Cleaning Validation of Pharmaceuticals

Cleaning validation in pharmaceuticals has a lot of attention as it is linked to the patient care. Cleaning validation is integrated together with quality system supported by Quality Risk Management Process so that risk is reduced while following the procedures. In few cases, high limits may be considered acceptable for chemical production unlike pharmaceutical production as the carry over risk is less for technical and chemical manufacturing. Here we outline the requirements that need to be fulfilled and put in practice.

In a Multi-purpose environment, defining Acceptable Daily Exposure (ADE) and Maximum Acceptable Carry Over (MACO) are mandatory.

Companies should be cautious in implementing cleaning procedures so that the limits are established within limits. The limits must be calculated on proper scientific rational.

Basing on Acceptable Daily Exposure (ADE) acceptance criteria should be calculated. Acceptable Daily Exposure sets the limit at which the patient may be exposed every day for a lifetime with risks that are in accordance with the adverse health effects and acceptable. These calculations are done under supervision of toxicologists and industrial hygienists who evaluate Occupational Exposure Limits (OEL).

1.1 Calculation of Acceptance Criteria basing on Health based data:

Principle: The main principle of calculating MACO is basing on ADE of next product carry over of the previous product is calculated.

Procedure: First ADE is calculated and further it is used in calculating MACO

                                                            NOAEL x BW

                                    ADE    =          ---------------------

                                                            UFc x MF x PK

                                                        ADE _previous x MBS _next

                                   MACO =           _{-------------------------------------}

                                                              TDD _next

1.2 Calculation of Acceptance Criteria based on Daily Dose

When toxicity data and therapeutic daily dose is available, this calculation is followed:

                                                            TDD _previous x    MBS _next

                                    MACO =         -------------------------------

                                                                SF x TDD _next

1.3 Calculation of Acceptance Criteria based on LD₅₀

When only LD₅₀ data is available (e.g. detergents, intermediates and chemicals) then MACO is calculated by calculating the NOEL number

                                    NOEL =          LD₅₀ x BW/ 2000

                                    MACO =         NOEL _previous x MBS _next

                                                          -------------------------------------

                                                               SF _next x TDD _next

Based on General limit, MACO _ppm are established by the given equation:

                                    MACO _ppm = MAXCONC x MBS

The general upper limit for a maximum concentration of contaminant in a subsequent batch is set to 5 to 500ppm of the previous product.

ADE                Acceptable Daily Exposure (mg/day)

MACO            Maximum Allowance Carry Over

NOAEL          No Observed Adverse Effect Level (mg/day)

PK                   Pharmacokinetic Adjustments

BW                  Body Weight of an average adult

MF                  Modifying Factor

UFc                 Composite Uncertainty Factor

TDD _next              Standard Therapeutic Daily Dose for the next product (mg/day)

MBS _next              Minimum batch size for the next product(s) (mg)

SF                    Safety factor (Based on TDD 100 is used normally in calculations)

2.1 Swab Limits

Maximum allowable Carry Over (MACO) are established from one batch to another using ADE or NOEL or TDD, additionally if total direct contact surface is known then from given equation value can be found out

                        Target Value =     MACO (µg) / Total Surface (dm2)

In method of analysis and detection limits this value can be used.

In accordance with the swab limits acceptance criteria is given as:

1. The cleaning result of an individual part shouldn’t exceed the maximum expected residue
2. The value of MACO shouldn’t exceed the total equipment train.

3.1 Rinse Limits

The residue amount remaining in the equipment after cleaning is evaluated by taking the rinse samples.

                                    Target value (mg/L) = MACO (mg) / Volume of rinse or boil (L)

4.1 Recovery Factor

When accuracy is determined, recovery is calculated and it should be given as the percentage of known impurity amount.

                                    M = M _Res/R

M                     True value of the residue remaining in the equipment after cleaning

M _res                      measured amount of residue

R                     Recovery in % divided by 100

In cleaning validation recovery value of more than 90% are not included for calculating M and values less than 50% are neglected. Recoveries of less than 90% are included in calculation of true value of M.

Acceptance criteria, maco, swab limits, recovery

• guidance on aspects of cleaning validation in active pharmaceutical ingredient plants. active pharmaceutical ingredients committee (apic). http://apic.cefic.org/pub/apic_cleaning_validation_2014.pdf. published may 2014. accessed june 2016.