patient safety and prevent cross-contamination.

2. Scope

This SOP is applicable to all cleaning validation activities conducted by the Analytical Method Development (AMD) department involving calculation of MACO limits for APIs used in production of pharmaceutical formulations.

3. Responsibilities

• Validation Scientist: Calculates MACO values using toxicity data and product-specific parameters.
• Analytical Scientist: Correlates MACO with analytical detection limits and sampling recovery.
• QA Executive: Reviews and approves calculated MACO values before implementation in validation protocols.

4. Accountability

The Head of Analytical Method Development is accountable for the accuracy, documentation, and scientific justification of MACO values used in cleaning validation studies.

5. Procedure

5.1 Determination of Acceptable Daily Exposure (ADE)

1. Obtain ADE value or use TDD (Therapeutic Daily Dose) of previous product.
2. Default safety factor of 1000 is used unless otherwise justified based on toxicity data.

5.2 MACO Formula

1. Use the following equation:
   
   MACO = (TDD of Product A × Batch Size of Product B) / (Safety Factor × TDD of Product B)
2. Units:
   • TDD = mg/day
   • Batch Size = mg or kg (convert appropriately)

5.3 Surface Area-Based MACO

1. MACO per surface area (MACO_SA) can be calculated as:
   
   MACO_SA = MACO / Total Equipment Surface Area
2. This helps in comparing analytical limits of detection with practical residue levels.

5.4 Application to Cleaning Validation

1. Determine worst-case product based on potency, toxicity, and usage frequency.
2. Ensure analytical methods can detect residue at or below MACO_SA.
3. Incorporate MACO values into acceptance criteria for swab and rinse methods.

5.5 Examples of MACO Calculation

1. Example:
   • Product A (previous): TDD = 500 mg/day
   • Product B (next): TDD = 1000 mg/day
   • Batch Size of B = 100 kg
   • Safety Factor = 1000
   • MACO = (500 × 100,000,000) / (1000 × 1000) = 50 mg

6. Abbreviations

• MACO: Maximum Allowable Carryover
• TDD: Therapeutic Daily Dose
• ADE: Acceptable Daily Exposure
• SA: Surface Area
• QA: Quality Assurance

7. Documents

1. MACO Calculation Sheet – Annexure-1
2. Surface Area Mapping Log – Annexure-2
3. MACO Summary Report – Annexure-3

8. References

• ISPE Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP)
• EMA Guideline on Shared Facilities
• FDA Guidance: Cleaning Validation
• ICH Q9: Quality Risk Management

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name	Siddharth Mehra	Ritika Singh	Sunita Reddy
Designation	Validation Scientist	QA Reviewer	Head – AMD
Department	Analytical Method Development	QA	Analytical Method Development

11. Annexures

Annexure-1: MACO Calculation Sheet

Product A	Product B	TDD A (mg/day)	TDD B (mg/day)	Batch Size B (kg)	Safety Factor	MACO (mg)
Paracetamol	Ibuprofen	500	1000	100	1000	50

Annexure-2: Surface Area Mapping Log

Equipment	Location	Surface Area (cm²)	MACO per cm² (µg/cm²)
Tablet Coater	Pan Interior	20000	2.5

Annexure-3: MACO Summary Report

MACO calculated for cross-contamination of Paracetamol into Ibuprofen batch. Final MACO = 50 mg; MACO/SA = 2.5 µg/cm². Analytical swab method validated to detect 1 µg/cm², hence suitable for use in cleaning validation.

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
21/05/2025	2.0	Updated calculation formula and added surface area-based MACO	Annual Review and Audit Compliance	Sunita Reddy
01/04/2022	1.0	Initial SOP Release	New SOP	QA Head