In-Process Quality Assurance Role in Pharma Industry_Dr. A.Amsavel.pdf

GMP : Role and responsibility of QA and IPQA.
Compliance of GMP & regulatory.

1. In-Process Quality
Assurance (IPQA)
Dr. A. Amsavel M.Sc., B.Ed., Ph.D.

2. Content
•GMP Introduction
•Consequences of non-compliance of GMP
•Role of Quality Assurance
•Role of In-process Quality Assurance (IPQA)
•Benefits of IPQA
•Do’s and Do’tsof 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

3. 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.

4. What Are Manufacturing A ctivities
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

5. 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

6. 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

7. Responsibilities of the Quality Unit(s)
ResponsibilitiesoftheQualityUnit(s)asperICHQ7-2.2.
TheQualityunit(s)should
1.involvedinallquality-relatedmatters.
2.reviewandapproveallappropriatequality-relateddocuments.
3.Themainresponsibilitiesshouldnotbedelegated.
Responsibilitiesshouldbedescribedinwritingandshould
include,butnotnecessarilybelimitedto:
4.Approvingallproceduresaffectingthequalityofintermediates
orAPIs,
5.Makingsurethatinternalaudits(self-inspections)are
performed
6.ApprovingintermediateandAPIcontractmanufacturers,

8. Responsibilities of the Quality Unit(s)
ResponsibilitiesoftheQualityUnit(s)asperICHQ7-2.2.
7.ApprovingchangesthatpotentiallyaffectintermediateorAPIquality,
8.Reviewingandapprovingvalidationprotocolsandreports,
9.Makingsurethatquality-relatedcomplaintsareinvestigatedand
resolved,
10.Makingsurethateffectivesystemsareusedformaintainingand
calibratingcriticalequipment,
11.Makingsurethatmaterialsareappropriatelytestedandtheresultsare
reported,
12.Makingsurethatthereisstabilitydatatosupportretestorexpirydates
andstorageconditionsonAPIsand/orintermediates,where
appropriate,
13.Performingproductqualityreviews(asdefinedinSection2.5)

9. Internal Audit (ICH Q7-2.4)
1.ToverifycompliancewiththeprinciplesofGMPforAPIs,regular
internalauditsshouldbeperformedinaccordancewithan
approvedschedule.
2.
Auditfindingsandcorrectiveactionsshouldbedocumentedand
broughttotheattentionofresponsiblemanagementofthefirm.
3.Agreedcorrectiveactionsshouldbecompletedinatimelyand
effectivemanner
.

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

11. IPQA and Its Role
•To ensure GMP and Regulatory compliance.
•To ensure In process checks areperformed 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.

12. 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 complaints and recalls.
•Ensure the traceability, process operation & compliance and data
Integrity.
•Line clearance ensures, the production area is free from contamination,
cross contamination between batches or product by immediate
verification
•Increase Productivity & Efficiency and faster and better decision making
•Achieve Customer Expectations
•Reduce Cost of Quality

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

14. Do’s & Don’t of IPQA
DO’S
•Monitoring process-CPP & CQA
•Line clearance
•Physical check of process, activities
and sampling
•BPR & ECR review, reporting
deviation if any and investigation
•Operating as per BPR, SOP, GMP &
Regulatory compliance
•Equipment calibration, Preventive
maintenance
•Support to validation
•Feedback to production & training
DON’TS
•Operating equipment
•Involve in production process
•Testing
•Product release
•Modifying process without proper
approval
•Short cuts, non-standard or non
regulated activities, advice to
deviate from GMP
•Hand in glove with production

15. SOP for IPQA Implementation
Establish SOP for IPQA activities by covering the below;
•Purpose, Scope & respobilityof IPQA
•Describe the following activities in the SOP
•Personal hygiene, Gowning & PPEs check at operating area
•Environment monitoring- Temperature, %RH & ΔPressure
•Clean room activity monitoring
•Support in Process validation & Cleaning Validation
•Sampling and methodology as appropriate
•Line clearance and matrixing

16. SOP for IPQA Implementation
SOP continuation…
•Monitoring Process Controls CPP and In-process Quality Control
(CQA)
•Packaging and Labelling 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 completed contemparious.
•Review BPR / ECR and verification of yield reconciliation

17. IPQA Checks / Verification
•General Check
•Before starting production
•During production
•After completion of production
•BPR Review
•Cleaning record review
•Line clearance
•Material

18. Clean Room Operation
Before start of production in Clean Room Operations :
IPQA shall check and ensure the following;
•Perform the line clearance and approve to start
•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 at first in first out basis
•Check the primary and secondary packaging materials
•Check the integrity of the sieves and connected metal detector
•Personnel Hygiene and habits.

19. Clean Room Operation
During manufacturing:
IPQA shall check and ensure the following;
•Personal hygiene, proper gowning & PPEs are used
•Equipment status board is updated and Log books or annexures are filled
•Ensure to prevent contamination and cross contamination
•Ensure the BMR/BPR is filled during operation
•Ensure that material used are approved and correct weight of material is
charged
•Confirm the Critical Process Parameter (CPP) & Critical Quality attributes
(CQA)
•Physical verification of material-tablet, capsule etc
•Yield reconciliation at end of each operation.

20. Clean Room Operation
During manufacturing:
•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
•Ensure the CAPA or change implemented if any from QA
•IPQA can stop production for further processing, if critical deviation
observed to ensure the compliance GMP and product quality.

21. 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.

22. 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 panelsetc.

23. 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.
•Physical check of cleaning
•Filled BPRs test reports, and unused BPRs of previous product
handed over to QA
•Removed unwanted document-unused BPRs, ECRs, forms, etc..

24. 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

25. 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.

26. 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.

27. Material Receipt, Storage & Dispensing
Material Receipt, Storage & Dispensing :
•Check material purchased is from approved vendor.
•Material is stored appropriately
•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.

28. 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.

29. 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.)

30. 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

31. 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

32. 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

33. ALCOA principle
ALCOA is an acronym representing the following
data integrity elements:
1.Attributable –Who performed and when?
2.Legible Record–Can it be read? Permanent
3.Contempor-–Recorded at the time the activity
aneous was performed
4.Original copy – Original record or certified true
5.Accurate –Error free

34. ALCOA Description
ALCOA Description/Explanation Comments
A
AttributableWho 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
Contemporan
eous 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?

35. ALCOA + (2 CEA)
ALCOA + Description/Explanation Comments
+1CompleteThe data must be whole; a complete
set
All data including repeat or reanalysis performed
21 CFR
211.194
+2
ConsistentThe 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

36. 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 personelat
shop floor.
•Monitor the effectiveness of CAPA
Challenges –Manageingdeviation, ensuring compliance in committed
production plan and environment handing documentation.

37. Thank you