IPQA in Pharma Industry

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In-Process Quality Assurance (IPQA)

• Dr. A. Amsavel M.Sc., B.Ed., Ph.D.

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Content

• GMP Introduction
• Consequences of non-compliance of GMP
• Role of Quality Assurance
• Role of In-process Quality Assurance (IPQA)
• Benefits of IPQA
• Dos and Dots of IPQA
• Check and monitoring of IPQA during intermediate
  and final product manufacturing
• Check and monitoring during Cleaning
• Line Clearance
• Batch record review
• IPQA in Material management
• Data integrity

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Objective of GMP

• What is tested is not sold
• What is sold is not tested
• Quality is not testing of product.
• Quality, Safety, and Effectiveness
• must be designed and built into the
  product.
• Each step in a manufacturing process must be
  controlled to maximize the probability that the
  finished product will meet all its quality and
  design specifications.

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What Are Manufacturing Activities

• GMP Shall be followed through out manufacturing
  activities
• Materials Management Vendor Management
• Equipment qualification, maintenance,
• Scale up / process validation
• Cleaning Cleaning validation
• Production and in-Process control
• Testing and Quality control
• Quality Assurance activities
• Batch release
• Change control

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Consequences of Violating GMP?

• Observation (483) of GMP violation or
  non-compliance report
• Warning letter / Import alert
• Recall.
• Seizure /Injunction.
• Debarment.
• Loosing Reputation / Image of the firm
• Fine / Imprisonment etc

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GMP Guidelines

• ICH Q7
• FDA CFR-210 211
• EudraLex Vol-4 EU Guidelines for GMP
• WHO-GMP
• Schedule M (Revised)
• PIC/S, GMP guide for API
• CEFIC and EFPIA , GMP for active ingredients

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Responsibilities of the Quality Unit(s)

• Responsibilities of the Quality Unit(s) as per
  ICH Q7- 2.2.
• The Quality unit(s) should
• involved in all quality-related matters.
• review and approve all appropriate
  quality-related documents.
• The main responsibilities should not be
  delegated. Responsibilities should be described
  in writing and should include, but not
  necessarily be limited to
• Approving all procedures affecting the quality of
  intermediates or APIs,
• Making sure that internal audits
  (self-inspections) are performed
• Approving intermediate and API contract
  manufacturers,

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Responsibilities of the Quality Unit(s)

• Responsibilities of the Quality Unit(s) as per
  ICH Q7- 2.2.
• Approving changes that potentially affect
  intermediate or API quality,
• Reviewing and approving validation protocols and
  reports,
• Making sure that quality-related complaints are
  investigated and resolved,
• Making sure that effective systems are used for
  maintaining and calibrating critical equipment,
• Making sure that materials are appropriately
  tested and the results are reported,
• Making sure that there is stability data to
  support retest or expiry dates and storage
  conditions on APIs and/or intermediates, where
  appropriate,
• Performing product quality reviews (as defined in
  Section 2.5)

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Internal Audit (ICH Q7-2.4)

• To verify compliance with the principles of GMP
  for APIs, regular internal audits should be
  performed in accordance with an approved
  schedule.
• Audit findings and corrective actions should be
  documented and brought to the attention of
  responsible management of the firm.
• Agreed corrective actions should be completed in
  a timely and effective manner.

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IPQA

• In-process Quality Assurance (IPQA) is part of
  QA
• To assure Drug Substance and Drug products are
  consistently produced as per quality standards
  and predefined specifications
• It is like internal audit as online / daily basis
• Assigned responsibility to ensure production
  process is carrying out as per SOP / MFR / BPR.
• To ensure that the Quality Management system is
  implemented consistently

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IPQA and Its Role

• In-process Quality Assurance (IPQA) is part of
  QA , it function is as below
• To assure Drug Substance and Drug products are
  consistently produced as per quality standards
  and predefined specifications
• It is like internal audit as online / daily basis
• Assigned responsibility to ensure production
  process is carrying out as per SOP / MFR / BPR.
• To ensure that the Quality Management system is
  implemented consistently

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IPQA and Its Role

• To ensure GMP and Regulatory compliance.
• To ensure In process checks are performed as per
  MFR during manufacturing.
• Monitoring CPP and CQA to ensure that product
  confirms to its specification.
• To guide the operator, supervisor and analyst
  regarding any deviation observed during the
  process.
• In case of non-compliance or deviation, during
  process, record the deviation report to QA for
  investigation and CAPA.

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How IPQA Helps the Firm

• Identifying potential Quality risk, Solving
  issues during production
• Ensure production is carrying out all the
  processes as per SOP and BPR during manufacturing
  to Produce Quality product.
• Help to prevent or reduce the risk of defective
  product, eliminate or reduce complaint and
  recall.
• Ensure the traceability, process operation
  compliance and data Integrity.
• LC- ensure the production area free from
  contamination, cross contamination between
  batches or product by verifying immediately
• Increase Productivity Efficiency and Faster and
  better decision making
• Achieve Customer Expectations
• Reduce Cost of Quality

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What are the benefits of IPQA

• Create a Quality-Driven Culture
• Streamline the Production
• Quality and Consistency
• Mange Risks Opportunities
• Maintain Traceability and Compliance
• Ensure product quality is built-in in the system
  and obtaining quality product
• Reduce the batch rejections and reduce the
  reprocessing
• Readiness for customer or regulatory audit at any
  time.

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Dos Dont of IPQA

• Donts
• Operating equipment
• Involve in production process
• Testing
• Product release
• Modifying process without proper approval
• Short cuts, not regulated activities, advice to
  deviate from GMP
• Hand in glove with production

• Dos
• Monitoring process- CPP, CQA
• Line clearance
• Physical Process check and sampling
• BPR ECR review, Deviation and investigation
• Operating as per BPR, SOP, GMP Regulatory
  compliance
• Equipment calibration, Preventive maintenance
• Support to validation
• Feedback to production training

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SOP for IPQA Implementation

• Established SOP for IPQA activities to cover the
  below
• Role and Scope of IPQA
• Describe the following activities in the SOP
• Personal hygiene, Gowning PPEs
• Environment monitoring
• Clean room activities monitoring
• Support in Process validation Cleaning
  Validation
• Sampling and methodology as appropriate
• Line clearance and matrixing

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SOP for IPQA Implementation

• SOP continuation
• Monitoring Process Controls CPP and In-process
  Quality Control (CQA)
• Packaging and Labeling Control
• Deviation Management, CAPA and Change Control
• In-process material, non- recoverable rejects,
  excess overprinted packing material etc
• Cleanliness and orderliness
• Material control- Dispensing, FIFO, traceability,
  reconciliation
• Documents are complete online .
• Review BPR / ECR and verification of yield
  reconciliation

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IPQA Checks / Verification

• General Check
• Before starting production
• During production
• After completion of production
• BPR Review
• Cleaning record review
• Line clearance
• Material

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Clean Room Operation

• Before start of production in Clean Room
  Operations
• IPQA shall checks and ensure the following
• Perform the line clearance and completed
• Ensure that SOPs, documents and records are work
  place
• Computer system is password protected while not
  in use.
• Preventive maintenance, calibration tag/label of
  Process Equipment
• Ensure the temperature, RH and pressure
  differential are within the limit
• Calibration and verification of balances
• Material issued / used -first in first out.
• Check the primary and secondary packaging
  materials
• Check the integrity of the sieves and connected
  metal detector
• Personnel Hygiene and habits.

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Clean Room Operation

• During manufacturing
• IPQA shall check and ensure the following
• Personal hygiene, proper gowning PPEs are used
• Equipment status board is updated
• Ensure the BMR/BPR is filled during operation
• Log books or annexures are filled
• Ensure that material used are approved and
  correct weight of material is chagrged
• Confirm the Critical Process Parameter (CPP)
• Critical Quality attributes (CQA)
• Yield reconciliation at end of each operation.

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Clean Room Operation

• During manufacturing
• Ongoing production quality parameter testing and
  in-process quality check performed on time.
• Shop floor activity compliance at each level.
• Sampling of product at various stages and various
  batches like Process Validation, Cleaning
  Validation, Trail Batch, Commercial Batch,
  ongoing production batches etc.
• Report the deviation if any action departure from
  standard or procedure acceptance criteria
• IPQA can stop production for further processing,
  if critical deviation observed to ensure the
  compliance GMP and product quality.

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Clean Room Operation

• Post production
• IPQA shall check and ensure the following
• Verify Batch production Record, packing records
  and cleaning record are completed
• Reports are verified attached to ECR/BPR
• Yield verification and reconciliation
• Label and status of finished product before
• Label and status of semi-finished product if any
• Ensure proper disposal of the rejected items.

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Line Clearance

• Line clearance is most important activity in
  Pharma industry
• IPQA shall check and ensure the following
• Equipment and its parts are cleaned as per
  cleaning procedure
• Equipment / machine are labelled with status as
  appropriate
• Equipment /machine change parts if any are
  cleaned and stored properly
• Dosing tanks, ML storage tanks, hoses, receivers
  are cleaned
• Cleaning of Utensils, sampling aids, scoops,
  other accessories
• Cleaning of Gaskets, pipe lines and valves and
  its record
• Consumables like filter pads, filter cloths,
  centrifuge bags are cleaned and stored in
  designated place.
• Cleaning of process area floor, ceiling,
  filters, grills, walls, doors, working tables,
  Pallets, and glass panels etc.

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Line Clearance

• Line Clearance
• Confirm new/ dedicated filter pads, filter
  cloths, hoses, and centrifuge bags are
  appropriate
• Raw materials, intermediates, and any other
  leftovers of previous products are removed
• Centrifuge bags, cartridge filters are changed /
  cleaned
• Ensure the area is free from previous products or
  residue.
• Ensure the area is free from previous products or
  residue.
• Filled BPRs test reports, and unused BPRs of
  previous product handed over to QA
• Removed unwanted document- unused BPRs, ECRs,
  forms, etc..

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Cleaning activity

• Check the following as part of Cleaning
  activities
• Cleaning of the area, vacuum cleaner, waste bin,
  utensils.
• Cleaning of equipment, associated accessories
• Check Equipment Cleaning Records (ECR) are filled
  
• Rinse or swab sample taken, tested and results
  complies
• Test method followed for cleaning sample analysis
• Confirm the cleaning test result meet the limit
• Perform visual checking and ensure the
  cleanliness
• Filter cleaning

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Intermediate/Chemical Manufacturing Area

• Checks at Intermediate/Chemical manufacturing
  area
• Documents records are in work place which have
  potential to create data integrity.
• Password protected computer system while not in
  use.
• Pre-start up record /check list is followed
• Random re-check weights.
• Cleaning and housekeeping records.
• Preventive maintenance and calibrations status
• Equipment and accessories verification for
  rusting, oil leakages, gaskets shedding.
• Line clearance compliance for the product change
  over.
• Calibration records for equipment/ instruments.

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Intermediate/Chemical Manufacturing Area

• Checks at Intermediate/Chemical manufacturing
  area
• Contemporary documentation
• Ensure the BMR/BPR s are recorded /filled during
  operation
• Confirm the Critical Process Parameter (CPP)
  Critical Quality attributes (CQA)
• Equipment status board / log book entry against
  the process flow.
• Equipment cleaning requirement for process.
• Material storage condition including controlled
  temperature storage
• Label issue and Control. In-process sampling and
  controls against the process and sampling plan.
• Purified water storage, distribution and usage.

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Material Receipt, Storage Dispensing

• Material Receipt, Storage Dispensing
• Check material purchased is from approved vendor.
• Material is stored appropriatly
• Material is tested and approved
• Verification of documents (PO, test report,
  label, registers, GRN, SOPs, etc).
• Random re-check weights.
• FIFO is followed.
• Dispensing and per batch requirement
• Cleaning and housekeeping records.

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Batch Production Record Review (6.7)

1. Written procedures should be established and
   followed for the review and approval of batch
   production and laboratory control records,
   including packaging and labeling, to determine
   compliance of the intermediate or API with
   established specifications before a batch is
   released or distributed.
2. Batch production and laboratory control records
   of critical process steps should be reviewed and
   approved by the quality unit(s) before an API
   batch is released or distributed.
3. Production and laboratory control records of
   non-critical process steps can be reviewed by
   qualified production personnel or other units
   following procedures approved by the quality
   unit(s).
4. All deviation, investigation, and OOS reports
   should be reviewed as part of the batch record
   review before the batch is released.

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Batch Cleaning Record Review

• 21 CFR 211.182 Equipment Cleaning and Use Log
• Verify equipment and usage log Cleaning log
  are correct
• Verify the Cleaning of equipment area are
  cleaned appropriately.
• All cleaning related logbooks are reviewed to
  indicate Date, Time, Product Lot Number of
  previous batch processed
• Before Batch Release, verify cleaning, room
  clearance and line clearance via Line Clearance
  Checklist(s) filed with the Batch Record.
• Equipment Cleaning Record should be reviewed
• Verifies the PCO / Line Clearance Checklist.
  Residual content is within the limit, physical
  verification Equipment is clean, Area is cleared
  of all previous batch materials, utensils,
  labels, etc.)

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Review of Records

• GMP requirement Record relevant to the
  manufacturing shall be reviewed
• Records shall be Reviewed to ensure the
  compliance
• Batch Production and Process Control Records
• Material used are traceable and quantity is as
  per standard (KSM, RM, reagents, Solvents,
  Catalyst, etc.
• Calculation verification of Yield
• Reconciliation of intermediate if used from
  multiple lots /batches
• Sampling and Testing of in-process materials
• Critical Quality Attributes- test results are
  meeting the specification
• Time Limits of Production as applicable
• Critical Process Parameters are as per standard
  limit
• Equipment Identification log book

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Review of Records

• Packaging and Labeling Control Records
• Label issuance and reconciliation
• Changes that occurred during the production,
  packaging, labeling, and testing operations for
  the batch.
• Laboratory Control Records-Sampling report, test
  Records / Raw Data
• Deviations and investigations related to the
  production, packaging, labeling, and testing
  operations for the batch.
• OOS and investigations
• Room / Area Cleaning Clearing Line Clearance
• Calibration of instruments balances
• HVAC system , Filter cleaning record

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Data Integrity

• Data integrity is critical to regulatory
  compliance, and the fundamental reason for 21 CFR
  Part 11.
• A - Attributable
• L Legible
• C Contemporaneous
• O Original
• A - Accurate
• Complete
• Consistent
• Enduring
• Available

D A T A
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ALCOA principle

• ALCOA is an acronym representing the following
  data integrity elements
• Attributable Who performed and when?
• Legible Record Can it be read? Permanent
• Contempor- Recorded at the time the
  activity aneous was
  performed
• Original copy Original record or certified
  true
• Accurate Error free

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ALCOA Description
ALCOA ALCOA Description/Explanation Comments
A Attributable Who performed an action and when? If a record is changed, who did it and why? Link to the source data. Who did it? Source data
L Legible Data must be recorded permanently in a durable medium and be readable. Can you read it? Is it permanent record
C Contemporaneous The data should be recorded at the time the work is performed and date/time stamps should follow in order. Was it done in Real Time?
O Original Is the information the original record or a certified true copy? Is it original or true copy?
A Accurate No errors or editing performed without documented amendments. Is it accurate?
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ALCOA (2 CEA)
ALCOA ALCOA Description/Explanation Comments
1 Complete The data must be whole a complete set All data including repeat or reanalysis performed 21 CFR 211.194
2 Consistent The data must be self-consistent Consistent application of date time stamps Date time stamps
3 Enduring durable lasting throughout the data lifecycle Recorded on controlled worksheets, laboratory notebooks, or electronic media. Medium -to record data
4 Available Readily available for review or inspection purposes Available/accessible for review/audit for the lifetime of the record. For the lifetime of the record
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Report by IPQA

• Preparation of report and submit to respective
  dept.-accptance
• Evaluate the report along with dept HODs
• Classify the category, area wise, type , person,
  repeated mistakes
• Take CAPA immediately for all critical
  observations.
• CAPA shall be time bound and fixing the
  responsibility
• Based on the repeated mistakes/ observations
  Train the personel at shop floor.
• Monitor the effectiveness of CAPA
• Challenges Manageing deviation, ensuring
  compliance in committed production plan and
  environment handing documentation.

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• Thank you