CLEANING VALIDATION (ACCEPTANCE CRITERIA)

CLEANING VALIDATION (ACCEPTANCE CRITERIA)

Introduction

Companies must demonstrate during validation that the cleaning procedure routinely employed for a piece of equipment limits potential carryover to an acceptable level. That limit established must be calculated based on sound scientific rational.

Methods of Calculating Acceptance Criteria

1.   Acceptancecriteria using health-based data PermittedDaily Exposure (PDE)

The procedure proposed in this document for determination of health based exposure limits for a residual active substance is based on the method for establishing the so-called Permitted Daily Exposure (PDE) as described in Appendix 3 of ICH Q3C (R4) “Impurities: Guideline for Residual Solvents” and Appendix 3 of VICH GL 18 on “residual solvents in new veterinary medicinal products, active substances and excipients (Revision)”. The PDE represents a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime.

Determination of a PDE involves (i) hazard identification by reviewing all relevant data, (ii) identification of “critical effects”, (iii) determination of the no-observed-adverse-effect level (NOAEL) of the findings that are considered to be critical effects, and (iv) use of several adjustment factors to account for various uncertainties. Appendices 3 of the ICH Q3C and VICH GL 18 guidelines present the following equation for the derivation of the PDE:

PDE =        NOEL x Weight Adjustment

F1 x F2 x F3 x F4 x F5

Application of adjustment factors

The PDE is derived by dividing the NOAEL for the critical effect by various adjustment factors (also referred to as safety-, uncertainty-, assessment- or modifying factors) to account for various uncertainties and to allow extrapolation to a reliable and robust no-effect level in the human or target animal population. F1 to F5 are addressing the following sources of uncertainty:

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.

From the ADE number, a MACO can be calculated according to:

                    ADEpreviousx MBSnext

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

        TDDnext

MACO       Maximum Allowable Carryover: acceptable transferred amount from the previous product into your next product (mg)

ADE             Acceptable Daily Exposure (mg/day)

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

MBSnext       Minimum batch size for the next product(s) (where MACO can end up) (mg)

BW                Is the weight of an average adult (e.g. 70 kg)

NOAEL         No Observed Adverse Effect Level (mg/kg/day)

 2.    Acceptance criteria based on Therapeutic Daily Dose

   

When limited toxicity data is available and the Therapeutic Daily Dose (TDD) is known, this calculation may be used. It is used for final product changeover API Process —A to API Process —B.

Procedure

Establish the limit for Maximum Allowable Carryover (MACO) according to the following equation.

TDDpreviousx MBSnext

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

SF x TDDnext

MACO          Maximum Allowance Carryover: acceptable transferred amount from the previous product into your next product (mg)

TDDprevious        Standard Therapeutic Daily Dose of the investigated product (in the same dosage from as TDDnext) (mg/day)

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

MBSnext        Minimum batch size for the next product(s) (where MACO can end up (mg)

SF                   Safety factor (normally 1000 is used in calculations based on TDD).

3.      Acceptance criteria based on LD50

In cases where no other data is available (e.g. ADE, OEL, TDD,…) and only LD50 data is available (e.g. chemicals, intermediates, detergents, …), the MACO can be based upon LD50 data.

Procedure

Calculate the so called NOEL number (No Observable Effect Level) according to the following equation and use the result for the establishment of MACO.

LD50 x BW

NOEL = ---------------------------

2000

From the NOEL number a MACO can be calculated according to:

NOELpreviousx MBSnext

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

SFnextx TDDnext

MACO         Maximum Allowance Carryover: acceptable transferred amount from the previous product into your next product (mg)

NOELprevious        No Observed Effect Level (mg/day)

LD50                Lethal Dose 50 in mg/kg animal. The identification of the animal (mouse, rat etc.) and the way of entry (IV, oral etc.) is important (mg/kg)

BW             Is the weight of an average adult (e.g. 70 kg) (kg)

2000             2000 is an empirical constant

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

MBSnext       Minimum batch size for the next product (s) (where MACO can end up)

SFnext           Safety factor

 4.      General Limit as acceptance criteria

If MACO calculations result in unacceptably high or irrelevant carryover figures, or toxicological data for intermediates are not known, the approach of a general limit may be suitable. Companies may choose to have such an upper limit as a policy. The general limit is often set as an upper limit for the maximum concentration (MAXCONC) of a contaminating substance in a subsequent batch.

Procedure

Establish MACOppm, based on a general limit, using the following equations.

                                                                                                                                 

MACOppm = MAXCONC x MBS

MACOppm         Maximum Allowable Carryover: acceptable transferred amount from the investigated product (“previous”). Calculated from general ppm limit.

MAXCONC        General limit for maximum allowed concentration (kg/kg or ppm) of “previous” substance in the next batch.

MBS                    Minimum batch size for the next product(s) (where MACO can end up)

E.g. for a general limit of 100 ppm: MACO = 0.01% of the minimum batch size (MBS), and for a general limit of 10 ppm: MACO = 0.001% of the minimum batch size (MBS).

Remarks: The ICH impurity document (Q 3) indicates that up to 0.1% of an individual unknown or 0.5% total unknowns may be present in the product being tested.

The safety factor (SF) varies depending on the route of administration (see below). Generally a factor of 200 is employed when manufacturing APIs to be administered in oral dosage forms.

Safety factors: Topicals  10        – 100

Oral products                  100      – 1000

Parenterals                      1000     – 10 000

Research products           10 000 – 100 000