DETERMINATION OF CLEANING VALIDATION ACCEPTANCE LIMITS FOR PHARMACEUTICAL MANUFACTURING OPERATIONS

Residue Limits:- Validating a cleaning process includes selecting target residues and setting limits for those residues following the cleaning process. Target residues are selected based on possible residues that can be left after the cleaning process. This requires an understanding of the cleaning process, and may require an investigation into possible degradation products that may occur during the cleaning process. Acceptable levels of those specific residues are based on what could occur should those residues contaminate the subsequently manufactured product. Analytical determinations of residues are usually required. In addition to those measurements, it is expected that the equipment will be visually clean. Examination of equipment for visual cleanness requires training of the observers and may require auxiliary lighting. A visual examination may be supplemented by use of a video camera for recording purposes or by use of a boroscope for pipes. In somecases, equipment may be disassembled for visual examination (and optionally for analytical sampling) to determine cleanness.

 

Limit in next product:- It is important in any discussion of ‘‘residue limits’’ to understand that limits for a cleaning process may be expressed in different ways. This includes the limit of the residue in the subsequently manufactured product, the limit of the residue on the cleaned equipment surfaces, and the limit of the residue in the analyzed sample. These are all related, but they are usually different numbers. For an active ingredient in the cleaning of a finished drug product, the limit in the next product is usually calculated based on application of a safety factor (usually 0.001 or lower) to the minimum daily dose of that active in the maximum daily dose of the subsequently manufactured product. The active or level of active in the subsequently manufactured product is irrelevant unless there is information about unusual deleterious interactions. This calculation is also independent of manufacturing issues such as batch size and equipment surfaces areas, and can be calculated solely on information about the dosing of the two products as follows:

u

Where

  • L1 is the limit of the active in the next product,
  • MinDA is the minimum (daily) dose of the active (the target residue),
  • MaxDSP is the maximum (daily) dose of the subsequently manufactured drug product, and
  • SF represents an appropriate safety factor. Care needs to be paid to selection of units;
  • L1 limit is usually expressed in mg/g (or ppm).

 

Limit per surface area:- The next limit calculated is usually the limit per equipment surface area. This is calculated based on the limit in the next product, the batch size of the subsequently manufactured product, and the equipment shared surface area. This is expressed as:

v

Where

  • L2 is the limit per surface area,
  • BS is the batch size, and
  • SSA is the shared surface area. Units should be consistent, and the
  • L2 limit is usually expressed in units of mg/cm2.

 

Limit in analytical sample:- The next limit is the limit in the analytical sample. If the sampling method involves swabbing, the surface area swabbed and the amount of diluent used for desorbing the swab must be considered. The limit per swab sample is then calculated as:

w

Where

  • L3 is the limit per analytical sample,
  • SA is the swabbed area, and
  • AD is the amount of diluent for swab elution. Here again units need to be consistent, and
  • L3 limit is usually expressed as mg/g or mg/ mL.

 

It should be clear that the limit in the analytical sample can be manipulated by changing the area sampled (higher areas result in larger limits per analytical sample) or the amount of diluent used (lower amounts result in larger analytical sample limits). If a sampling rinse is used (in place of swabbing), SA effectively becomes the total surface area of the equipment, and AD becomes the volume of solution used for the sampling rinse.

 

Non-dose limits:- For residues (such as cleaning agents) that do not have a defined dose, some measure of toxicity, such as an acceptable daily intake (ADI), is used for residue limit purposes. If the subsequently manufactured product is an in vitro diagnostic (IVD), and has no defined dose, then some evaluation of the effects of target residues on the performance or stability of the IVD product should be performed. These non-dose factors are used only for the L1 limit; there are no changes for calculation of L2 and L3 limits.

 

Limits for multiple subsequent products:- When a residue limit is to be calculated for a product where there may be more than one subsequently manufactured product, calculations should be made to compare the surface area residue limits (L2 limits) by using each subsequent product. If the manufacturing order is not to be restricted, the cleaning validation of the first product should be established using the lowest surface area limit.