Introduction
This guidance provides points to consider when selecting Dosage and Toxicity data for use in the Cleaning Limits calculations.
This guidance is intended to standardise the approaches currently taken in selecting source data to be used in the cleaning limits calculations.
Recommendation & Rationale
Toxicity Data considerations
When selecting data for use in the Toxicity Maximum Allowable Residue (MAR) calculations, the following points should be considered:
For consistency, use of Acute Oral LD50 values obtained using rats as the study population is recommended to be used. The justification for utilising rat acute oral LD50 values is based on a commonly referenced article on this subject. Layton et al suggests that a safety factor to be used in calculating the Acceptable Daily Intake (ADI) be in the range of 1×10-3 to 5 x10-6. This factor is based on small mammal and oral rat data. The MAR formula, therefore, require the overall safety factor of 5 x 10-6 {5 x 10-4 in the No Observable Effect Level (NOEL) calculation and another 1 x 10-2 in the ADI calculation, which incorporates the NOEL}. The ADI is used in the Toxicity Maximum Allowable Residue (MAR) calculation. The safety factor of 5 x10-4 has been reported in other literature articles for NOEL and appears to generally be accepted in the industry.
In cases where rat acute oral LD50 values are not available, but other species’ toxicity data are available, the acute oral LD50 value of the next largest mammal can be used. Likewise, if oral LD50 data are not available, LD50 data from other administration routes may be used.
For API intermediates without available toxicity data, the toxicity of the subsequent API could be used in the limits calculations if the intermediate is the same molecule as the API (e.g. crude API) or a base form of an API salt, for example. Alternatively (and more commonly), in cases where intermediate toxicity data are not available, the calculation may be conducted for the Wt% MAR only, omitting the Toxicity MAR calculation altogether.
Include a reference of the source of the compound toxicity data used in the toxicity MAR calculations in site documentation.
Another approach to calculate the toxicity MAR can be found in the Draft ISPE Baseline guide on Risk-MAPP .
Toxicity data for residual organic solvents in which the process controls (e.g. drying or flushing etc.) after cleaning with organic solvents are not in place or effective removal of the residual solvent cannot be demonstrated, ICHQ3 guide9 limits could be used as a basis for calculating residual organic solvent limits after cleaning. A toxicity MAR could be used as comparative limits in the cleaning limit calculations.
Therapeutic Dose Data considerations
The following points can be considered when selecting Dose data to be used in the calculations of Maximum Allowable Residue for Therapeutics (MART) or Dose MAR:
In cases where multiple formulations of an API are being produced in Drug Product (DP) manufacturing, or if the specific dosage form and/or dose to be used is unknown (e.g. APIs for external sales), then the most conservative published minimum therapeutic dose (TA) of the API for all DP formulation uses should be utilised in the MART calculations.
In the DP manufacturing plant where more than one dosage form or delivery system (e.g. oral tablet, injectable liquid, topical cream/ointment) of the same API are produced on a given equipment item, the minimum therapeutic dose [TA] (used in the numerator of the equation) is specific to the drug product dosage form/delivery system.
For the selection of the SF for an oral dosage form the following is recommended:
- Do the dose calculation using a SF of 1/1000
- Evaluate if the Residue Acceptable Limit (RAL) is practical and achievable.
- If the RAL limit obtained is practical and achievable, then a SF of 1/1000 should be used for the dose calculation.
- If on the contrary, the limit obtained is not practical and achievable then evaluate the risk of contamination and take into consideration the product type. If the product does not have a safety concern (e.g. cytotoxic) then perform the dose limit calculation with a SF of 1/100.
Normalize the dosage of the AH product to a 70 kg human (e.g. if the maximum daily dose of the AH is 15mg/kg/day, if normalized to a human dose (multiply by 70 kg; will result in 1,050 mg/day for an adult of 70 kg).
If the equipment is used to produce AH products only:
- Use MART and RALT Equations for actives
- Minimum and maximum therapeutic dosages
- Usually on animal weight basis (mg/Kg or mg/lb)
- May have same (Minimum = Maximum) Dose
- Safety factors (e.g. 1/1000) and Default MART (10 ppm) are same as with human health.
Recommendations for MART calculations when a pediatric product and a product for adult use are manufactured in the same equipment:
Option 1: Use the lowest published TA for MART calculation (for pediatric and adult). Evaluate Product A (to be cleaned) and Product B (next product) with respect to their intended uses (e.g. adult or pediatric drug product) for each changeover. For example, if it is a pediatric drug product A to pediatric drug product B changeover, then use the pediatric dose for Product A in the MART calculation.
Option 2: Normalize the dose whenever a pediatric product is involved in the calculation. Document the average body weight factor for the adult (usually a 70 kg adult) and for the pediatric patient used for MART calculations. Refer to the following example.
For ophthalmic products, use the published TA or daily dose as TA (if TA is not specified in the reference or if it is not possible to estimate the TA) for MART calculations. If the TA is reported in drops, determine the equivalency of one drop in ml. For example 1 drop/day is equal to 0.03 ml and each drop contains 50 mcg of active X; therefore the maximum daily dose is 1.5 mcg of X/drop.
The maximum daily dose is calculated over a 24-hour period (e.g. Take one 500 mg tablet per 8 hour period = 500 mg x 3 times/day = max daily dose of 1,500 mg/day. For a liquid the maximum daily dose = maximum number of doses in a day x µl in one dose or mg in one dose.
The minimum therapeutic dose is the minimum amount of drug that may be administered, usually express as weight (e.g. mg).
Include a reference of the source of the dose data used in the dose MAR calculations in the site documentation.