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

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Annual Product Quality Review(APQR)
Dr. A. Amsavel M.Sc., B.Ed., Ph.D.
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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

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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

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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

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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.
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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

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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.

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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

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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.

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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

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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

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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.

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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.

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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

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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.

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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

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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,

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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

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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

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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

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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

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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

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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.

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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

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

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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

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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 ?

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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 ?

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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)

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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.

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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
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Typical Trend Chart
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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

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Normal distribution
Histogram follows NORMAL DISTRIBUTION Process
meets the Specification, consistent and capable
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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
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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
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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
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• Thank You