In many of the recent Cleaning Memos, I have referred to cleaning validation residue limits using my shorthand system of L0, L1, L2, L3, L4a, L4b and L4c. The reason for doing this was to avoid possible confusion by use of terms like “maximum acceptable carryover” (MAC), “surface area limit” (SAL), “acceptable residue level” (ARL), and “swab residue limit” (SRL). Some people like my shorthand system; others use some variation of it; while others will use a system specific to their company. Another reason for the “L” system is that it is more compact to use (takes up less space on the page, particularly when used in tables presenting data for limit values). Below are the shorthand “abbreviations” for limits I have used for drug product manufacture for the past thirteen years, and still find useful. It is critical to mind the units at each point.
L0 The safe amount of residue that can be administered to a person on a daily basis for a long time period. The units for this are mass units, such as mcg or mg. Note that L0 values for a given residue may be different depending on the route of administration (e.g., oral, injectable, topical). Furthermore, L0 may be adjusted based on a limited time of potential exposure. L0 may be calculated by formulas such as 0.001 of the minimum daily dose of an active, by the Risk-MaPP Acceptable Daily Exposure (ADE) calculations, by the EMA Permitted Daily Exposure (PDE) determination, or by an LD50 determination (generally only for cleaning agents). This is also the point where the dose based L0 can be compared against the health based L0 and the lower number carried forward.
L1 This is the safe concentration of residue in the next manufactured drug product. This is typically in concentration units such as ppm, mcg/g, or mcg/mL. This, of course, makes certain assumptions about the route of administration and time frame of exposure in determining the L0 amount. For finished drug product manufacture, it is calculated by dividing the L0 value (however that L0 value is determined) by the maximum daily dose of the next drug product. For example, in the case of tablets it would be the average tablet weight times the maximum number of tablets taken daily. Note that for those of you who use a “default” L1 value such as 10 ppm in your carryover calculations, that 10 ppm value is typically used as the L1 value whenever it is more stringent (that is, lower) than any calculated L1 value. [Note that if you are manufacturing drug substances and not drug products, L1 is calculated by dividing the L0 value by the maximum daily dose of the next drug substance.]
L2 This is the total amount of residue allowed in a batch of the next drug product, and therefore the total amount allowed on shared product-contact surfaces of the equipment train. This is typically in mass units, such as mcg, mg or g. It is calculated by multiplying the L1 value by the minimum batch size of the next manufactured drug product. [Note that if you are manufacturing drug substances and not drug products, L2 is calculated by multiplying the L1 value by the minimum batch size of the next manufactured drug substance.]
L3 This is the amount of residue allowed per surface area of product contact surfaces. This is typically in units of mass per surface area, such as g/cm2 or mcg/in2. It is calculated by dividing L2 by the total product-contact surface area of the equipment train. This L3 can also be compared to the visual residue limit (VRL) determined through a visual coupon study to possibly establish that a visual assessment is stringent enough to meet the L3 limit value.
L4a This is the amount of residue per swab (for swab sampling). It is in mass units, typically mcg or mg. L4a is calculated by multiplying the L3 value by the area swabbed (typically 25 cm2 or 100 cm2). For clarification, if two swabs (for example, one wet and one dry) are used on the same location, L4a is not the amount per swab, but the combined amount for two swabs. [Note that the L4a limit can be increased by swabbing a larger surface area.]
L4b This is the concentration limit in the liquid (such as water or solvent) the swab is extracted into. This is typically in units such as ppm, mcg/g, or mcg/mL. It is calculated by dividing the L4a limit by the amount of liquid used to extract the swab. [Note that the L4b limit can be increased by extracting the swab in a smaller volume of liquid.]
L4c is the concentration limit in the liquid (such as water or solvent) that is used for rinse sampling. This is typically in units such as ppm, mcg/g, or mcg/mL. If the entire equipment train is rinsed as a unit, L4c can be calculated by dividing L2 by the amount (or volume) of liquid used to sample the equipment in the rinse sampling process. If items in the equipment train are sampled independently of each other, then L4c is calculated by multiplying L3 by surface area of the equipment item sampled, and then dividing that result by the amount (or volume) of liquid used in the rinse sampling process for that specific equipment item. Note that the rinse volume is not necessarily the entire process rinse volume, but rather the amount of the final rinse solution needed to adequately contact all equipment surfaces to adequately remove and quantify residues on the surfaces. [Note that the L4c limit can be increased by performing the rinse sampling with a smaller volume of liquid.]
Note that other terms can and have been used in the industry. However, the “L” terms have no significant connotations (except that they are associated with me), so that is one reason I prefer them. A second reason for using them is that terms like MACO/MAC (originally Maximum Allowable Carryover, referring to the total amount of residue that can be carried over from the cleaned equipment to the next manufactured product) have been used in so many different ways by different companies that it seems futile to try to have people in the industry use the term in the same way (incidentally, MACO/MAC as originally defined is the same as the L2 value).
I mentioned that some may use variations of this “L” system. For example in the India Pharmaceutical Alliance (IPA) “Cleaning Methodology and Validation Best Practices Document” (May 2021) uses a variation but avoids “L0” and “L4b”. It avoids L0 by specifying that a L1 value can be calculated based on a HBEL criterion and a dose-based criterion, with the L1 value resulting in the lowest concentration being utilized for subsequent L2 calculations. (Note that the IPA document does not present the use of a default 10 ppm value as a L1 if 10 ppm is more stringent than the calculated values.) I’m not sure why the L4b term is not used by the IPA, since some companies will report analytical values as concentration in the extracted swab solution (although I do realize it is easy to move back and forth between L4a and L4b by utilizing the amount of solution used to extract the swab). If you use the IPA terminology, just realize that the IPA terms L1, L2, L3, L4a, and L4c basically have the same meanings as in my “L” system.
It is also important to point out here that in the June 2022 Cleaning Memo, I also introduced an “M” system for expressing the measured analytical values obtained in a cleaning validation protocol. The “M” values corresponds to the “L” values, but help separate out the measured values obtained in the execution of a protocol from the limit values calculated before execution of the protocol. The “M” values can then be compared to the corresponding “L” values to determine whether the acceptance criteria are being met. Here is what I proposed, which is essentially substituting the letter “M” for the letter “L” that was used in the system for limits. “M” here refers to the “measured value” for a specific sample or situation. So, here is the system:
M0: Equivalent daily amount potentially taken based on the measured sample analytical value
M1: Equivalent residue concentration in the next batch based on the measured sample analytical value
M2: Equivalent total amount of residue per batch based on the measured sample analytical value
M3: Equivalent amount of residue per surface area based on the measured sample analytical value
M4a: Measured amount (per swab) for a specific swabbed location
M4b: Measured concentration in swab extraction liquid for a specific swabbed location
M4c: Measured concentration in the rinse liquid for a specific rinse sample
In each case, the M value refers to the measured value (or equivalent value calculated based on the measured analytical result for a specific sample). While the L values (the limits) are typically the same for a given protocol, the M values (based on the analytical values measured for a specific sample) will more typically vary.
This Cleaning Memo is designed to be a refresher for use of these shortcut terms.
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