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Stability Studies- an Overview - Prashant Mengshetti - Webs

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					STABILITY STUDY

  Prashant S Mengshetti
        B.Pharm, MS (Pharma Tech)
  Quality Assurance Dept.
  E-mail: mengshettips@gmail.com
        http://www.prashant-
        mengshetti.webs.com
Why to Perform Stability ?
v GMP indicates that the purpose of stability testing of the final packaged
  product is to assure that a drug product meets applicable standards of
  identity, strength, quality and purity at the time of use
v The Purpose of stability testing is to provide evidence on how the
  quality of an active substance or pharmaceutical product varies with
  time under the influence of a variety of environmental factors such as
    Ø   Temperature
    Ø   Humidity
    Ø   Light.
 Stability Establishes :
    ü   Retest period for the drug substance
    ü   Shelf life for the drug product
    ü   Recommend a storage conditions

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Why to Perform Stability ?
v Because physical, chemical or microbiological changes might
   impact the
    Ø   efficiency and
    Ø   security of the final product


v Purpose Of Stability Studies In Active Ingredient
   Ø To ascertain suitability of the active ingredient for particular
     product shelf life.
   Ø To ascertain shelf life of the product.
   Ø To determine storage condition of the product



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Stability
What is Retest Period ?
Ø The period of time during which API is expected to remain within its
   specifications and therefore can be used in the manufacture of a given Drug
   Product. Provided the API is stored under defined storage condition

Ø After this period, a batch of API destined for use in the Drug product,
   should be retested for compliance with the specifications and used
   immediately.

Ø A batch of API can be retested multiple times and a different portion of the
   batch used after each retest as long as it continues to comply with
   specifications.


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Stability
What is Expiry/ Expiration date ?
Ø The date placed on the container label of a DS /DP designating the time
   prior to which a batch of DS/DP is expected to remain within the approved
   shelf life specification under defined storage conditions

Ø No retesting is permitted beyond expiration date and the DS / DP (drug
   substance/drug product) must not be used




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Stability- where & why ?
v Stability Studies are preformed on
Ø Drug Substances (DS)
  The unformulated drug substance that may subsequently be
  formulated with excipients to produce the dosage form
Ø Drug Products (DP)
   The dosage form in the final immediate packaging intended for
   marketing
Ø and represents
￿￿controlled and documented determination of acceptable
  changes of the drug substance or drug product


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Legal Requirement for Stability ?
v 21 CFR 211.166- STABILITY TESTING GMP
ü To assess stability characteristics to determine storage conditions
  and expiration dates.
ü Written stability program includes sample size, test interval, storage
  conditions, specific methods and container closure.
v   INDIA -Schedule M ( Point 16.10 )
ü The Quality Control Department shall conduct stability studies of
  the products to ensure and assign their shelf-life at the prescribed
  conditions of storage.
ü All records of such studies shall be maintained.


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Stability – what are changes ?
 Any physical, chemical or microbiological change in the product
 potentially impact the efficiency and integrity of the final product
 and may therefore directly or indirectly impact patients’ health.
 There are three major types of “changes”:
  1) Physical Changes

  2) Chemical Changes

  3) Microbiological Changes




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Stability – what are changes ?
1)   What are Physical changes ?
     q Appearance
     q Melting Point
     q Clarity and colour of solution
     q Crystal modification (Polymorphism)
2) What are Chemical changes ?
    q    Increase in Degradation Product
    q    Decrease of Assay.
3) What are Microbiological changes ?
    q    Growth of Microorganism
    q    change in the efficiency of preservative contents
        (e.g., antioxidant, antimicrobial preservative)

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Examples for Stability testing designs
v Testing scope for DRUG SUBSTANCES
   q   Physical-chemical properties
        – Appearance
       – Water content
       – pH
       – Color / clarity of solution
       – Thermo analytical stability
          » Melting point
          » Polymorphism
   q   Chemical properties
       – Assay
       – Degradation products
   q   Microbial properties
       – (Microbial purity)

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Examples for Stability testing designs
v Testing scope for TABLETS
   q   Physical properties   – Appearance
                          – Mean mass
                          – Water content
                          – hardness
                          – Disintegration
                          – Dissolution
   q   Chemical properties    – Assay
                             – Degradation products
   q   Microbial properties – (Microbial purity)
   q   Container Closure system properties- Functional Tests
                                                (e.g.- extraction from blisters)
                                    Prashant S Mengshetti                          11
Examples for Stability testing designs
v Testing scope for CAPSULES
   q   Physical properties   – Appearance
                          – Mean mass
                          – Mean Filling Mass
                          – Water content (Capsule & Content)
                          – Disintegration
                          – Dissolution
   q   Chemical properties    – Assay
                             – Degradation products
   q   Microbial properties – (Microbial purity)
   q   Container Closure system properties- Functional Tests
                                                 (e.g.- extraction from blisters)
                                     Prashant S Mengshetti                          12
Climatic Zones & Storage Conditions
 The world has been divided in to four climatic zones with countries being assigned to the
  relevant zones. This is the largely the work of W Grimm (Grimm 1985) who used the
  mean kinetic temperature (MRT) as the basis of

                    Climatic Zone                               Long-term Testing conditions

Climatic Zone – I
                                                                      210 C /45 % RH
Temperate Climate

Climatic Zone II
                                                                      210 C /60 % RH
Mediterranean, Subtropical Climate

Climatic Zone III
                                                                      300 C /35 % RH
Hot & Dry Climate
Climatic Zone IV-A
                                                                      300 C /65 % RH
Hot & Humid Climate
Climatic Zone IV-B
                                                                      300 C /75 % RH
Hot & Very Humid Climate

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Countries in Climatic Zone I & II
q Europe -
           All countries
q Americas –
           Argentina, Bolivia, Chile, Canada, Peru, USA, Uruguay
q Asia -
           Afghanistan, Armenia, Aserbaidschan, China, Georgia, Iran, Israel,
           Japan, Korea (north & south), Lebanon, Nepal, Syria, Turkey …..
q Africa –
           Egypt, Algeria, Libya, Morocco, Namibia, Ruanda, Zambia,
           Zimbabwe, South Africa, Tunisia …
q Australia –
           Australia, New Zeeland

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Countries in Climatic Zone III & IV
q Americas –
        Bahamas, Barbados, Belize, Brasilia, Costa Rica, Ecuador Colombia,
        Nicaragua, Guatemala,
q Asia -
        Bahrain, Bangladesh, India, Indonesia, Iraq, Cambodia, Qatar, Laos,
        Malaysia, Kuwait, ,Myanmar, Pakistan, Philippines, Singapore, UAE,
        Thailand, Vietnam
q Africa –
       Angola, Ethiopia, Benin, Botswana, Burkina Faso
q Oceania
       Fiji, Marshall Islands, Micronesia, Papua New-Guinea

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Finished Product Stability Testing
v Stability Testing
Ø The purpose of stability testing is to provide evidence on how the
  quality of a Finished Product varies with time under the influence of
  a variety of environmental conditions such as temperature, humidity
  and light and to establish a shelf-life for the Finished Product, to
  determine the storage conditions and the in-use stability.
Ø Study should be performed in the claimed commercial packaging
  (container-closure)
Ø Storage conditions and frequency of testing according to ICH
  Q1A(R2)



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Finished Product Stability Testing
v Specification

Ø Should include those attributes that are susceptible to change during
   storage and are likely to influence quality, safety and/or efficacy

Ø Should cover as appropriate, the physical, chemical, biological and
   microbiological attributes, preservative content and functionality
   tests (e.g. for a dose delivery system)

Ø Shelf life acceptance criteria should be derived from consideration
   of all available stability information



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Finished Product Stability Testing
v Testing Frequency
Ø Long-term conditions :
    every 3 months over the first year, every 6 months over the
    second year and annually thereafter
Ø Accelerated storage conditions:
   minimum of 3 points including the initial and final time points
   (e.g. 0, 3, & 6 months) from a 6-month study
Ø Intermediate Conditions :
   When testing at the intermediate storage condition is called for as a result
   of significant at the accelerated storage condition, a minimum of 4 time
   points, including the initial and final time points (e.g. 0, 6, 9 & 12 months)
   from a 12-month study is
     recommended.
Ø Reduced designs i.e. matrixing or bracketing can be applied, if
   justified.
                                     Prashant S Mengshetti                      18
Finished Product Stability Testing
v Standard Storage Conditions in accordance with ICH Q1A (R2)
  and ICH Q1F
 Zone I & II                         Temperature          Relative Humidity

 Long term or Real Time studies         250 ± 20 C           60± 5%RH

 Intermediate conditions                300 ± 20 C           65± 5%RH

 Accelerated studies                    400 ± 20 C           75± 5%RH

 Zone III & IV
 Long term or Real Time studies         300 ± 20 C           65± 5%RH

 Accelerated studies                   400 ± 20 C /          75± 5%RH


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Finished Product Stability Testing
 The Descriptions long –term testing or real- time testing refer to
 conditions under which the product will remain stable for the
 specified period. It is up to the applicant to decide which conditions
 should be selected – climatic zones I&II (25 C/60% RH) or Climatic
 zone III&IV (30 C/65% RH)
 The Accelerated testing conditions are at least 15 C higher then the
 long term study conditions and are intended to increase the rate at
 which degradation reaction takes place thus reveling quality changes
 at an early stage. Intermediate conditions are applied if the quality
 changes occurring under accelerated conditions are too great. These
 Conditions are also known as fallback conditions


                                Prashant S Mengshetti                 20
Finished Product Stability Testing
 If “significant change” occurs under accelerated studies, additional
 testing at the intermediate storage condition required
 The ICH states that “significant change” in drug product defined as
  q   A 5% change in assay from its initial value
  q   Any degradation product exceeding its acceptance criterion
  q   Failure to meet acceptance criteria for appearance, physical attributes,
      or functionality tests (e.g. colour, phase separation, resuspendability,
      caking, hardness, dose delivery per actuation)
  q   Some changes in physical attributes (e.g. softening of suppositories,
      melting of creams, partial loss of adhesion for transdermal products)
      may be expected under accelerated conditions
  q   Dissolution specification for release of stability must be
      same (may affect Bio Equivalence)

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Finished Product Stability Testing
Example of significant change -
The Assay value is still within limit but the change during stability is
more than 5.0 %

     Release Assay Limit                                     95.0 to 103 %
     Stability Assay Limit                                   92.5 to 103.0 %
     Release Assay                                              101.0 %
     24 month Assay                                              93.0 %
     Loss in Potency                                             8.0 %

                       This is a significant Change
                                     Prashant S Mengshetti                     22
Contents of Stability Protocol
I) Batch Tested :
     This contains details of
          1) Name of the Product 2) Batch Number./Batch Numbers 3) Batch Size
          4) Mfg date                 5 )Exp. Date              6) Shelf Life
          7) Date of initial analysis 8)Stability study site
II) Study Objective & Scope :
III) Responsibilities of various departments:
          Quality Control / Regulatory Affairs/ Quality Assurance
IV) Product details :
          1) Drug substances & excipients 2) Packaging information
V) Testing Plan :
          Schedule of stability testing / Sampling Time points
VI) Test Parameters :
          Test to be performed & Specification
                                         Prashant S Mengshetti                  23
Contents of Stability Protocol
VII) Stability data :

VIII) Conclusion :

v The Stability Protocol must be dated & signed by the responsible personnel
   with a signature indicating QA approval.




                                   Prashant S Mengshetti                   24
Contents of Stability Report
I) Batch Tested :
        This contains details of
       1) Name of the Product      2) Batch Number./Batch Numbers 3) Batch Size
       4) Mfg date                 5 )Exp. Date                   6) Shelf Life
       7) Date of initial analysis 8)Stability study site

II) Study Objective :

III) Details of the Manufactured Batch/Batches:
IV) Storage conditions :
       1) Type of Study
       2) Storage Conditions
       3) duration of study at the time of submission

                                     Prashant S Mengshetti                        25
Contents of Stability Report
V) Packaging     details :
VI) Stability Data :
     Test performed, Specification & Test result at various stability conditions and
     time points.
VII) Conclusion   :

v The Stability Report must be dated & signed by the responsible personnel
   with a signature indicating QA approval.




                                      Prashant S Mengshetti                            26
        DRUG PRODUCT STABILITY TESTING SYSTEM
      Major factors                                Planning of Stability Testing

                                                 Laboratory Batches
         Guidelines                                - Stress stability
                                                  - Accelerated stability & Long-term stability



      Stability Protocol                         Primary Batches
                                                 Three (3) batches
                                                 -Accelerated stability
                                                 - Long-term stability & Intermediate stability
Storage conditions for samples


   Validation Test Methods                       Production batches
                                                 First three (3) batches
                                                 According to application for MA

    Bracketing & Matrixing
                                                 Products on the market
                                                 One (1) batch each year
                                                  - Follow-up stability
     Evaluation of Results


Change Control Procedure                                 In case of variation Individual
                                                                 requirements

                                 Prashant S Mengshetti                                            27
Requirements for performing Stability Studies
q Storage capacities
     • Stability chambers
     • Stability cabinets
     • Refrigerators
     • Freezers
q Monitoring and Alert System
q Back-up capacities
q 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
q Equipment Qualification


                                             Prashant S Mengshetti   28
Requirements for performing Stability Studies
v Equipment Qualification
   q    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 according 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
   q   Periodic Requalification / Calibration
   q   Requalification period: e.g. 12 month
   q   Temperature / humidity mapping (e.g. 2 hours)


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Most Frequent 483’S Observation on Stability

Ø   Failure to Establish Stability Procedures and Expiration Dates.
Ø   Expiration Dating not Supported By Data.
Ø   Failure to Follow Established Stability Protocols.30
Ø   Failure to Use or Validate Stability Indicating Methods.
Ø   Stability Protocols not signed by Quality Unit.
Ø   Stability Samples were not Representating of current Formulations.
Ø   No Qualification Data for Stability Chambers.
Ø   No Investigation and Documentation of OOS.
Ø   No Shipping Records for Stability Samples, Lots Not Traceable.
Ø   No Proper Log Book Entries.
Ø   No Pack Simulation.
Ø   Sample analysis beyond point.

                                Prashant S Mengshetti                    30
.


    THANK YOU




       Prashant S Mengshetti   31

				
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