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Performing Stability studiesPerforming Stability studies
Ulrich MarkensHead of QC Testing Labs AsiaSGS Life Science Services
Hyderabad, Mumbai, Ahmedabad - INDIAMarch 24th, 26th, and 28th 2007
2
FDA Warning Letter Report 2006
2005 2006 ∆
Drugs (part 211)
17 20 18%
Blood, Blood products, Biologicals(part 600 606, 610, 630, 640, 680)
9 10 11%
Medical devices (part 820)
107 79 -26%
3
FDA Warning Letter Report 2006 (cont’d)
Top 5 findingsTop 5 findings
4
Index
1 General Information
2 Examples for Stability testing design
3 Climatic Zones
4 ICH and Guidelines overview
5 ICH Q1A Guideline
6 Other relevant ICH Guidelines
7 Requirements for performing Stability studies
5
Why Stability?
Provide a 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, • and light
Establish a • re-test period for the drug substance or a • shelf life for the drug product and • recommended storage conditions
Because physical, chemical or microbiological changes might impact the
• efficiency and • security of the final product
*) Definition according to ICH Q1A(R2)
1 - General Information
6
Where and Why?
Stability Studies are preformed on
Drug Substances (DS)• … the unformulated drug substance that may subsequently be
formulated with excipients to produce the dosage form
Drug Products (DP)• .. the dosage form in the final immediate packaging intended for
marketing
and represents
controlled and documented determination of acceptablechanges of the drug substance or drug product
1 - General Information
7
What are changes?
Physical changes• Appearance• Melting point• Clarity and color of solution• Water• Crystal modification (Polymorphism)• Particle size
Chemical changes• Increase in Degradation products• Decrease of Assay
Microbial changes• Growth of microorganism
1 - General Information
8
Stability studies at different stages
1. Stress- and accelerated Testing with drug substances
2. Stability on pre-formulation batches
3. Stress testing on scale-up Batches
4. Accelerated and long term testing for registration
5. On-going Stability testing
6. Follow-up StabilitiesScope
• Solubility Profile• Hygroscopicity• Thermal stability
(Melting point, Polymorphism)• Chemical stability
1 BatchUp to 3 month Ad 1Ad 1
Selection of samples• API, excipient, batches
Scope• Appearance• Appropriate physical-chemical parameter• Assay / Degradation products
Up to 3 month Ad 2Ad 2
Scope• Determination of expire date • Determination of preliminary specifications• Release of clinical batches• Monitoring of samples during the clinical phases• Definition of storage conditions• Definition of Tests for registration stability
Up to 36 month Ad 3Ad 3
1 - General Information
9
2 Examples for Stability testing designs
10
Examples for stability testing designs
Testing scope for DRUG SUBSTANCES
• Physical-chemical properties– Appearance– Water content– pH– Color / clarity of solution– Thermo analytical stability
» Melting point» Polymorphism
• Chemical properties– Assay– Degradation products
• Microbial properties– (Microbial purity)
2 - Examples for Stability testing design
11
Examples for stability testing designs (cont’d)
Testing scope for TABLETS
• Physical-chemical properties– Appearance– Mean mass– Water content– Hardness– Disintegration– Dissolution
• Chemical properties– Assay– Degradation products
• Microbial properties– Microbial purity
• Container closure system properties– Functionality tests (e.g. extraction from blister)
2 - Examples for Stability testing design
12
Examples for stability testing designs (cont’d)
Testing scope for CAPSULES
• Physical-chemical properties– Elasticity– Mean mass– Mean filling mass– Water content (Capsule and content)– Disintegration– Dissolution
• Chemical properties– Assay– Degradation products
• Microbial properties– Microbial purity
• Container closure system properties– Functionality tests (e.g. extraction from blister)
2 - Examples for Stability testing design
13
Examples for stability testing designs (cont’d)
Testing scope for oral LIQUID FORMS
• Physical-chemical properties– pH– Color & clarity of solution– Loss on weight– Viscosity– Particle size distribution (for oral suspensions only)
• Chemical properties– Assay– Degradation products– Content preservatives– Degradation preservatives– Content antioxidants
• Microbial properties– Microbial purity
• Container closure system properties– Functionality tests
2 - Examples for Stability testing design
14
Examples for stability testing designs (cont’d)
Testing scope for LIQUID FORMS for inj. and PARENTERALIA
• Physical-chemical properties– pH– Loss on weight– Color & clarity of solution
• Chemical properties– Assay– Degradation products– Content preservatives– Degradation preservatives– Content antioxidants
• Microbial properties– Microbial purity
• Container closure system properties– Functionality tests
2 - Examples for Stability testing design
15
Examples for stability testing designs (cont’d)
Testing scope for SEMI LIQUID FORMS
• Physical-chemical properties– Appearance, odor, homogeneity, consistency– Loss on weight– Viscosity– Content uniformity (within the container)
• Chemical properties– Assay– Degradation products– Content preservatives– Degradation preservatives– Content antioxidants
• Microbial properties– Microbial purity
• Container closure system properties– Functionality tests
2 - Examples for Stability testing design
16
3 Climatic Zones
17
Climatic Zones / Storage conditions
*) Table taken from USP28 – NF23, General chapter <1150>
3 – Climatic Zones
Climatic ZoneCountries Temp. MKT humidity Temp. humidity
°C °C % r.h. °C % r.h.
Climatic Zone I "Temperate"
Japan, United Kingdom, Northern Europe, Canada, Russia, United States
Climatic Zone II"Mediterranean, Subtropical"
Japan, United States, Southern Europe
Climatic Zone III "Hot, dry"
Iran, Iraq, Sudan
Climatic Zone IV"Hot, humid"
Brazil, Ghana, Indonesia, Nicaragua, Philippines
7627,426,7
30 35
7030
21,6
26,4 27,9 35
60255222
Calculated data Derived data
20 20 42 21 45
18
Countries of climatic zone I and II
Europe• all countries
Americas• Argentina, Bolivia, Chile, Canada, Peru, USA, Uruguay …
Asia• Afghanistan, Armenia, Aserbaidschan, China, Georgia, Iran,
Israel, Japan, Corea (north & south), Lebanon, Nepal, Syria, Turkey …..
Africa• Egypt, Algeria, Libya, Marocco, Namibia, Ruanda, Sambia,
Simbabwe, South Africa, Tunesia …
Australia• Australia, New Zeeland
3 – Climatic Zones
19
Countries of climatic zone III and IV
Americas• Bahamas, Barbados, Belize, Brasilia, Costa Rica, Ecuador,
Guatemala, Colombia, Nicaragua …
Asia• Bahrain, Bangladesh, India, Indonesia, Iraq, Cambodia,
Qatar, Kuwait, Laos, Malaysia, Myanmar, Pakistan, Philippines, Singapore, Thailand, UAE, Vietnam …..
Africa• Angola, Ethiopia, Benin, Botswana, Burkina Faso …..
Oceania• Fiji, Marshall Islands, Micronesia, Papua New-Guinea ….
3 – Climatic Zones
20
4 ICH and Guidelines overview
2 Examples for Stability testing design
3 Climatic Zones
4 ICH and Guidelines overview
5 ICH Q1A Guideline
6 Other relevant ICH Guidelines
7 Requirements for performing Stability studies
21
What or Who is ICH?
ICH stands for International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human use
Objectives of ICH• Harmonization of registration applications within the three regions of
the EU, Japan and the United States. • ICH is a joint initiative involving both regulators and industry as equal
partners in the scientific and technical discussions of the testing procedures which are required to ensure and assess the safety, quality and efficacy of medicines
4 – ICH and Guidelines overview
22
What or Who is ICH?
There are Six Parties directly involved in the decision making process
• EU: European Commission - European Union • EFPIA: European Federation of Pharmaceutical Industries and
Associations • MHLW: Ministry of Health, Labor and Welfare, Japan • JPMA: Japan Pharmaceutical Manufacturers Association • FDA: US Food and Drug Administration • PhRMA: Pharmaceutical Research and Manufacturers of America
There are additionally observers installed to act as a link withnon-ICH countries and regions
• WHO• The European Free Trade Area (EFTA),
represented by Swissmedic Switzerland • Health Canada
4 – ICH and Guidelines overview
23
A brief History of ICH
1980s• Harmonization of regulatory requirements was pioneered by the
European Community, as the European Union moved towards the development of a single market for pharmaceuticals.
• The success achieved in Europe demonstrated that harmonization was feasible.
• At the same time there were bilateral discussions between Europe, Japan and the US on possibilities for harmonization.
1989• At the WHO Conference of Drug Regulatory Authorities (ICDRA), in
Paris, specific plans for action began to materialize.
1990• The birth of ICH took place at a meeting in April 1990 in Brussels
where Representatives of the regulatory agencies and industry associations of Europe, Japan and the USA met
4 – ICH and Guidelines overview
24
Guidelines
ICH Guidelines• Quality Guidelines “Q” (chemical and pharmaceutical QA)
– details see next slide• Safety Guidelines “S” (in vitro and in vivo pre-clinical studies)
– covering Carcinogenicity Testing, Genotoxicity Testing, Toxicokinetics and Pharmacokinetics ….. etc.
• Efficacy Guidelines “E” (clinical studies in human subject)– Covering clinical safety, Dose Response Studies, Good Clinical
Practices, Clinical evaluation …. etc.• Multidisciplinary Guidelines “M”
– Covering Medical Terminology, Electronic Standards for Transmission of Regulatory Information …… etc.
– Important for Stability ! » Guideline M4: The Common Technical Document (CTD)
4 – ICH and Guidelines overview
25
Guidelines
ICH Q-Guidelines (Quality)
• Stability Testing in Climatic Zone I and II (Q1A)• Photostability Testing (Q1B)• Stability Testing for New Dosage Forms (Q1C)• Bracketing and Matrixing Designs (Q1D)• Evaluation of Stability Data (Q1E)• Stability Testing in Climatic Zones III and IV (Q1F)• Validation of Analytical Procedures (Q2)• Impurities (Q3)• Biotechnological Products (Q5)• Specifications (Q6)
4 – ICH and Guidelines overview
26
Guidelines
ASEAN* Guidelines• Stability Studies of Drug products • Validation of Analytical Procedures• Common Technical Dossier (ACTD) for the registration of
pharmaceuticals
FDA (Food and Drug Administration)• Guidance for Industry: Stability Testing of Drug Substances and Drug
Products; June 1998– One fits all document– Considers ICH Q1A, Q1B, Q1C and Q5CWithdrawn by FDA
In June 2006
* ASEAN Members: Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, Vietnam
4 – ICH and Guidelines overview
27
Guidelines
WHO• WHO TRS 863, Annex 5: “Guidelines for stability testing of
pharmaceutical products containing well established drug substances in conventional dosage forms”
USP (US Pharmacopeia)• USP 29 <1150> Pharmaceutical Stability
EMEA (European Agency for the Evaluation of Medicinal Product)
• Note for Guidance on Stability Testing of existing active substance and Related Finished products (Draft), February 2002
etc.
4 – ICH and Guidelines overview
28
FDAFDAFDA
ASEANASEANASEAN
WHOWHOWHO
Guidelines
ICH Q1AICH Q1AICH Q1A
ICHQ1B
ICHICHQ1BQ1B
ICH
Q1CICH
ICH
Q1CQ1C
ICH
Q1DIC
HIC
HQ
1DQ
1DICHQ1F
ICHICHQ1FQ1F
ICHQ1E
ICHICHQ
1EQ
1E
ICHQ2
ICHICHQ2Q2
ICHQ5
ICHICHQ5Q5
Stability Testing of New DS and DP (Climatic Zone I and II)
Photostability Testing
Bracketing and Matrixing
New Dosage FormsEvaluation of Stability Data
Stability Testing in Climatic Zones III and IV
Analytical Validation
Biotechnological Products
ICHQ3A/B/C
ICHICHQ3A/B/CQ3A/B/C ICH
Q6A/BICHICH
Q6A/BQ6A/BImpurities
Specifications
4 – ICH and Guidelines overview
29
5 ICH Q1A Guideline
30
ICH Q1A Guideline
Objectives• Define common principles valid for both Drug Substances and
Products• Ensures that all data derived from DS can be used for further
development of DP
Scope• Adresses the information to be submitted in registration applications
for – new molecular entities (NMEs) and – Associated drug products
• Dedicated to climatic Zone I and II• Does not currently seek to cover the information to be submitted for
– abbreviated or abridged applications– variations– clinical trial applications
5 – ICH Q1A Guideline
31
Structure / Sections
1. General
2. Stress Testing • Comprehensive Stress testing for Drug Substances• Photostability for Drug products
3. Selection of batches
4. Container closure system
5. Specifications
6. Testing frequency
7. Storage conditions
8. Stability commitment
9. Evaluation
10. Statements / Labeling
5 – ICH Q1A Guideline
32
Section 1 - General
Drug Substance• Information on the stability of the drug substance is an integral part of the
systematic approach to stability evaluation
Drug Product• The design of the stability studies should be based on knowledge of the
– behavior and – properties of the drug substance and from – stability studies on the drug substance and on – experience gained from clinical formulation studies.
• The likely changes on storage and the rationale for the selection of attributes to be tested in the formal stability studies should be stated
5 – ICH Q1A Guideline
33
Section 2 - Stress Testing
Drug Substance• carried out on a single batch• Should include the effect of temperatures (in 10°C increments above that for
accelerated testing), humidity (e.g., 75% RH or greater) where appropriate, oxidation, and photolysis
• Should evaluate the susceptibility to hydrolysis across a wide range of pH values when in solution or suspension
• Examining degradation products under stress conditions is useful in establishing degradation pathways and developing and validating suitable analytical procedures.
• Photostability testing should be an integral part of stress testing
Drug Product• Photostability testing should be conducted on at least one batch• Conditions are described in ICH Q1B.
Results from these studies will form an integral part of the information provided to regulatory authorities
5 – ICH Q1A Guideline
34
Section 3 - Selection of Batches
Drug Substance• At least three primary batches of the drug substance. • 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.
Drug Product• At least three primary batches of the drug product• The manufacturing process used for primary batches should simulate that to be
applied to production batches and should provide product of the same quality and meeting the same specification as that intended for marketing
• 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.
• Batches should be manufactured by using different batches of drug substance• Stability studies should be performed on each individual strength and container
size of the drug product unless bracketing or matrixing is applied ICH Q1
5 – ICH Q1A Guideline
35
Section 4 - Container Closure System
Drug Substance• Container closure system should be the same as for storage and distribution
(or should be able to simulates the packaging proposed)
Drug Product• Tested dosage form should be packaged in the container closure system
proposed for marketing– Including any secondary packaging and container label– Studies carried out on the drug product outside its immediate container or in other
packaging materials can form a useful part of the stress testing of the dosage form or can be considered as supporting information, respectively.
5 – ICH Q1A Guideline
36
Section 5 - Specifications
Drug Substance and Drug Product• Stability studies should include testing of attributes that are susceptible to
change during storage and are likely to influence quality, safety, and/or efficacy• Analytical procedures should be validated and stability indicating• References: ICH Q2, ICH Q3A/B, ICH Q6
Drug Product• The testing should cover, as appropriate, the physical, chemical, biological,
and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial preservative), and functionality tests (e.g., for a dose delivery system).
• Shelf life acceptance criteria should be derived from consideration of all available stability information.
• It may be appropriate to have justifiable differences between the shelf life and release acceptance criteria based on the stability evaluation and the changes observed on storage.
• A single primary stability batch of the drug product should be tested for antimicrobial preservative effectiveness (in addition to preservative content) at the proposed shelf life for verification purposes, regardless of whether there is a difference between the release and shelf life acceptance criteria for preservative content
5 – ICH Q1A Guideline
37
Section 5 - Specifications / “Significant change”
Drug Substance • failure to meet its specification
Drug Product• 5% change in assay from its initial value• Any degradation product’s exceeding its acceptance criterion• Failure to meet the acceptance criteria for appearance, physical attributes, and
functionality test e.g.:– color, phase separation, resuspendibility, caking, hardness, etc
• Failure to meet the acceptance criterion for pH• Failure to meet the acceptance criteria for dissolution for
12 dosage units
5 – ICH Q1A Guideline
38
Section 6 - Testing frequency
Long term Storage condition• Frequency should be every 3 months over the first year, every 6 months over
the second year, and annually thereafter through the proposed retest period (For drug substances with a proposed re-test period of at least 12 months)
Accelerated storage condition • a minimum of three time points, including the initial and final time points (e.g.,
0, 3, and 6 months), from a 6-month study is recommended
Intermediate storage condition • When testing at the intermediate storage condition is called for as a result of
significant change at the accelerated storage condition, a minimum of four time points, including the initial and final time points (e.g. 0, 6, 9, 12 months), from a 12-month study is recommended
Reduced designs, (matrixing or bracketing) where the testing frequency is reduced or certain factor combinations are not tested at all, can be applied, if justified Q1D
Applicable for DS and DPApplicable for DS and DP
5 – ICH Q1A Guideline
39
Section 7 - Storage conditions
Storage should be evaluated under storage conditions that test thermal stability and, if applicable, sensitivity to moisture
The storage conditions and the lengths of studies chosen should be sufficient to cover storage, shipment, and subsequent use
The long term testing should cover a minimum of 12 months’ duration on at least three primary batches
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 outside the label storage conditions (e.g. during shipping)
The general case applies if the DS / DP is not specifically covered by a subsequent section. Alternative storage conditions can be used, if justified.
Applicable for DS and DPApplicable for DS and DP
5 – ICH Q1A Guideline
40
Section 7 - Storage conditions (cont’d)
Drug Product• Stability testing of the drug product after constitution or
dilution, if applicable, should be conducted to provide information for the labeling on the preparation, storage condition, and in-use period of the constituted or diluted product.
• This testing should be performed on the constituted or diluted product through the proposed in-use period on primary batches at initial and final time points and, if full shelf life long term data will not be available before submission, at 12 months or the last time point for which data will be available.
• Additional data accumulated during the assessment period of the registration application should be submitted to the authorities if requested.
5 – ICH Q1A Guideline
41
Section 7 - Storage conditions (cont’d)
Drug substances - General case
Drug substances - intended for storage in a Refrigerator
Drug substances - intended for storage in Freezer
5 – ICH Q1A Guideline
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
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
Study Storage condition Minimum time period covered by data at submission
Long term -20°C ± 5°C 12 months
42
Section 7 - Storage conditions (cont’d)
Drug products - General case
Drug products - packaged in Semi-permeable containers
5 – ICH Q1A Guideline
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
Study Storage condition Minimum time period covered by data at submission
Long term 25°C ± 2°C / 40% ± 5% r.h. or30°C ± 2°C / 35% ± 5% r.h. 12 months
Intermediate 30°C ± 2°C / 65% ± 5% r.h. 6 months
Accelerated 40°C ± 2°C / NMT 25% r.h. 6 months
43
Section 7 - Storage conditions (cont’d)
Drug products - intended for storage in a Refrigerator
Drug products - intended for storage in a Freezer
5 – ICH Q1A Guideline
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
Study Storage condition Minimum time period covered by data at submission
Long term -20°C ± 5°C 12 months
44
Section 8 - Stability Commitment
If Submission includes stability data from three production batches covering the proposed re-test period / shelf life, a post approval commitment is not necessary.
Otherwise a commitment should be made• Study don’t cover proposed re-test period / shelf life :
– Continue through the proposed re-test period / shelf life • Less than three production batches used:
– Enlarge studies with additional production batches, to a total of at least three
• No production batch used:– Commitment to place the first three production batches on
stability through the proposed re-test period / shelf life and on accelerated studies for 6 months.
Applicable for DS and DPApplicable for DS and DP
5 – ICH Q1A Guideline
45
Section 9 - Evaluation
Determine the time at which the 95 one-sided confidence limit for the mean curve intersects the acceptance criterion
• Calculation of re-test period (DS)• Calculation of shelf life (DP)
If the batch-to-batch variability is small, it is advantageous to combine the data into one overall estimate
If it is inappropriate to combine data from several batches, theoverall shelf life should be based on the minimum time a batch can be expected to remain within acceptance criteria
Any evaluation should cover not only the assay, but also the levels of degradation products and other appropriate attributes.
Reference: ICH Q1E
Applicable for DS and DPApplicable for DS and DP
5 – ICH Q1A Guideline
46
Section 9 – Evaluation (cont’d)
93
94
95
96
97
98
99
100
101
102
0 5 10 15 20 25 30 35 40
month
% o
f Dec
lara
tion
Proposed shelf life orRe-test period
5 – ICH Q1A Guideline
47
Section 10 – Statements / Labeling
General• A storage statement should be established for the labeling in
accordance with relevant national/regional requirements• Statement should be based on the stability evaluation of the drug
substance / drug product• Terms such as “ambient conditions” or “room temperature” should be
avoided.
Drug Substance• Retest date should be displayed on the container label if appropriate.
Drug Product• There should be a direct link between the label storage statement
and the demonstrated stability of the drug product. • An expiration date should be displayed on the container label.
Applicable for DS and DPApplicable for DS and DP
5 – ICH Q1A Guideline
48
Submission
At Submission you need at least the following stability data of the Drug product
• Based on three primary batches• Derived from same formulation as proposed for marketing• packaged in the same container closure system as proposed for
marketing
5 – ICH Q1A Guideline
Condition Temp. humidityt=0 t=1 t=3 t=6 t=9 t=12
Long term 25°C 60%
Intermediate 30°C 65%
Accelerated 40°C 75%
Testing data from timepoint
49
6 Other relevant ICH Guidelines
50
Photostability Testing ► ICH Q1B ◄
Purpose• Simulation of the impact of Fluorescence lamps which are used in
Hospitals – visual Range between 400 nm and 800 nm
• Assessing the impact of near UV light which should represent Sunlight behind a window
– UV Range 320 nm to 400 nm
General• Photostability characteristics of new drug substances and products
should be evaluated to demonstrate that light exposure does not result in unacceptable change
• Testing is carried out on a single batch of material (DS / DP)
6 – Other relevant ICH Guidelines
51
Photostability Testing ► ICH Q1B ◄
Procedure• Tests on the drug substance• Tests on the exposed drug product outside of the immediate pack• Tests on the drug product in the immediate pack (if necessary)• Tests on the drug product in the marketing pack (if necessary)
By using• Illumination of not less than 1.2 million lux hours • and an integrated near ultraviolet energy of not less than 200 watt
hours/square meter• These requirements are fulfilled by the Suntest CPS (Atlas Corp.),
which is equipped with a Xenon lamp
6 – Other relevant ICH Guidelines
52
Stability Testing for New Dosage Forms ► ICH Q1C ◄
General• A new dosage form is defined as a drug product which is a
different pharmaceutical product type, but contains the same active substance as included in the existing drug product approved by the regulatory authority
– immediate release tablet to modified release tablet– oral to parenteral– capsule to tablet– solution to suspension
Procedure• Same procedure as described in ICH Q1A(R2)• Reduced stability database at submission time (e.g., 6 months
accelerated and 6 months long term data from ongoing studies instead of 12 month)
6 – Other relevant ICH Guidelines
53
Bracketing and Matrixing ► ICH Q1D ◄
Full Design• A full study design is one in which samples for every combination of
all design factors are tested at all time points
Reduced Design• A reduced design is one in which samples for every factor
combination are not all tested at all time points• Before a reduced design is considered, certain assumptions should
be assessed and justified.
!! The potential risk should be considered of establishing a shorter retest period or shelf life than could be derived from a full design due to the
reduced amount of data collected !!
!! !! The potential risk should be considered of establishing a shorter retest period or shelf life than could be derived from a full design due to the
reduced amount of data collected !!
6 – Other relevant ICH Guidelines
54
Bracketing and Matrixing ► ICH Q1D ◄
0.10 mg0.10 mg
0.25 mg0.25 mg
0.50 mg0.50 mg
1.00 mg1.00 mg
2.00 mg2.00 mg
PP - BlisterPP - Blister
Alu - BlisterAlu - Blister
Glas BottlesGlas Bottles
HDPE bottlesHDPE bottles
-20°C-20°C
+ 5°C+ 5°C
+ 25°C / 60%+ 25°C / 60%
+ 30°C / 65%+ 30°C / 65%
+ 40°C / 75%+ 40°C / 75%
Film coated tablet
Film Film coated coated tablettablet
Dosage strengthDosage Dosage strengthstrength
Packaging material
Packaging Packaging materialmaterial
Storage conditionStorage Storage
conditioncondition
Snowball effect
6 – Other relevant ICH Guidelines
55
Bracketing and Matrixing ► ICH Q1D ◄
Bracketing
• 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
!! If the stability of the extremes is shown to be different, the intermediates are considered no more stable than the least stable extreme !!
!! !! If the stability of the extremes is shown to be different, the intermediates are considered no more stable than the least stable extreme !!
6 – Other relevant ICH Guidelines
A B C A B C A B C A B C A B C
PVC Blister
Alu Blister
Aclar Blister
HDPE Bottles
0.10 mg 0.25 mg 0.50 mg 1.00 mg 2.00 mg
56
Bracketing and Matrixing ► ICH Q1D ◄
Matrixing
• 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
!! Due to the reduced amount of data collected, a matrixing design on factors otherthan time points generally has less precision in shelf life estimation and yields a
shorter shelf life than the corresponding full design!!
!! !! Due to the reduced amount of data collected, a matrixing design on factors otherthan time points generally has less precision in shelf life estimation and yields a
shorter shelf life than the corresponding full design!!
6 – Other relevant ICH Guidelines
57
Bracketing and Matrixing ► ICH Q1D ◄
Matrixing on Time Pointsand Factors
Matrixing on Time Pointsand Factors
Matrixing on Time PointsMatrixing on Time Points
KeyKey
6 – Other relevant ICH Guidelines
58
Bracketing and Matrixing ► ICH Q1D ◄
Matrixing is applicable, if you (have)• good knowledge of data variability• expect high stability of the product• supporting data available
In general, a matrixing design is applicable if the supporting data indicate predictable product stability
Matrixing is appropriate when the supporting data exhibit only small variability
!! Requires large-scale planning (excellent statistical know ledges) !!!! Requires large!! Requires large--scale planning (excellent statistical know ledges) scale planning (excellent statistical know ledges) !!
6 – Other relevant ICH Guidelines
59
Bracketing and Matrixing ► ICH Q1D ◄
6 – Other relevant ICH Guidelines
Bracketing Matrixing
1 Stress Testing with drug substances --- ---
2 Stability on pre-formulation batches ---
3 Stress Testing on scale-up batches ---
4 Registration stability ---
5 On-going stability ( )
6 Follow-up stability ( )
Most appropriate DesignDevelopment processStage
60
Evaluation of Stability Data ► ICH Q1E ◄
7
6
5
4
321
Principles of extrapolation of stability data to establish a retest period or shelf life
Defines when extrapolation is applicable
Requires data from at least three batches (DS or DP)
The decision tree outlines a stepwise approach and offers 7 different opportunities to calculate data
Maximum retest period / shelf life “Y” is defined as:Up to 2x, but not exceeding 12 months beyond the period covered by long-term data
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Stability Data Package for Registration Applications in Climatic Zones III and IV ► ICH Q1F ◄
Covers non ICH regions• Zone III = Hot dry (30°C/35%)• Zone IV = Hot humid (30°C / 70%)
Refers to WHO Technical Report Series, No 863, Annex 5“Stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms”
General case
Aqueous-based drug products (packaged in semi-permeable containers)
No intermediate storage condition
6 – Other relevant ICH Guidelines
Study Storage condition Minimum time period covered by data at submission
Long term 30°C ± 2°C / 65% ± 5% r.h. 12 months
Accelerated 40°C ± 2°C / 75% ± 5% r.h. 6 months
Study Storage condition Minimum time period covered by data at submission
Long term 30°C ± 2°C / 35% ± 5% r.h. 12 months
Accelerated 40°C ± 2°C NMT 25% ± 5% r.h. 6 months
Withdrawn by ICH
in June 2006
62
ICH Zone IV discussions at WHO Meeting*
Calculations based on meteorological data have demonstrated that the existing long-term stability conditions (30°C/65%RH) do not reflect climatic conditions in many countries which have hotand very humid areas, such as• Brazil, Cuba, China, India and all of the • ASEAN countries.
The stability of a product depends not only on the nature of thepackaging material but also on factors such as conditions duringpackaging, pack design and pack geometry, including headspace.
It is desirable to achieve a single harmonized, long-term stability testing condition for Zone IV
*) STABILITY STUDIES IN A GLOBAL ENVIRONMENT, (Geneva, 13-14 December 2004)
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ICH Zone IV discussions (cont’d)
The following options were proposed and discussed.
a) Revert 30°C / 70% r.h. as the long term condition for Zone IV as it is likely that considerable data are already available. This might serve a potential platform for future harmonization between ICH and WHO
b) Change to 30°/75% r.h. as the long-term stability testing condition for Zone IV in the interest of patient safety worldwide
c) Add an new climatic Zone IVb to accommodate hot and very humid areas (30°/75%). The present Zone IV (30°C/65%) would become Zone IVa
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ICH Zone IV discussions (cont’d)
Feedback from WHO member was quite different • ASEAN countries prefer option b) 30°C / 75% which is also
stipulated in the “ASEAN guideline on stability study of drug product” published in February 2005.
• ICH members prefer option a) 30°C / 70%• IGPA (International Generic Pharmaceutical Alliance) prefers
option a) 30°C / 70%• Amazonien countries, which represents Bolivia, Brazil,
Colombia, Cuba, Ecuador, Peru, Venezuela and Surinam prefers option b) 30°C / 75%, which is already their current legal requirement.
Feedback from WHO members not represented at the meeting was also requested …………….. by end of March 2005 at the latest
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ICH Zone IV discussions …. current status
At 40th WHO expert committee meeting (Oct. 2005) a decision was made that the WHO stability guidelines should be amended to reflect conditions for Zone IV as follows:
• Zone IVa: 30°C / 65% r.h.• Zone IVb: 30°C / 75% r.h
It was agreed that each individual Member State within the former Zone IV would need to indicate whether its territory should be classified as Zone IVa or IVb
This process is now on-going
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ICH Zone IV discussions …. consequences
Early stage stability studies becomes more important, because you must clearly understand the robustness of your product (moisture and it’s relation to temperature)
Maybe you must use a more protective packaging material
Define a globally acceptable stability protocol, like
6 – Other relevant ICH Guidelines
Temp./ humidity Condition Climatic Zonet=0 t=1 t=3 t=6 t=9 t=12 t=18 t=24 t=36
25°C / 60% r.h Long-term I and II x - x x x x x x x
30°C / 65% r.h. Intermediate Long-term
I and II III and IV a
- - (x) (x) (x) (x) (x) (x) (x)
30°C / 75% r.h. Long-term IV b - - x x x x x x x
40°C / 75 % r.h. Accelerated I, II, II and IV - (x) x x - - - - -
50°C Stress - - (x) x - - - - - -
Timepoint
67
Validation of Analytical Methods ► ICH Q2(R1) ◄
The objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose
Typical validation characteristics which should be considered and are covered by the guideline are as follows:
AccuracyPrecision
RepeatabilityIntermediate Precision[Reproducibility]
Specificity
AccuracyPrecision
RepeatabilityIntermediate Precision[Reproducibility]
Specificity
Detection Limit (LOD)Quantitation Limit (LOQ)LinearityRangeRobustness
Detection Limit (LOD)Quantitation Limit (LOQ)LinearityRangeRobustness
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Impurities in DS / DP ► ICH Q3A/B(R) ◄
Listing, Reporting, Identification and Qualification of Degradation Products
• Reporting Threshold– A limit above (>) which a degradation product should be reported
• Identification Threshold– A limit above (>) which a degradation product should be identified– Achieving of the structural characterization
• Qualification Threshold– A limit above (>) which a degradation product should be qualified– Process of acquiring and evaluating data that establishes the biological
safety of an individual degradation product or a given degradation profile
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Stability Testing of Biotechnological / Biological Products ► Q5C ◄
The Guideline describes how to establish a stability program forBiotechnological and Biological Products because of their particularly sensitivity to environmental factors.
Some variations to ICH Q1A / F
• Selection of Batches contains also Intermediates– because of their possible criticality for the final product
• Stability Indicating Profile– Because mostly there is no single stability indicating assay – Other type of analytical methods are applicable, e.g. electrophoresis, gel filtration,
peptide mapping
• Accelerated conditions from Q1A / F are not appropriate for Biotechnological/Bilological products, so the conditions should be selected on a case-by-case basis
• Testing frequency varies depending on the shelf-life– Shelf life < 1 year: t = 0, 1, 2, 3, 6, 9, 12– Shelf life > 1 year: t = 0, 3, 6, 9, 12, 18, 24, 36, 48, 50 (same as Q1A)
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7 Requirements for performing Stability studies
71
Instrumentation
Storage capacities• Stability chambers • Stability cabinets• Refrigerators• Freezers
Monitoring and Alert System
Back-up capacities
Supporting environment • Database for tracking of pull-dates • Ensure full traceability of samples• SOPs
– Labeling and Storage of Samples– Handling of Stability studies– (Re)-Qualification of systems– Deviations– Access to storage area
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Equipment Qualification
Initial Qualification• Empty unit• Simulated regular use (e.g. filled with packaging materials)• Simulated breakdown (e.g. power failure, water failure)• Qualify Climatic condition (Requirements acc. to ICH Q1A)
– Stability of conditions over a predefined time period (e.g. 24 hours)– Temperature and Humidity Mapping (e.g. 15 points)
• Qualify Monitoring and Alert System– Computerized System?
» 21CFR11 compliance
Periodic Requalification / Calibration• Requalification period: e.g. 12 month• Temperature / humidity mapping (e.g. 2 hours)
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Guidelines
Study Design & Storage conditions• ICH Q1 Guidelines
– Storage duration & conditions– Stability design (Bracketing / Matrixing)– Evaluation of data– Photostability testing
• ICH Q5C– Stability Testing of Biotechnological / Biological products
• In Asia: Asean Guideline on Stability study of drug product
Method Development & Validation (Revalidation)• ICH Q2 Guidelines• EMEA Guidelines
Transfer of Analytical Methods• No guidelines available
7 – Requirements for performing Stability studies
74
….. and how do you test for stability?
75
Your contact in India
SGS IndiaDr. MeenakumariTicel Biotech ParkTaramani Road, TaramaniChennai 600 113
customercare.lssindia@sgs.com
www.sgs.com
Your contact in India
SGS IndiaDr. MeenakumariTicel Biotech ParkTaramani Road, TaramaniChennai 600 113
customercare.lssindia@sgs.com
www.sgs.com
Thank you for your attention
Any questions?
Thank you for your attention
Any questions?
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