Appropriately calculating swab and rinse limits can be challenging. While best practice guidances have provided these equations to industry, how to apply the terms and what they represent is not well defined. This memo will explain and give examples of how to appropriately calculate limits for product residues, starting from a maximum allowable carryover (MACO) limit down to swab and rinse residue limits. In addition, special considerations that should be factored into the calculations, where appropriate, will be discussed.
First and foremost, limits should be based on toxicological or pharmacological data using a health-based exposure limit (HBEL) such as an acceptable daily exposure (ADE) or a permitted daily exposure (PDE) that has been reviewed and approved by an expert (i.e., a toxicologist) [1].
When an ADE/PDE cannot be established for early clinical products, it may be appropriate to use a threshold of toxicological concern (TTC) that has been reviewed and approved by an expert before use. These HBELs are used to calculate the MACO of product residue (Product A) that would be safe in the minimum batch (MBS) at the maximum daily dose (MDD) of the subsequent product (Product B) according to the following formula [2, 4].
Where:
(MACO) Maximum Allowable Carry Over – The total amount of a target residue allowed in a batch of the next manufactured product.
(PDE) Permitted Daily Exposure – A dose that is unlikely to cause an adverse effect if an individual is exposed by that route at or below this dose every day for a lifetime. This term is synonymous with the term acceptable daily exposure (ADE). (Product A)
(TTC) Threshold of Toxicological Concern - of Product A
MBS: Minimum Batch Size - The smallest batch of the subsequent product manufactured on the equipment after cleaning of the previous product. (Product B)
MDD: Maximum Daily Dose - The maximum daily dose of the subsequent product manufactured on the equipment after cleaning of the previous product. (Product B)
Let’s work through an example. Details of product-specific data for two products, referred to as Product C and Product D, are shown below. The MACO of Product C going into Product D is calculated using the PDE for Product C, the MBS for Product D, and the MDD for Product D. It is vital that the appropriate values are used, the HBEL (i.e., ADE, PDE, or TTC) of the previous product manufactured before cleaning, as well as the MDD and MBS of the subsequent product manufactured after cleaning. Any other combination of these values will result in an inaccurate MACO. Therefore, the maximum amount of Product C considered safe to carry over into the next batch of Product D is 4,958.33 mg.
Product C | Product D |
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Before we can derive our swab and rinse limits, we must establish each sampling method's recovery factor. A recovery factor is established to correct the swab and rinse limits to account for any shortcomings of the sampling method in its ability to remove residues from the equipment surfaces. The recovery factor is based on data from the recovery studies performed to demonstrate the suitability of each sampling method in combination with the chosen analytical method. It is derived from the lowest average percent observed for any material of construction (MOC) at any soil concentration for the respective sampling method.
Once the MACO and recovery factor are determined, the swab and rinse limits can be derived. There are two approaches for determining the swab limit. In the first approach, the swab limit is expressed as the residue concentration in a fixed amount of solvent used for extracting the swab sample (SEA). In the second approach, the swab limit is expressed as the mass of the residue per swab sample. In both approaches, the ratio between the sampled surface area (SSA) and the total shared surface area of the equipment train (TSA) must be considered in the swab limit equation to ensure swab results are representative of the residue level present throughout the entire equipment train. The swab limit for approach one should be calculated according to the following equation [2, 4]:
Where:
(MACO) Maximum Allowable Carry Over – The total amount of target residue allowed in a batch of the next manufactured product, as determined in the first equation.
(SSA) Sampled Surface Area – Equipment surface area to be sampled using the sampling method.
(Rf) Recovery Factor for Swab – The fractional amount of residue that can be recovered utilizing a swab sampling method.
(TSA) Total Shared Equipment Surface Area – The total shared multi-use direct product contacting surface area of an equipment train that is shared between two products and can contribute to cross-contamination.
(SEA) Solvent Extraction Amount – Volume of solvent that swab samples are desorbed in.
The swab limit using approach two should be calculated according to the following equation [4]:
Where:
MACO: Maximum Allowable Carry Over - The total amount of target residue allowed in a batch of the next manufactured product, as determined in the first equation
SSA: Sampled Surface Area – Equipment surface area to be sampled using the sampling method.
Rf: Recovery Factor for Swab – The fractional amount of residue that can be recovered utilizing a swab sampling method.
TSA: Total Shared Equipment Surface Area – The total shared multi-use direct product contacting surface area of an equipment train that is shared between two products and can contribute to cross-contamination.
Rinse limits should be expressed as a residue concentration in the fixed rinse sampling volume [1], where the volume represents the amount of solution required to thinly coat the equipment surfaces sampled. Typically, rinse samples are pulled for individual pieces of equipment because it is impractical to sample an entire equipment train. Therefore, the ratio between the equipment surface area sampled (SSA) and the total shared direct product contact surface area of the equipment train shared between two products (TSA) must be accounted for in the rinse limit calculations. The following calculation should be used to derive the rinse limits for individual equipment sampled with consideration for the TSA [2, 4].
Where:
(MACO) Maximum Allowable Carry Over - The total amount of target residue allowed in a batch of the next manufactured product, as determined in the first equation.
(SSA) Sampled Surface Area – The equipment surface area to be sampled using the sampling method.
(Rf) Recovery Factor for rinse - The fractional amount of residue that can be recovered by utilizing a rinse sampling method.
(TSA) Total Shared Equipment Surface area - The total shared multi-use direct product contacting surface area of an equipment train that is shared between two products and can contribute to cross-contamination.
(RV) Rinse Volume – The final rinse volume to collect the rinse sample. This volume should be the minimum volume required for the solution to contact the entire sampled surface area of the equipment (SSA).
In some cases, the ratio between the equipment surface area to be sampled (SSA) and the total shared surface area of the equipment train (TSA) may be equivalent and thus cancel out. [4] In these situations, the equivalency must be demonstrated with documented justification for omitting these factors in the rinse limit calculations. Below is the simplified rinse limit expression where the ratio between the SSA and TSA has been documented and justified to be equivalent [4].
Where:
(MACO) Maximum Allowable Carry Over - The total amount of target residue allowed in a batch of the next manufactured product, as determined in the first equation.
(Rf) Recovery Factor for rinse - The fractional amount of residue that can be recovered by utilizing a rinse sampling method.
(RV) Rinse Volume – The final rinse volume to collect the rinse sample. This volume should be the minimum volume required for the solution to contact the entire sampled surface area of the equipment (SSA).
Building on the previous example, the MACO of Product C into Product D was determined to be 4,598.33 mg. Taking the derived MACO and the recovery factor determined for both swab and rinse of Product C, the swab and rinse limit can be calculated with consideration for the sampling area and the shared surface area of the equipment train. The swab limit with respect to the MACO of Product C into Product D would be 5.24 (𝑚𝑔/𝑚𝐿) or ppm.
Where,
MACO of Product C into Product D = 4,598,330 (mg)
Swab sample surface area = 25 cm2
Product C recovery factor for swab = 0.73
Total shared surface area of the equipment train = 400,500 cm2
Solvent Extraction Amount = 40 mL
The rinse limit with respect to the MACO of Product C into Product D would be 5.15 (𝑚𝑔/𝑚𝐿) or ppm.
Where,
MACO of Product C into Product D = 4,598,330 (mg)
Equipment surface area to be sampled = 20699 cm2
Product C recovery factor for rinse = 0.65
Total shared surface area of the equipment train = 400,500 cm2
Rinse Volume = 30,000 mL
A few things to consider when calculating swab and rinse limits. A recovery factor should not be confused with a correction factor, which is a numerical constant used to correct analytical results. While it may be appropriate in some instances to determine a correction factor based on data from swab and rinse recovery studies, this constant should only be used to correct an individual swab or rinse result. It cannot be applied to correct swab and rinse residue limits because it is not representative of the worst-case for the fractional amount of residue that can be recovered by a respective sampling method. Additionally, if total organic carbon (TOC) analysis will be used to analyze residues, the carbon content of the molecule of interest must be calculated and accounted for in swab and rinse residue limits by multiplying the limit by the carbon content of the product in decimal form.
Establishing appropriate swab and rinse residue limits for the MACO permitted in the batch of the following product is a critical part of a cleaning validation program and assures health agencies that the risk for adulteration is adequately controlled.
Contributors: Joanna Joseph, Jenna Carlson, and Samson Goodrich
References-
EMA. (2014). EMA/CHMP/CVMP/SWP/169430/2012. Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities.
ASTM. (2023). E3418-23. Standard Practice for Calculating Scientifically justifiable Limits of Residues for Cleaning of Pharmaceutical and Medical Device Manufacturing Equipment and for Medical Devices.
FDA. (1993). Guide to Inspections Validation of Cleaning Processes.
PDA. (2012). Technical Report No. 29 (Revised 2012). Points to Consider for Cleaning Validation.
ISPE. (2020). Guide: Cleaning Validation Lifecycle – Applications, Methods, and Controls