In July 2014, I wrote a Cleaning Memo on the subject of preferential transfer of residues. That is a topic I have subsequently covered in standard seminars and webinars. Another way that I have referred to this topic is “non-uniform contamination”. By “non-uniform contamination” I do not mean that on the cleaned equipment that there are different levels (or amounts) of a given residue on different surfaces within that equipment. That generally is the case, and is part of the basis for selecting “worst case” swab locations. What I mean is non-uniform contamination of the next product made on that cleaned equipment. That is, residues from certain areas of the cleaned equipment may transfer only to a small portion of the next product made. The reason I have tried to use the term “preferential transfer of residues” is so as not to confuse these issues.
The two most common examples of preferential transfer involve vial filling and tablet compression. In vial filling, residues on the cleaned filling needles and the associated filling equipment are not likely to transfer equally to product in every vial that is filled, but are more likely to transfer to the first few vials that are processed. With a tablet press, residues on the cleaned dies and punches are also not likely to transfer evenly to all tablets produced in a batch. Rather residues are more likely to be transferred to the first few tablets manufactured. In this Cleaning Memo we will focus on specific issues in preferential transfer for tablet compression.
Note that for tablet compression, residues on cleaned surfaces may transfer to the initially processed tablets of the next product generally by strictly physical phenomena, such as compression forces and friction forces. If that occurs, the transferred residues are likely to reside on the outer surfaces of the compressed tablets. If physical action is the main factor in transfer, my belief is that it is more likely for the initially processed tablets that residues of the manufactured product will be transferred to the equipment surfaces rather than residues on the equipment being transferred to the tablets being processed. Realize this is just my belief, but I believe it is reasonable. Until the lack of any transfer of residues from the surface to the manufactured tablets can be clearly established, it is best to address the possibility that it might occur, and use one of several techniques deal with that possible preferential transfer.
The typical approach in tablet manufacture utilizes the reasonable assumption that if preferential transfer occurs, the residues on the cleaned equipment surfaces will be transferred only a certain number of initially processed tablets. It is common practice in tablet manufacture to discard a certain number (or weight) of tablets before tablets are accepted for customer (patient) use. How many tablets ae discarded will depend on how many are made before the process “lines out” to produce tablets of expected consistent quality as determined by quality control tests (such as tablet weight consistency). There is no universally applicable number of tablets that should be discarded, since this may depend on things such as the formulation, the equipment, and the process parameters. However, in you facility you probably already have a number or weight for a given product/equipment combination that is typically discarded in initial processing.
If that is the case, how can you establish that such a practice is effectively dealing with the possibility of preferential transfer? Four options are presented below, starting with the simplest (no additional analytical measures) to the most complex (involving the possible need for significant analytical method development).
Option A
This is usual approach I have presented in the past. It involves determining the following to be used in Equation 1 (below).
L1: Calculated limit of residue in next product (in mcg/g)
L3: Calculated limit of residue per surface area (in mcg/sq.cm.)
SA: Surface area involved in preferential transfer (in sq.cm.)
TW: Weight of one tablet (in g)
Note that L3 utilizes the cumulative product contact surface area of the entire product train (granulator, blender, tablet press, etc.).
Then, the number of required discarded tablets to deal with preferential transfer is:
No. of discarded tablets = (L3)*(SA) / (L1)*(TW) (Equation 1)
If you are not familiar with the L1, L2, L3, etc. terminology I typically use for residue limits, please consult the September 2012 Cleaning Memo.
Clearly this approach could be used first if one has not established how many tablets should be discarded as the equipment “lines out”. However, this type of calculation may overstate the number of tablets to be discarded to deal with preferential transfer. Also, just because Equation 1 gives a certain value as to the amount to be discarded, if the amount to be discarded based on “lining out” of the process is higher, that higher number should be utilized for discarding initial production.
Option B
This option is a new one (at least for me). It requires more evaluation of existing analytical chromatograms provided suitable chromatograms are available. If they are not available, then some analytical testing will be required. However, this generally will not require the development of a new analytical method. In this option, a comparison is made between the impurity profile due to the prior API in the initially produced tablets and the impurity profile of the blended powder before that powder is processed on the compression equipment. The analytical method is the same HPLC method used as part of QC for the powder/tablet formulation. This comparison involves looking at the impurity profile (in the chromatograms) in each case (powder and tablets) to determine if there is any significant difference which could be attributed to the API of the prior active processed on the compression machine. If preferential transfer on the compression equipment is all made to the discarded tablets, then a reasonable assumption is that the impurity profile of the good tablets should be the same as that of the blended powder. That comparison may mean that the current practice of discarding tablets adequately addresses the issue of preferential transfer.
If in this Option B evaluation there is an indication that the current practice of discarding a fixed number of tablets might be insufficient, it may be possible to repeat the evaluation using a larger number of discarded tablets.
Finally, in such evaluation using Option B (as well for Option C and Option D), the tablets analyzed might be a composite sample containing tablets from all locations in multistation compression equipment.
Option C
This is another option that I don’t think I have ever publically discussed. It involves analyzing the impurity profile of tablets produced over time. This assumes that you use a method like HPLC to analyze (a) the “beginning” samples of the production batch (those processed immediately after discarding a fixed number of tablets as the process lines out), (b) the “end” samples of the production batch, and (c) tablets at one or more interval between the beginning and the end. Furthermore, it assumes that the prior manufactured batch on the compression machine has a different active (API). This means that the product batch evaluated should be limited to the first batch in a campaign.
If this were done, the “beginning” tablets tested should be those first tablets made after the discarded tablet were disposed of; this would insure that any preferential transfer, if it occurred, could be identified in the impurity profile of those initial tablets. Note further that all the processing steps (including granulation, blending, and compression) are preferably on equipment that had previously processed the same prior product with a different API. The reason for this latter stipulation is that the compressed tablet might also contain transferred residues from those earlier processing steps (such as from granulation), and those transferred API residues should form a baseline concentration in the next product. It is preferable to deal only with one prior API, rather than having one prior API residue from the granulation step and a different prior API residue from the blending step.
In such an Option C evaluation is done in a prospective manner, it would also be helpful to also do an impurity profile on one or more portions of the discarded tablets, but preferably on the initially discarded tablets. This way it might be possible to measure higher levels of preferentially transferred residue in those discarded tablets. If a significant improvement in the impurity peak due to the prior API were seen in going from the discarded tablets to the initially “good” tablets, and if there is no change in the impurity profile from the beginning and end of “good” tablets, then it is a reasonable conclusion that (a) preferential transfer does in fact occur and (b) the current practice of discarding tablets adequately addresses the issue of preferential transfer.
Option D
A fourth option is actually to measure residues in the initially produced tablets to see if the residue in the tablet is below the calculated L1 limit, which may be in mcg/g or mcg/tablet. This is generally not a preferred approach because you are quantitatively measuring residue of the previous active in the new product (and we know that measuring residues at low levels in water or a solvent is difficult enough without having to address a new possible interference sources). It may not be likely that a validated analytical method for the prior API in the prior formulation would be suitable, but if so you would have to demonstrate that fact. Therefore, it may involve significant effort to develop an analytical method to measure the residue of the previous API in the processed tablets. The L4 limit in the analytical sample for the tablet itself may also be much lower than the residue limit typically used in a swab sample, because it involves a direct measure of tablet and the other involves collection of residue from the surface and extracting a swab in a fixed volume of liquid. This is one reason why for cleaning validation purposes, it is preferable to focus on the measured residue captured from cleaned equipment surfaces rather than directly measuring residues in the product itself.
Final Comments
All these evaluations assume that residues on the product contact equipment surfaces are preferentially transferred to first number of tablets processed. If the residue of the prior API were to transfer uniformly (that is, the same amount transferred to the first tablets as to the last tablets), then preferential transfer does not occur, and these evaluations can be ignored (although you may still discard an initial number of tablets for other product quality concerns). If residues come off evenly, then preferential transfer is not an issue. If the residue comes off randomly (say only after 100,000 tablets are processed), there is no logical way to deal with this situation (although it is not a likely scenario for a tablet press).
If the number of tablets that should be discarded is found to be more than more than your current practice, then there are two options. One option is to discard more tablets. Another option is to use Option A and make the prior cleaning process L3 limit for the compression equipment involved in preferential transfer (that is, the equipment involved in the surface area value you used in the calculation) more stringent than the rest of the equipment train (the “rest” includes granulator and blender). If the L3 for the compression equipment is halved, the number of tablets determined in Equation 1 is also cut in half. Of course, this also means that the cleaning process for the compression equipment product contact surfaces may have to be improved, and that the LOD/LOQ of the analytical method might have to be lowered.
Note also that in some situations, the product contact parts of the tablet press (such as the dies and punches) may be dedicated to only one formulation. In that situation, the surface areas of the dies and punches would not be included in the surface area involved in preferential transfer, and concerns about preferential transfer from those surfaces may be eliminated.
Also, for options 2, 3 and 4 where tablets are being analyzed, make sure that any equipment used to dissolve the formulation does not have residues that might interfere with the analysis by providing another source of unknown peaks in the chromatogram. For example, if dissolution testing equipment is used, that equipment should be “double cleaned” with a thorough rinse, optionally followed by an ultra-pure acetone rinse. In any case, a blank sample should be run side-by-side to help assure no extraneous interferences due to that equipment.
Finally, this issue of preferential transfer applies to tablets that are uncoated (or coated tablets before they are coated). There is typically no API in the coating solution itself, so the idea of preferential transfer of residues from the coater is generally not relevant.
The purpose of this Cleaning Memo is for me to have a document to refer individuals to when I am asked questions about preferential transfer in tablet processing.
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