S (1– O (1– D (1–

Failure Mode Potential Effect RPN Existing Controls Mitigation / Action

10) 10) 10)
Residue after cleaning of Cross contamination to next Cleaning SOP, PDE-based MACO, swab/rinse testing,
9 4 6 216
reactor batch visual check enhanced cleaning validation
Powder leakage during Spread to adjacent Local exhaust Closed transfer system, dedicated isolator,
8 5 7 280
milling equipment/area system area cleaning
Contamination transfer via Double gowning, training, periodic
Personnel gown breach 7 3 6 126 Gowning SOP
gown/gloves monitoring
Improper HVAC Airborne cross- HVAC alarms, Dedicated AHU for potent API, interlock
9 3 8 216
differential pressure contamination monitoring system
Utensil reuse without SOP for utensil Dedicate utensils or validate cleaning
Residual carryover 8 4 7 224
cleaning cleaning with MACO

Failure Mode Possible Effect S O D RPN Controls / Mitigation

Inadequate cleaning of Residual Sacubitril Valsartan Validated cleaning procedures, swab & rinse limits, visual
9 5 6 270
reactor/dryer contaminates next product inspection, dedicated equipment for potent steps
Airborne API particles spread to Dedicated AHU, differential pressure monitoring, HEPA
HVAC failure (cross-flow) 8 3 5 120
other areas filtration
Material mix-up during Wrong API/Intermediate enters
10 2 3 60 Barcode/QR system, line clearance, double checks
dispensing process
Operator gowning/hygiene
API particles carried on garments 7 3 4 84 Personnel training, gowning procedure, entry/exit air showers
failure
Shared vacuum line
API residues enter common line 8 2 5 80 Dedicated/demountable hoses, validated line cleaning
contamination
 Potential Effect (on
Process Step Failure Mode Possible Cause Existing Controls S O D RPN Recommended Action
product/patient)
Vendor Strengthen supplier
Raw material Wrong vendor / Non-qualified Impurity introduction,
qualification, CoA 8 4 4 128 audit, incoming RM
procurement contaminated RM supplier failure in reaction
verification testing
Automation in
Wrong material Human error, Cross-contamination, Barcode system,
Dispensing 9 3 3 81 weighing, double
weighed poor labeling wrong API line clearance
verification
Inadequate Periodic re-
Cross-contamination Other product Cleaning validation,
Reaction cleaning, valve 10 3 3 90 qualification of
in reactor contamination equipment logbook
leak cleaning
Increase cleaning
Residual material in Incomplete Carryover to next Cleaning validation
Filtration/Drying 9 4 4 144 frequency, additional
filter/dryer cleaning product with swab/rinse
rinse
Monitor airborne
Dust generation → Contamination of Closed system,
Milling Poor containment 10 3 2 60 particulate, dedicated
cross-contamination adjacent area HVAC
mill if needed
Ineffective cleaning SOP non- Validated cleaning Periodic cleaning
Contamination of next
Equipment cleaning (carryover of compliance, limits (MACO), 10 3 4 120 verification, operator
product
Sacubitril Valsartan) method limitation swab/rinse retraining
QA check, line Introduce barcode
Packaging/Labeling Wrong label affixed Human error Mix-up of products 9 2 3 54
clearance scanning
Analyst error,
Out of specification Release of Second review, Automation, periodic
QC testing data integrity 10 2 3 60
not detected contaminated batch audit trail data integrity training
issues

Process Flow for Risk Assessment

1. Raw material procurement & storage
 o API intermediates, solvents, reagents, packing material.
o Risk: wrong material issue, contamination during storage.
2. Weighing & dispensing
o Shared balance/area → risk of cross-contamination or mix-up.
3. Synthesis / Reaction steps
o Equipment sharing → risk of residues.
o Solvent recovery → cross-contamination.
4. Isolation / Filtration / Drying
o Risk of incomplete cleaning of filters/dryers.
o Dust carryover.
5. Milling / Sieving
o High dust generation → airborne cross-contamination.
6. Packaging & Storage
o Mix-up of labels, wrong batch release.
7. Cleaning of Equipment
o Risk of inadequate cleaning → residue carryover.
8. Final Testing & Release
o Risk of OOS/OOT overlooked, data integrity gaps.

🔹 4. Example FMEA Table (simplified)

Process Step Potential Failure Mode Effect on Other Product S O D RPN Mitigation / Control
Raw material Contamination, wrong API Vendor qualification, QC ID test for all
Wrong material received 9 3 3 81
procurement manufactured materials
Segregated dispensing booths, line clearance,
Weighing/dispensing Material mix-up in balance Cross-contamination 8 4 3 96
barcoding
Residue of Sacubitril Validated cleaning procedure with MACO
Reaction Contamination of next batch 10 4 4 160
Valsartan in reactor calculation
Filtration/Drying Incomplete cleaning of API residue → contamination 9 3 5 135 Dedicated filters where feasible, validated
 Process Step Potential Failure Mode Effect on Other Product S O D RPN Mitigation / Control
dryer cleaning SOPs
Closed system milling, HEPA filtration, PPE,
Milling Dust carryover Cross-contamination 10 5 4 200
containment
Label reconciliation, QA checks, barcode
Packaging Label mix-up Wrong product released 10 2 2 40
verification
Inadequate cleaning Cleaning validation (worst-case), swab/rinse
Equipment cleaning Residual API contamination 10 5 5 250
validation test, periodic revalidation
Contaminated product Audit trail review, second-person verification,
Final testing Data integrity failure 9 2 5 90
released QA oversight

🔹 5. Mitigation Controls
 Technical Controls: Closed systems, dedicated equipment (if feasible), HEPA filtration, isolators, validated cleaning (MACO, PDE-
based).
 Procedural Controls: SOPs for line clearance, weighing, segregation, gowning, batch coding.
 Quality Controls: Analytical testing, swab/rinse analysis, changeover verification, environmental monitoring.
 Organizational Controls: Training, periodic risk reassessment, deviation handling, audit trail reviews.

🔹 6. Cleaning Risk Assessment (Critical for Multi-product Facility)

 Perform MACO (Maximum Allowable Carryover) calculation based on PDE (Permitted Daily Exposure) of Sacubitril Valsartan.
 Validate cleaning for worst-case scenario equipment.
 Swab and rinse recovery studies.
 Define acceptance limits (µg/cm²).
 Frequency of revalidation.
🔹 7. Conclusion of Risk Assessment
 List all high-risk areas (RPN > 80/100).
 Document mitigation and re-calculate RPN after controls.
 Residual risk should be acceptable.
 Final approval by QA Head.