.

MATRIXING:

MATRIXING Example of matrixing design on time points for a product in two strengths (S1 and S2) are shown in Table: The term “one-half reduction” refer to the reduction strategy initially applied to the full study design. A “one-half reduction” initially eliminates one in every two time points from the full study design. The reductions are less than one-half due to the inclusion of full testing of all factor combinations at some time points. These example include full testing at the initial, final, and 12-month time points. The ultimate reduction is therefore less than one-half (24/48) and is actually 15/48. 59

MATRIXING DESIGN:

60 MATRIXING DESIGN one-half reduction Time points (months) 0 3 6 9 12 18 24 36 S1 Batch 1 + + - - + - + + Batch 2 + - + + + - + + Batch 3 + - + - + + - + S2 Batch 1 + - + + + + - + Batch 2 + + - - + + - + Batch 3 + + - + + - + + + indicates- Sample tested Example of Matrixing Design on Time Points for a Product with Two Strengths

RECOMMENDED LABELLING STATEMENTS:

RECOMMENDED LABELLING STATEMENTS Recommended labelling statements for APIs & FPPs 61 Testing condition under which the stability of the API/ FPP has been demonstrated Recommended labelling statement 25 °C/60% RH (long-term) 40 °C/75% RH (accelerated) “Do not store above 25 °C” 25 °C/60% RH (long-term) 30 °C/65% RH (intermediate, failure of accelerated) “Do not store above 25 °C” 30 °C/65% RH (long-term) 40 °C/75% RH (accelerated) “Do not store above 30 °C” 30 °C/75% RH (long-term) 40 °C/75% RH (accelerated) “Do not store above 30 °C” 5 °C ± 3 °C ”Store in a refrigerator (2 °C to 8 °C)” -20 °C ± 5 °C “Store in freezer”

Additional labelling statements for use where the result of the stability testing demonstrates limiting factors:

Additional labelling statements for use where the result of the stability testing demonstrates limiting factors 62 Limiting factors Additional labelling statement, where relevant FPPs that cannot tolerate refrigeration “Do not refrigerate or freeze” FPPs that cannot tolerate freezing “Do not freeze” Light-sensitive FPPs “Protect from light” FPPs that cannot tolerate excessive heat, e.g. suppositories “Store and transport not above 30 °C” Hygroscopic FPPs “Store in dry condition”

CONCLUSION:

CONCLUSION 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. 63

REFERENCES:

REFERENCES 64 1) ICH Q1A (R2): Stability testing of new drug substances and products ( http://www.ich.org/LOB/media/ MEDIA419.pdf ). 2) ICH Q1B: Photostability testing of new drug substances and products ( http://www.ich.org/LOB/media/ MEDIA412.pdf ). 3) ICH Q1C: Stability testing of new dosage forms ( http://www.ich.org/LOB/media/MEDIA413.pdf ). 4) ICH Q1D: Bracketing and matrixing designs for stability testing of new drug substances and products ( http://www.ich.org/LOB/media/MEDIA414.pdf ). 5) ICH Q1E: Evaluation for stability data ( http://www.ich.org/LOB/media/MEDIA415.pdf ). The following ICH Guidelines may be consulted in the context of stability testing:

REFERENCES:

REFERENCES 6) The WHO stability guideline – Stability testing of active pharmaceutical ingredients and finished pharmaceutical products (WHO Technical Report Series, No. 953, Annex 2, 2009) 7) V.SAI KISHORE’s Drug regulatory affairs (pg no 227-288) 65

THANK U:

66 THANK U