**There are various calculation and formulas required for the Calculation of MACO (Maximum allowable Carry Over), PDE (Permitted Daily Exposure) and NOEL (No Observed Effect Level) in Cleaning Validation.**

**All these formulas are helpful in implementing the correct cleaning validation matrix and plan at facility**. **Herewith are detailed full proof formulas which will build error free design of Cleaning Validation Matrix and Calculation of MACO/PDE **

**Permitted Daily Exposure (PDE):**

**PDE** is the amount of a specific substance for
which the occurrence of an adverse effect is unlikely in an individual.

**Formula for Calculation PDE:**

Where

**LD50** = the 50
% of lethal dose of the target residue in an animal, typically in mg/kg of body
weight (by appropriate route of administration)

**BW** = body weight of the patient taking next
product

**F1** = A factor (values between 2 and 12) to
account for extrapolation between species

**F2** = A factor of 10 to account for
variability between individuals

**F3** = A factor 10 to account for repeat-dose
toxicity studies of short duration, i.e., less than 4-weeks.

**F4** = A factor (1-10) that may be applied in
cases of severe toxicity, e.g. non-genotoxic carcinogenicity, neurotoxicity or
teratogenicity

**F5** = A variable factor that may be applied if
the no-effect level was not established. When only an LOEL is available, a
factor of up to 10 could be used depending on the severity of the toxicity.

**Formula for Calculation MACO from PDE:**

**MACO**

**MACO** = Maximum Allowable Carry Over

**MBS**
= Minimum Batch Size of the next Product

**LDD** = Largest Daily Dose of the Next Product to be Manufactured in the same equipment

**NOEL (No-Observed-Effect Level)**

No-Observed-Effect Level: The highest dose of substance at which there are no biologically significant increases in frequency or severity of any effects in the exposed humans or animals.

**Formula for Calculation NOEL:**

Where

**NOEL** is the No
Observed Effect Level

**LD50** = the 50
% of lethal dose of the target residue in an animal, typically in mg/kg of body
weight (by appropriate route of administration)

**BW** = body weight of the patient taking next
product

**MF1** =
modifying factor or factors selected by the toxicologist (cumulative modifying
factors selected are generally not more than 1000)

*[Reference PDA Technical Report No. 29
(revised)-Points to Consider for Cleaning Validation, Point 5.3.2.2-Toxicity
Calculations Based on LD _{50} Data]*

**Formula for Calculation MACO from NOEL:**

Where

**SDI**
= Safe Daily Intake of the residue

**NOEL** = No
Observed Effect Level

**MF2** =
modifying factor or factors selected by the toxicologist (cumulative modifying
factors selected are generally not more than 1000)

*[Reference PDA Technical Report No. 29 (revised)-Points to Consider for Cleaning Validation, Point 5.3.2.2-Toxicity Calculations Based on LD _{50} Data]*

MACO (Maximum Allowable Carry Over)

**Formula for Calculation of MACO by Using SDI:**

Where

**MACO** = Maximum Allowable Carry Over

**SDI**
= Safe Daily Intake of the residue

**MBS**
= Minimum Batch Size of the next Product

**LDD**
= Largest Daily Dose of the Next Product to be Manufactured in the same
equipment

*[Reference PDA Technical Report No. 29
(revised)-Points to Consider for Cleaning Validation, Point 5.3.2.2-Toxicity
Calculations Based on LD _{50} Data]*

**Dose Criteria**

MACO (Maximum Allowable Carry Over)

**Formula for Calculation of MACO by Using Dose Criteria:**

Where

**TD** is the Minimum Therapeutic Dose of Product
A

**MACO** = Maximum Allowable Carry Over

**MBS**
= Minimum Batch Size of the next Product B

**LDD**
= Largest Daily Dose of the Next Product to be Manufactured in the same
equipment

**10 PPM Criteria**

**Formula for Calculation of MACO by Using 10 PPM Criteria:**

Where

0.01 is equivalent to 10 PPM

**MACO** = Maximum Allowable Carry Over

**MBS**
= Minimum Batch Size of the next Product B in ml

**Calculation for Concentration Limits:**

**Calculation for Swab Limits:**

**Swab** **Limits** ** (µg/Swab) or PPM**

Where

**MACO** is derived from the above
equations

**100 cm ^{2}**

^{ }

_{=}

^{ }Swab Area is Standard as 100 cm

^{2}

Shared equipment surface area is the shared area of Product B

**1000** is the conversion factor from mg
to µg / PPM

**Calculation for Rinse Limits:**

*[Reference PDA Technical Report No. 29 (revised)-Points to Consider for Cleaning Validation, Point 5.6 –Limits in Protocol Samples]*

Conclusion

Cleaning Validation in Pharmaceutical Industry should be designed very carefully and the calculation for designing matrix plays a very important role. A small calculation error can leads to the big gap in the system. Therefore, it should be performed very carefully. As on date there are ready to install software available for executing cleaning validation calculation, however, it has to be evolved a lot more.

**Raman **is a versatile experienced Bio-pharmaceutical professional with more than 12 year of experience in Sterile and Non-Sterile Formulations. Raman is working in different aspects of Sterile Validations and designing Pharmaceuitcals Quality Systems for the next century. He is a versatile and tech savvy professional who believe the Quality is the foundations of Growing Organizations