Cross Contamination 2 - The Numbers
The EMA regulations require a risk assessment and also suggests a methodology to be followed. If you don't know what figures are required than you cannot design the facility or the operations. The figure is a total for the contamination by whatever route. Historically the only quantative approach was for cleaning validation. Whatever residues were left on equipment after cleaning were assummed to make their way into the next product that used the equipment. The maximum residues were set at 1/1000th of the minimum theraputic dose (of the contaminant) that was likely to be taken in a maximum does of the following product.
Fourman & Mullen Approach
Histroically In cleaning validation the approach has been based on work by Fourman & Mullen and referenced in FDA guidance to set a limits that results where;
- Residual material being 1/1,000th of its theraputic dose in the maximun daily dose of any successive batch.
- The parts are visibly clean, and,
- any residuals are less than 10ppm in teh following batch
Obviously the calculation depends on the potency of the active in the first batch,the one that leaves the residue, and the size of the batch and maximum theraputic doese of the following batch. So any calculations have to consider teh worst cases. To illustarte the point we have done a worked calculation below.
The Maximum Acceptable Carry Over, MACO, can be calculated based on the commonly used limit that no more than one thousandth (0.001) of the minimum daily dose of a current product will appear in the maximum daily dose of a subsequent product. This is not always a useful calculation as is shown below and may be best applied to set in reference to the smallest following batch with the smallest therapeutic dose.
First Batches.
Product A | Product B | |
Minimum daily dose | 500mg | 5mg |
Safety Factor, 1/1000 | ||
Acceptable Daily Intake, ADI | 0.5mg | 0.005mg |
Followed by one of either two batches
Following Batch | Product C | Product D |
Active/ Excipient
Ratio active:excipient |
5/ 220
1:44 |
500/750
1:1.5 |
Batch Size, kg | 50 kg | 1000 kg |
Maximum daily dose (Active) | 80 mg | 4,000 mg |
Tablet weight containing maximum daily dose of active | 3,520 mg | 6,000mg |
ADI for Product A, from above in a maximum daily intake of the following batch |
0.5mg in a tablet weight of 3,520mg
1 in 7,040 |
0.5mg in a tablet weight of 6,000mg
1 in 12,000 |
Maximum Allowable Carry Over
for Product A |
In a 50kg batch
7.102 mg 7g |
In a 1,000kg batch
83,333 mg 83g |
Repeat the calculation for product B
ADI for Product B, from above in a maximum daily intake of the following batch |
0.005mg in a tablet weight of 3,520mg
1 in 704,000 |
0.005mg in a tablet weight of 6,000mg
1 in 1,200,000 |
Maximum Allowable Carry Over
for Product B |
In a 50kg batch
71 mg |
Ina 1,000kg batch
0.83 mg |
So we get varying figures for the acceptable limits following the 1/1,000 rule. If we took 10 ppm then this is more onerous.
EMA Risk Based Approach
The EMA guide uses Permitted Daily Exposure, (PDE), values as a basis for establishing appropriate limits for all contamination. The figure is the intake that is not expected to cause an adverse effect in an individual, even with a lifetime of exposure.
The PDE or data to calculate it is not readiliy available. However the methordology used to establish the PDE is similar to that used to establish Occupational Health Limits [OEL]. Teasdale [3] suggests an adaption of the OEL could be used as a PDE based on the assumptions that the inhaled volume of air over 8 hours is 10m ^{3} Thus the OEL is multiplied by 10m ^{3} to give a value in units of mass.
Using the materials above.
Product A | Product B | |
OEL 8hr | 10 mg/m ^{3} | 0.004 mg/m ^{3} |
PDE, taken as OEL level inhaled in 8 hours, in 10m ^{3} air | 100 mg |
0.04 mg |
Where no OEL is established alternative routes exist to arrive a PDE.
However
Certain substances will be genotoxic or allegenic and these have either no limit or set figures as limits. See Guidelines
References
[1] Fourman,
G.L. and Mullen, M.V., "Determining Cleaning Validation Acceptance Limits
for Pharmaceutical Manufacturing Operations," Pharm. Technol. 17(4), 54-60
(1993)
[2]
FDA Guide to Inspections; Validation of Cleaning Processes
[3] A. Teasdale, "EMA Guideline on Setting Health-Based Exposure Limits,"
Pharmaceutical Technology 40 (1) 2016.