**This SOP contains old and New approach( HBEL) **

**OLD APPROACH**

**1.0 OBJECTIVE:**

To define the procedure for calculation of Maximum Allowable Carryover[MACO] in cleaning validation.

**2.0 SCOPE:**

The Procedure is applicable calculation of Maximum Allowable Carryover[MACO] in cleaning validation. in company Name.

**3.0 RESPONSIBILITY**

3.1 QC-Chemist

**4.0 ACCOUNTABILITY**

4.1 Head – Quality control

4.2 Head – Quality Assurance

**5.0 PROCEDURE: **

**5.1. Batch to Batch cleaning:**It is the cleaning in between the batches. The general acceptance criteria is "Visually Clean"

**5.2. Through cleaning:**It is the cleaning process that can be done in scheduled intervals i.e may for one month of continuous batch processing.

**5.3. Product change over Cleaning :**it is cleaning process which can be performed during the product change over.

The maximum allowable carryover for the product change over can be derived with the following methods

5.31 Based on Therapeutic Dose

5.32 Limiting the allowable carry over to 10 ppm in cases :

-- For products where therapeutic dosage information is not available.

-- For Research and Investigatory drugs.

5.3.3 Limiting the allowable carry over to 1000 ppm in change over involving Intermediates.

**5.3.1 Based on Therapeutic Daily Dose**

Establish the Maximum allowable carryover [MACO] According to the following equation.

**TDD[previous] x Minimum Batch Size**

**MACO**= -------------------------------------------------

**Safety Factor x TDD[next]**

TDD[previous] : Standard Therapeutic dose of the investigated Product [Previous product]

TTD[next]: Standard therapeutic dose of the daily dose for the next product

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

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

**Safety factors**: Topicals 10-100, Oral products 100 -1000, Parenterals 1000-10 000

**Example**:

Product A will be cleaned out. The product has a standard daily dose of 10 mg and the batch size is 200 kg. The next product B has standard a daily dose of 250 mg and the batch size is 50 kg. Both A and B are administrated orally and SF is set to 1000. Calculate the MACO for A in B!

10 (mg) x 50 000 000 (mg)

MACO = ----------------------------------------------- = 2 000 (mg)

1000 x 250 (mg)

Result: MACO is 2 g (2000 mg) - - Example 1

Now product B in example 1 will be cleaned out. The following product is product A in example 1. Calculate the MACO for B in A!

250 (mg) x 200 000 000 (mg)

MACO = ----------------------------------------------- = 5 000 000 (mg)

1000 x 10 (mg)

Result: MACO is 5 kg (5 000 000 mg)- - Example 2

In API manufacture it is possible to obtain a very high MACO figure. In example 2, the figure obtained is clearly unacceptable.

**5.3.2**

**Based on Toxicological Data**

In cases in which a therapeutic dose is not known (e.g. for intermediates and detergents), toxicity data may be used for calculating MACO.

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 (g/kg) x 70 (kg a person)

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

2000

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

NOEL x MBS

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

SF x TDDnext

MACO Maximum Allowable Carryover: acceptable transferred amount from the investigated product ("previous")

NOEL : No Observed Effect Level

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

70 kg: 70 kg is the weight of an average adult

2000: 2000 is an empirical constant

TDDnext: Largest normal daily dose for the next product

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

SF: Safety factor

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

**5.3.3**

**General Limit:**

If the calculation methods based on therapeutic doses or toxicological data 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 chose to have such an

**upper limit as a policy.**The general limit is often set as an upper limit for the maximum concentration of a contaminating substance in a subsequent batch.

The concentration (CONC) of the investigated substance which can be accepted in the next batch, according to dose related calculations, is:

MACO

CONC = ------------------------------

MBS

A general upper limit for the maximum concentration of a contaminating substance in a subsequent batch (MAXCONC) is often set to

**5-100 ppm**depending on the nature of products produced from the individual company (e.g. toxicity, pharmacological activity,

**10 ppm in APIs is very frequent**).

If the calculated concentration (CONC) of the previous product (based on MACO calculated from therapeutic doses/tox data) exceeds the general upper limit (MAXCONC), then MAXCONC level will be the limit.

**Procedure**

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

**MACOppm = MAXCONC x MBS**

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).

**Example**:

A product B will be cleaned out. The product has a standard daily dose of 250 mg and the batch size is 50 kg. The next product A has a standard daily dose of 10 mg and the batch size is 200 kg. The general limit of the company is 10 ppm. Calculate the MACOppm for B in A!

MACOppm = 0.00001 (mg/mg) x 200 000 000 (mg) = 2000 (mg)

Result: MACOppm is 2 g (2 000 mg)

In the worst case a maximum of 2 g of B may appear in API A. This is more reasonable than the limit 5 kg calculated in example 2.

**NEW APPROACH**

Maximum allowable carry over[MACO] calculation is changed in APIC [ Active pharmaceutical ingredients committee] and the same was accepted by almost all regulatory bodies. So we need to change from TDD based calculation to HBEL calculation.

The Maximum Allowable Carryover (MACO) should be based upon the Health-Based Exposure Limits (HBEL), which can be an Acceptable Daily Exposure (ADE) or Permitted Daily Exposure (PDE), calculated when sufficient data is available. The principle of MACO calculation is that you calculate your acceptable carry-over of your previous product, based upon the HBEL, into your next material

**MACO =HBEL ****previous **x **MBS****next **x **PF / TDDnext x SF**

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

**HBEL** : Health-Based
Exposure Limit (mg/day) of the previous compound

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

**TDDnext : **Maximum
Therapeutic Daily Dose for the next material (mg/day)

**PF : **Purging
Factor reflects the ability of a process
to reduce the level of the previous product in the downstream synthetic route
of the next material (in case the next material is not yet the final API). The
default value is “1” unless R&D can provide case-specific purging ability
evidence (e.g. in case of control LOD limitation.)

**SF**: Safety factor reflects the effects from the
interaction between previous product and next material. This factor should be
applied in case of a risk for patient safety. Possible risk are for example
contra-indications, possible allergens, risk for children, previous products
that should not be taken daily, next material which is only applied once, but
with daily controlled release of the active product, etc (case-by-case
specific). Assessed by a toxicologist. In case of no effects from the interaction between previous
product and next material can be found the default value is “1”

**Example 1:**

Product A will be cleaned out. The product has an ADE of 2 Î¼g and the batch size is 200 kg. The next product B has a standard daily dose of 250 mg and the batch size is 50 kg. Calculate the MACO for A in B.

**MACO =HBEL ****previous **x **MBS****next **x **PF / TDDnext x SF**

**Product A details:**

ADE= 2Âµg= 0.002mg

Batch Size: 200 kg

**Product B Details: **

TDD=250mg

Batch Size: 50Kg

Safety factor = 1

Purging Factor= 1

MACO = 0.002 (mg) x 50 000 000 (mg)x1 / 250 (mg)x1 =400 (mg)

**Result: MACO is 0.4 g (400 mg)**

**Example 2:**

Product A will be cleaned out. The product has an ADE of 20 Î¼g and the batch size is 50 kg. The next product B has a standard daily dose of 250 mg and the batch size is 200 kg. Calculate the MACO for A in B.

**Product A details:**

ADE= 20Âµg= 0.020mg

Batch Size: 50 kg

**Product B Details: **

TDD=250mg

Batch Size: 200Kg

Safety factor = 1

Purging Factor= 1

MACO = 0.020 (mg) x 200 000 000 (mg)x1 / 250 (mg)x1 =400 (mg)

**Result: MACO is 1600mg(1.6gm)
this is too high**

**Then we will go for General limit**

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

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

**MACO **= **MAXCONC **x **MBS**

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

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

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

For Drug
products maxconc is 10 ppm and for drug products it is 100 ppm

**Example:**

Product A will be cleaned out. The product has an ADE of 20 Î¼g and the batch size is 50 kg. The next product B has a standard daily dose of 250 mg and the batch size is 200 kg. Calculate the MACO for A in B.

**MACO **= **MAXCONC **x **MBS**

MBS =200Kg

MAXCONC = 10mg/kg x 200kg

=2000 mg

**Note: calculation of ADE and PDE shall be in next article. **