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Annual Product Quality Review (APQR)_GMP_Dr.A. Amsavel

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Annual Product Quality Review (APQR) Guidelines / Requirement Responsibility Procedure Documents and Data Required Check list Preparation, evaluation and documentation Eg. Trend Charts, process capability Recommendation and Conclusion – PowerPoint PPT presentation

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Title: Annual Product Quality Review (APQR)_GMP_Dr.A. Amsavel


1
Annual Product Quality Review(APQR)
Dr. A. Amsavel M.Sc., B.Ed., Ph.D.
2
An Overview
  • Annual Product Quality Review (APQR)
  • Guidelines / Requirement
  • Responsibility
  • Procedure
  • Documents and Data Required
  • Preparation, evaluation and documentation
  • Eg. Trend Charts, process capability
  • Recommendation and Conclusion

3
Questions?
  • What is an Annual Product Review?
  • What is the objective of APR?
  • Who are all responsible?
  • How Procedure has to be prepared?
  • What are the data must be presented in an annual
    product review?
  • How should an Annual Product Review be organized?
  • How to prepare the report ?
  • Recommendation and conclusion

4
APR, PQR or APQR
  • USA Annual Product Review
  • Europe, the EU GMP Guideline uses the term
    "Product Quality Review".
  • APQR should be conducted for all commercial
    product.
  • APQR should confirm the State of Control of
    product, manufacturing process, and quality.
  • Requirement or expectations are almost same
  • There are few differences, it is explained
    subsequently

5
Purpose of Annual Product Review
The purpose of Annual Product Review is to verify
the consistency of the process, to assess trends,
to determine the need for changes in
specification, production, manufacturing and/or
control procedures and to evaluate the need for
revalidation. This is to be conducted for each
commercial product. Annual Product Reviews are
important for communication between
manufacturing, quality and regulatory Affairs, to
enable quality improvement processes. Content and
management of Annual Product Reviews must be
established according to GMP requirement /
directive.
6
Reference / Guidelines
  • All GMP Guidelines refer the requirement of APQR
  • CFR 211.180 (e)
  • ICH Q7 (2.5) for API
  • PICS (PP-PE 009-14 Part I PE 009-12 API-Part
    II)
  • WHO- GMP TRS 986- Annex-2 (PP) TRS957, Annex 2
    (API).
  • EU GMP EudraLex - Volume 4 Part-2 GMP for APIs
    and Part-1, Volume 4 EU GMP for Medicinal
    products Chapter 1

7
Requirement 21 CFR 211.180 (e)
  • US FDA requirement for APR is to evaluating, at
    least annually, the quality standards of each
    drug product to determine the need for changes
    in drug product specifications or manufacturing
    or control procedures.
  • the manufacturing controls (Critical process
    parameter, quality attributes yield etc)
  • evaluate the compliance status of the manufacture
    and to identify areas of improvement or need for
    revalidation
  • A review of a representative number of batches,
    whether approved or rejected, and records
    associated with the batch
  • A review of complaints, recalls, returned or
    salvaged drug products, and investigations
    conducted under Sec. 211.192 for each drug
    product.

8
Requirement ICH Q7 for APIs
  • 2.5 Product Quality Review
  • 2.50 Regular quality reviews of APIs should be
    conducted with the objective of verifying the
    consistency of the process. Such reviews should
    normally be conducted and documented annually and
    should include at least
  • A review of critical in-process control and
    critical API test results
  • A review of all batches that failed to meet
    established specification
  • A review of all critical deviations or
    non-conformances and related
  • investigations
  • A review of any changes carried out to the
    processes or analytical
  • methods

9
Requirement ICH Q7 for APIs
  • A review of results of the stability monitoring
    program
  • A review of all quality-related returns,
    complaints and recalls and
  • A review of adequacy of corrective actions
  • 2.51. The results of this review should be
    evaluated and an assessment made of whether
    corrective actions or any revalidation should be
    undertaken. Reasons for such corrective action
    should be documented. Agreed corrective actions
    should be completed in a timely and effective
    manner.

10
Requirement EU GMP
  • EU Guidelines to Good Manufacturing Practice
    Medicinal Products for Human and Veterinary Use
    Part I Quality Management
  • Product Quality Review
  • 1.5 Regular periodic or rolling quality reviews
    of all licensed medicinal products, including
    export only products, should be conducted with
    the objective of verifying consistency of the
    existing process, the suitability of current
    specifications for both starting materials and
    finished product to highlight any trends and to
    identify product and process improvements. Such
    reviews should normally be conducted and
    documented annually, taking into account previous
    reviews, and should include at least

11
Requirement EU GMP
  • A review of starting materials and packaging
    materials used for the product, especially those
    from new sources
  • A review of critical in- process controls and
    finished product results
  • A review of all batches that failed to meet
    established specification(s) and their
    investigation.
  • A review of all significant deviations or
    non-conformances , their related investigations,
    and the effectiveness of resultant corrective and
    preventative actions taken
  • Note The requirements mentioned in red is
    different from ICH Q7 and same as WHO TRS and
    PICS guideline

12
Requirement EU GMP
  • A review of all changes carried out to the
    processes or analytical methods
  • A review of the results of the stability
    monitoring programme and any adverse trends
  • A review of all quality- related returns,
    complaints and recalls and the investigations
    performed at the time
  • A review of Marketing Authorisation variations
    submitted/ granted/ refused, including those for
    third country (export only) dossiers.

13
Requirement EU GMP
  • A review of adequacy of any other previous
    product process or equipment corrective actions.
    For marketing authorisations like new, variation
    or post-marketing commitments
  • The qualification status of relevant equipment
    and utilities, e.g. HVAC, water, compressed
    gases, etc
  • A review of Technical/Quality Agreements to
    ensure that they are up to date.

14
Benefit or Use
  • Meeting the Regulatory Commitments and
    Requirements
  • Help to minimize the OOS results and deviations
  • Minimize the risk of Rework or Reprocessing
  • Decrease downtime
  • Increase productivity
  • Decrease the Risk of Product Recalls
  • Improve communication between production,
    engineering, quality and regulatory functions

15
Responsibilities
  • Responsibilities lies with QA
  • Establish an SOP with responsibility and process
    of APQR
  • Individual departments have to provide the data
    and participating in the APQR process.
  • Reviews should normally be conducted and
    documented
  • The Quality Unit, as the central position, should
    request this review and coordinate the necessary
    work. Can develop format/ check list to get
    information.
  • Production, Engineering , Maintenance , Purchase,
    etc. are also need to be involved.
  • Senior Quality Management must approve the APQR.

16
SOP for APR
  • Written procedures shall be established and it
    must be followed
  • Procedure must cover at least one-year rolling
    period. Can be on calendar year
  • The review all products manufactured and should
    be completed within 60 calendar days
  • In case product not manufactured in the year of
    review, shall review stability and complaint,
    Recall Returns etc.
  • Review all batches manufactured (accepted
    /rejected /destroyed)
  • The review of all batches which fail to meet
    specification and the review of critical
    deviations in the production, Laboratory facility
    etc
  • Assessment of data, documents and electronic
    records in the review

17
SOP for APR
  • Review of the starting materials used and change
    of vendor of KSM
  • Review of the In-process control test results,
    quality attributes of intermediate and final
    product.
  • Review of process parameters and output or yield
  • Review of all quality related returns, complaints
    and recalls and the investigations performed
  • Review the stability data and adverse trends if
    any
  • Result of verification of reserve samples
  • Equipment addition or retired, Qualification/requa
    lification, calibrationPM
  • Review of any changes carried out in the
    processes equipment , specifications or
    analytical methods, facility,

18
SOP for APR
  • Review of action taken for the recommendation of
    the previous year PQR
  • Review of adequacy of corrective actions
    implemented and effectiveness
  • Review the critical utilities like HVAC, water,
    compressed gases
  • Result of Environment monitoring/ Bio-burdon
  • Water test results- conductivity, TOC trend etc
  • If it is common utilities, it can be documented
    separately.
  • Review of technical agreements and ensure it is
    updated.
  • All the above details shall be covered in the
    SOP. Prepare trend data, statistical analysis
    with conclusion and recommendation

19
Review and Preparation of APR
  • Collect the data and tabulate the selected
    parameters, for review and documentation. Example
  • Key starting material /Critical material
  • Critical quality parameters of finished
    product/blended
  • Batch No, test parameters, test result of
    intermediates API
  • Critical in-process controls test results,
    process parameters
  • No. of batches manufactured, and corresponding
    yields
  • No. Or of batches rejected, reworked or
    reprocessed
  • No. of Batches under OOS, non-conformance /
    deviation
  • Quantity or No. of Complaints, returns etc

20
Review of Documents SystemData collection and
review
  • Manufacturing instructions and packaging
    procedures
  • Changes in the process and validation status
    after change
  • Batch Production Records
  • Process parameters actual and standard
  • IPC test data, deviations, Yield, Cpk,
  • Equipments change
  • Environment monitoring
  • Quality Control Data
  • Changes to specifications or methods
  • Validation status of the test methods
  • Analytical Instruments equipment Qualification,
    calibration
  • Deviation or incident

21
Review of Documents systemData collection and
review
  • Quality Management System
  • Deviations, OOS, Failure cause analysis
  • Customer complaint, Returns, recalls
  • Reprocess, rework / salvage of material
  • Vendor status
  • Change of vendor, qualification and approval
  • Deviations, rejections of raw material
  • Facility
  • Change of facility, utility , HVAC, compressed
    gases etc
  • Requalification of HVAC, temperature,
    differential pressure environment monitoring -
    bio-burden and deviation if any

22
Review and Preparation of APR
  • Review of Stability data / Hold time data
  • Adverse trend if any
  • Changes to packaging material or Process
  • Review of Water system Changes, qualification,
    chemical and microbial trend, deviation if any
  • Review of technical agreements with contact
    manufacturing, testing Lab and service providers
    ensure it is updated
  • Result of verification of reserve samples and
    report deterioration if any
  • Regulatory Issues and annual update requirement
    if any

23
Conclusion and Recommendations
  • Prepare the detailed report for each elements and
    present the required data, trend chart , review
    all the data, report the observation based on the
    findings. Report the conclusion and
    recommendation based on the overall review.
  • Observations/Recommendations and conclusion
  • A conclusion statement must be written to assess
    if the product consistently meets its quality
    attributes, and if not, what actions need to be
    taken,
  • The results of the APR must be evaluated and an
    assessment made whether corrective or preventive
    action or any re-validation is necessary.
  • Rationale for such CAPAs must be documented.

24
Conclusion and Recommendations
  • State of validation, consistency of process
    parameter quality attributes.
  • Any spike or OOT in the data have to explained
    and justified
  • Following are the examples for recommendation,
    but not limited to
  • Product process improvement
  • Analytical method improvements
  • Revision of specification
  • In-process or final product specification review
  • Revalidation, Requalification
  • Product recall or withdrawal
  • New packaging
  • Training
  • Vendor control
  • Calibration and maintenance

25
  • How to Collect Data, Preparation, Review and
    Documentation of APR
  • A Practical Approach

26
Organizing Documents
  • List the documents and Records to be reviewed
  • Arrange all the relevant documents, BPRs, Test
    records log books, calibration, computer system,
    data from external source as required
  • QMS documents, deviations, failures/
    nonconformity, Complaints, investigation and CAPA
    reports Change control , Returns, Recalls, etc
  • Validation, Qualification, Stability data,
    Utility data, etc
  • Prepare the template for entering the data
  • Use check list to prevent the missing data

27
Check List for APQR
  • Is there any outstanding Validation commitments
    from last PQR
  • or corrective and preventive action plans?
  • Is process in a validated state or revalidation
    needed ?
  • Is the qualification / Requalification of
    Equipment adequate?
  • Are there any significant findings from the
    data/trend in the manufacturing process, starting
    materials, or packaging materials ?
  • Are all change controls implemented, and closed?
  • Any annual update to be submitted regulatory
    agencies?
  • Are all change controls, deviations, OOS
    investigation, complaints are reviewed,
    investigated, CAPA implemented, and closed?
  • Is corrective/ preventive action is adequate and
    effective ?

28
Check List for APQR
  • Are there any significant findings related to the
    following
  • changes performed ?
  • specifications or test methods ?
  • deviations and non- conformances ?
  • out of specification results ?
  • rejected batches, quality-related returns,
    customer complaints, or recalls ?
  • the stability data monitoring ?
  • retain sample examination ?
  • Are all post- marketing commitments to
    Authorities met ?
  • Are all the Technical Agreements in place and
    up-to-date ?

29
Review of Deviations
  • Review of Deviations from the Validated state,
    investigation and CAPA
  • A review of all batches that failed to meet
    established specification(s) and their
    investigation
  • Significant/critical deviations, Out of
    Specification Results and related failure
    investigations.
  • Review for adequacy and effectiveness of
    corrective and preventative actions
  • Changes effected and variations during the period
    (e.g. process, suppliers, equipment, critical
    utilities)
  • Changes of product specifications or methods
    (e.g. analytical changes, and results)

30
Preparation of Trend Charts
  • Trend Analysis Perform trend analysis for the
    result of in-process, release test parameters and
    results of the stability monitoring with graphic
    representation with basic statistical data.
  • Prepare control chart, other types of chart
  • Appropriate statistical tools may be used to
    assess process capability for large number of
    batches.
  • Mean, maximum, minimum, standards deviations, six
    sigma, RSD
  • If any drift in process, out of trend, evaluate
    the causes and take appropriate action and
    improve performance
  • Review specifically at recurring causes and
    identify appropriate actions to reduce the
    frequency and improve performance.

31
Data Collection- Example
S.No Batch number MC Assay Related substances by HPLC Related substances by HPLC Related substances by HPLC Residual solvent Residual solvent
S.No Batch number MC Assay Imp-A Imp-K Sum of impurities Methanol Toluene
54 XXYYZZZ 0.28 100.1 0.06 0.00 0.00 0.10 0.00
55 XXYYZZX 0.24 100.0 0.05 0.00 0.00 0.04 0.00
56 XXYYZZY 0.31 99.9 0.06 0.00 0.00 0.02 0.00
Mean Mean Mean 0.27 100.0 0.06 0.00 0.00 0.04 0.00
Standard Deviation Standard Deviation Standard Deviation 0.05 0.1 0.01 0.01 0.00 0.03 0.01
Minimum Minimum Minimum 0.16 99.7 0.05 0.00 0.00 0.00 0.00
Maximum Maximum Maximum 0.35 100.3 0.07 0.04 0.00 0.13 0.04
RSD RSD RSD 18.37 0.1 10.38 529.84 0.00 77.93 366.42
Natural specification Limit Natural specification Limit Natural specification Limit 0.12 99.6 0.04 -0.02 0.00 -0.06 -0.03
µ 3s µ 3s µ 3s 0.41 100.4 0.07 0.02 0.00 0.14 0.03
Specification Range Specification Range Specification Range NMT 0.4 98.0-102.0 NMT 0.1 NMT 0.1 NMT 0.5 NMT 0.3 NMT 0.2
32
Typical Trend Chart
33
Process Capability
  • Normal Distribution
  • µ s 68.26
  • µ 2s 95.44
  • µ 3s 99.73
  • µ is mean value s is standard deviation
  • The capability of the process to meet the
    specifications determined by stability of the
    process, the range of variation and the process
    aim point

34
Normal distribution
Histogram follows NORMAL DISTRIBUTION Process
meets the Specification, consistent and capable
35
Process Capability Index
  • Process Capability Index Calculation
  • Cpk (SU SL)/ 6 s (s- Standard deviation,
  • If Specification is one sided
  • Cpk (SU X)/ 3 s
  • Cpk (X - SL)/ 3 s

SU- Upper spec limit SL- Lower spec limit X- Base
value of one side (s- Standard deviation,
CPk Value Process Capability
1 1.33 Cpk Satisfiable enough
2 1.00 Cpk lt 1.33 Adequate
3 Cpk lt 1.00 Inadequate
36
Process Capability Index (Cpk)
  • Assumption- Chemical process-A give Yield
    range100 -120kg, Standard deviation 3.4 and
    mean is 12kg. Calculate the process capability
  • 20
  • Cp -------
  • 63.4
  • Cp 0.98
  • Process in not capable, there is inconstant

Assumption- Chemical process-A give Yield range
100 -120 kg Mean is 111kg and
standard deviation 2.2. Calculate the process
capability 20 Cp -------
62.2 Cp 1.52 Process is capable constant
37
Stability Trend Chart
Assay
Mean 99.7
Standard Deviation 0.1
Minimum 99.4
Maximum 99.9
RSD 0.1
Natural specification Limit Natural specification Limit Natural specification Limit Lower Limit 99.3
( µ 3s) Upper Limit 100.0
Specification or Parameter Range Specification or Parameter Range Specification or Parameter Range 99.0 to 100.5 99.0 to 100.5
38
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