Documentos de Académico
Documentos de Profesional
Documentos de Cultura
Agenda
Overview of stability studies during drug product Lifecycle Stability considerations during early development Review ICH and WHO stability guidelines Stability requirements to support registration Post approval stability
Definition of Stability Consistent product quality and therapeutic benefit over the product shelf-life under various environment conditions
Product Understanding
Manufacturing Manufacturing Process Process Container Container Closure Closure
File IND
File NDA
Approval
PrePreclinical clinical
Phase II Phase
Phase II Phase II
Stability studies to monitor product quality and support post approval changes
Chemical and physical property of API Excipient compatibility Manufacturing process Interaction with packaging materials
API
Packaging Selection
PACKAGED PRODUCT
EXCIPIENTS
and 3 Amines --> N-oxide, hydroxylamine by oxidation --> Acid by oxidation -->Acid/Alcohol by hydrolysis
Aldehyde
Esters/Lactones
Polymorphs
Resuspendibility Aggregation
Excipient Compatibility
ICH Q8 guidance recommends evaluating drug-excipient interactions as part of the design of a stable formulation. For solutions and suspensions, the solution studies indicate which buffer to use and the optimum pH. For solids, the compatibility studies are more extensive with the objective to establish which excipients can be used with the intended drug.
- Binary excipients compatibility studies - Trial formulations (DOE)
Case Study 1
An compound with a carboxyl functional group is the candidate for a HFA MDI formulation development. Due to poor aqueous solubility, ethanol was chosen as co-solvent and the experimental formulation was put on accelerated stability. A degradant peak was observed and it reached >3% at 3 month time point.
The sample was send to the LC-MS lab for peak ID. Question: What is the structure of the degradant? Answer: its the ethyl ester of the API.
Hint: Know your chemistry.
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Case Study 2
Trace level of Aldehydes in common excipients
Cause of gelatin cross-linking Reactive with primary and secondary amine Present as trace level impurities or formed by excipient degradation (e.g. PEG or Tween)
-Leonardo Allain and W. Peter Wuelfling, Merck Research Labs, AAPS Stability Workshop, 2009
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Case Study 2
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Case Study 2
Compendial: PVP and Ethylcellulose in USP Wet chemistry techniques (one is enzymatic and the other is colorimetric)
100 ppm limit test 100 ppm formaldehyde ~ 10% API (mol/mol) (assuming 0.5 g formulated drug with 2-5% drug load)
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Case Study 2
Excipients Avicel HPMC PEG 400 PEG 4000 Tween 80 Triglycerides Polyoxyl 35 Opadry white Kollicoat Formaldehyde (ppm) 1.1 12.3 65.0 0.5 1.5 -20 0.2 1.4 4.7 13.7
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Manufacturing Process
Choose manufacturing conditions to improve stability
- Exposure to solvents
Exposure to temperature
- Drying time and temperature
Stability of in-process materials Drug Product may be tested to identify critical process parameters
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Potential drug absorption or adsorption to container closure Effect of container orientation Potential for leachables
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File IND
File NDA
Approval
PrePreclinical clinical
Phase II Phase
Phase II Phase II
Stability studies to monitor product quality and support post approval changes
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the purpose of stability testing is 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 and light, and to establish a retest period for the drug substance or a shelf-life for the drug product and recommended storage conditions -ICH Q1A(R2): Stability testing of new drug substance and product (2003)
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Stability Guidelines
US: FDA (1998 draft and 1987 guidance withdrawn, June 1 2006) EU: EMEA (European Medicines Agency), CPMP Japan: MHLW (Ministry of Health, Labor and Welfare: Drug Approval and Licensing Procedures in Japan, 2008) ASEAN (Association of Southeast Asia Nations) Brazil (Resolucao-Re No 1, July 29, 2005) China (Chinese Pharmacopeia 2005) SADC (Southern African Development Community), Medicines Control Council: Stability January 2005
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FDA withdraws stability and CMC information related guidance documents on June 1, 2006:
Not because following them will lead to problem with drug registration But because these documents are overly prescriptive, which is not consistent with the FDAs current thinking of providing broad guidance In the meantimerefer to the following ICH documentsas alternative resources
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ICH Guidelines
Founded 1990 ICH region European Union, Japan and US Regulators and pharmaceutical industry representatives Stability was one of the first issues discussed and harmonized
Step3 Step3
Step4 Step4
Step5 Step5
Regulatory Consultation
Adopt
Implement
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Q1F: Stability Data Package for Registration Applications in Climatic Zones III and IV was withdrawn June 2006 and decided to leave definition of storage conditions in Climatic Zones III and IV to the respective regions and WHO.
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Evaluation of climate condition by each Member State results in the recommendation of long term storage conditions More severe conditions are acceptable
-WHO Technical Report Series, No. 953, 2009: Stability testing of active pharmaceutical ingredients and finished pharmaceutical products
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Additional Guidance Provided in WHO Document: Testing parameter recommendations Storage statement and labeling guidance Covers new drug and marketed product
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File IND
File NDA
Approval
PrePreclinical clinical
Phase II Phase
Phase II Phase II
Stability studies to monitor product quality and support post approval changes
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Sample size and test intervals Storage condition Reliable, meaningful and specific test methods Store the drug product in the proposed container for marketing Testing of drug product for reconstitution at time of dispensing as well post reconstitution
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Solid Orals Europe Primarily PVC, PVC/PVDC blisters Often opaque rather than clear blisters
- color: white, blue or green
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Regional Solid Oral Simple blister with Al/PE film over wrap Glass bottle
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Test Methods/Specifications
Q6 : Specifications for New Drug Substances and Products - Q6A: Specifications: Chemical Substances,
Oct 1999
Q2(R1): Validation of Analytical Procedures: Text and Methodology, Oct 1994 Q3A(R2): Impurities in New Drug Substances (Revised Guideline) Oct 2006 Q3B(R2): Impurities in New Drug Products (Revised Guideline) June 2006 Q1E : Evaluation of Stability Data, February 2003
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X = Appearance (n=1), Assay/RS (n=2),Dissolution (n=6), Water Content (n=2) [ ] = number of bottles pulled ( ) = Optional testing only when significant changes occurs under accelerated conditions
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25C/60%RH
[2] X
[2] X [2] X
[2] X [2] X -
[2] X [2] X -
[2] X [2] X -
[2] X [2] X -
[2] X [2] X -
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30C/65%RH
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40C/75%RH
[2] X
X = Appearance (n=1), Assay/RS (n=2),Dissolution (n=6), Water Content (n=2) [ ] = number of bottles pulled Note: There is no intermediate condition for Zone III/IV
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25C/60%RH
[4] X
[4] X -
[50] XPSL -
[50] XPSL -
200
30C/65%RH
90
40C/75%RH
[4] X
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X = Appearance including color and clarity, Assay/RS, Preservative content, pH P = Particulate matter by HIAC S = Sterility, Bacterial Endotoxin, Antimicrobial effectiveness, Container Closure integrity L = Leachables [ ] = number of bottles pulled ( ) = Optional testing only when significant changes are observed under accelerated conditions
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25C/40%RH
[4] X
[4] X -
[50] XPSL -
[50] XPSL -
200
30C/65%RH
90
40C/20%RH
[4] X
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X = Appearance including color and clarity, Assay/RS, Preservative content, pH P = Particulate matter HIAC S = Sterility, Bacterial Endotoxin, Antimicrobial effectiveness, Container Closure Integrity L = Leachable, [ ] = number of bottles pulled ( ) = Optional testing only when significant changes are observed under accelerated conditions
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Total Stored
10 10
[10] W -
[10] W -
[10] W -
[10] W -
40C/20%RH
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W = Weight Loss (n=10) Note1 : The same 10 units are used for weight loss test as in-and-out of the chamber stability samples. The stability coordinator and lab analyst need to coordinate testing to minimize the time the samples are out of the chamber. Note 2: 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 40C/NMT 25% RH.
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Batch Selections
Stability studies should be performed on each individual strength and container size of the drug product unless bracketing or matrixing is applied. At least three primary batches
Final formulation Manufacturing process simulating production batch Product with same quality and meeting same specification
In container closure system as proposed for marketing At least two of the three are pilot scale* The third batch can be smaller, if justified Using different batches of API (if possible)
* For solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger.
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For NDAs: Three primary batches 12 months long term 6 months accelerated 6 months intermediate if significant changes @ accelerated May statistically project expiry up to 6 months past real time data
For ANDAs One batch 3 months accelerated 3 months satisfactory accelerated data may permit 24 month expiry
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In-use stability
Photostability
One batch In the proposed container and closure systems ICH Q1B option 1 or option 2
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Product shelf-life Product shelf-life and and Storage Conditions Storage Conditions
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Stability Commitment
When available long term stability data on primary batches do not cover the proposed shelf life granted at the time of approval, a commitment should be made to continue the stability studies post approval in order to firmly establish the shelf life.
Submission data from 3 production batches, continue long term study through proposed shelf-life. Submission data from <3 production batches, set more production batches on to make up the required three with same protocol. Submission data not from production batches, first 3 production batches to set on stability through proposed shelf-life long term and 6 months accelerated.
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File IND
File NDA
Approval
PrePreclinical clinical
Phase II Phase
Phase II Phase II
Stability studies to monitor product quality and support post approval changes
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21CFR 314.81 Sponsors are required to report to FDA district office within 3 working days of a problem being identified.
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EU
Major Changes
Type II
Moderate potential to have Moderate potential to have an adverse effect an adverse effect
Moderate Changes
Type IB
Minor Changes
Minimal potential to have an Minimal potential to have an adverse effect adverse effect
Type IA
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