Clean,Dirty Equipment Hold time study

GOOD VALIDATION PRACTICE (cGVP) CLEANING VALIDATION
1

Dear All, Pls provide your input

  1. Do CEHT and DEHT need to validate in each cleaning validation study?
  2. What are the parameter to be considered for identification of worst case molecule for hold time studies ?
  3. If I am performing only BET evaluation after cleaning, for cleaning validation, and not evaluating bio burden, is it fine? (As we manufacture injectable, the cleaned equipment will go for sterilization after cleaning, hence is it required to perform bio burden level after cleaning, in cleaning validation?)

Regards,
Sandip

2

dear all,

pls give me idea for CEHT & DEHT…
for CEHT: sampling done at intial, after 1 ,2 & 3 rd day…
but what is critria for DEHT?

3

Sterilization can increase endotoxin levels, so bioburden is required. DEHT and CEHT should be production related (over a long weekend and NOT 30 days). Since, it is the cleaning effectiveness of the cleaning procedures that is being studied, each study should have a DEHT and CEHT.

4

CEHT is the time after cleaning before use
BEHT is the time after use and before cleaning
Do you also have a SEHT or Sterile Effective Hold Time?

CEHT/SEHT shows that the method in which you store them (coverings, location, environment, time, etc.) are sufficient so that the equipment isn’t soiled between cleaning and use. These all should be part of the validation.

BEHT shows that the soil/molecule doesn’t become harder to clean with time. This is especially pertinent to proteins or other molecules which can denature while left on the surface of the equipment (think scrambled eggs in a frying pan - clean them quickly and they come right off, but if you wait then they become super hard to clean).

If this is for a sterile product (it appears this is a sterile injectible) these hold times should also be part of your media fill (sterile process simulation study) as well. I’m not sure if the sterile hold time needs to be re-confirmed every 6 months (typical of a media fill). I believe each operation (sterile hold time is an operation/condition) needs to be tested every year, but a media fill needs to be tested every 6 months - please confirm with WHO and ISO and FDA guildelines (and any other regulatory agency rules which must be met in your market).

I’m not sure if you need to do BET testing after cleaning, but before sterilization. Or if testing after sterilization is sufficient. Can’t help you there. Sorry.

5

One more question here, like DEHT to be performed for all hard to clean , cleaning validation worst case product, what parameter I have to consider for CEHT, means is CEHT to be performed on highest equipment surface area train, ot it can be performed on any equipment train ? Is this one time activity ?

Thanks

6

CEHT is a one time activity and in the validation study to demonstrate that your cleaning procedure is effective. I generally choose a stainless steel drum or fill tank that is representative of the equipment train (material of construction) rather than a specific piece of equipment (unless it has specific attribute like nooks and cranies).

7

Thanks Boomer,
Suppose I have one facility having 5 equipment train, the whatsoever equipment I will choose, of course will be representative of train, can you specify, from this 5 equipment train which train I will select, I mean what criteria to keep in mind while selecting equipment train for CHT.

Thanks for reply

8

Is change in equipment /cleaning procedure will require to evaluate the requirement of CHT ?

9

Yes. If the change is substantial and affects TACT (time, action, concentration, temperature) of the cleaning procedure.

10

It depends. In theory, all 5 must be cleaning validated (if their manufacturing process is unique like tablets, softgels, parenterals…). If you have 2 lines that make the same DP tablets (for instance) then no. In your ‘cleaning validation’ protocol you must segregate using ‘risk analysis’ the lines and drug products (DP) on health based limits (ADE).

11

Thanks Boomer,
However My que. was specific to CHT, not for CV.

Thanks a lot for your reply

12

Again it depends! I presume you have a separate cleaning procedure for tablets, softgels… It is you cleaning procedures that determine your number of CHT’s. But you can use the same ‘stainless steel’ drum (representative of the equipment trains/lines) for your separate cleaning procedures.

13

Anwering the initial question, what parameters to consider for Clean Effective Hold Time: in brief your equipment should be confirmed to be clean after cleaning, and you will have a data point for that. Then you hold your equipment for the CEHTime, and show that it doesn’t get contaminated during that time.

Contamination during the CEHT can come from various sources, but the primary one is the environement. If the equipment isn’t stored well, or if the environment is dirty/dusty, then your CEHT will be smaller. So during CEHT testing you should document how the equipment is stored (following an approved SOP) is it wrapped, covered, boxed up, left out, etc. You should also document where the equipment is stored (warehouse, closet, shelf, etc.). You should also document how the equipment is labeled and controlled for use. You don’t want someone unwrapping it, and then wrapping it back up while they are looking for another part.

1 Like
14

Thanks all for your input;
One more question related to DEHT,

Do we need to test for impurity after holding the equipment in dirty condition,
rationale- during cleaning process and hold the equipment dirty, the API get degraded.
If yes- how impurity matters ? if No- why not ?

Thanks
Sandip V. Patel

15

If you are testing using a non-specific test method (TOC or conductivity or pH), then you will likely test for the degredant at the same time, and be fairly accurate.

Even if using a specific test method (HPLC) In my experience we tested only for API (using HPLC) for 99% of the products. Remember, your allowable limits calculations has a safety factor built in (10, 100, 1000, etc.). This safey factor likely makes up for missing a few molecules of API which had degraded into something else.

Testing for degradants is a lot of additional work. What degredants are you looking for? What concentrations are expected, allowable, OK? I would 1st ask the question if you are expecting degredants in an appreciable manner? Also, would those degredants be adverse/toxic, or more toxic than the original API?

But, if you said yes that you expect a lot of degredants, then I wouldn’t see it passing stability testing at all. Maybe degredant testing would be needed for radiological products?

If your HPLC methods for finished product testing, can also be used for swab testing, then there is no reason to not look for degredants at the same time. But otherwise in the majority of cases degredant testing is probably not required during cleaning validation.

16

The objective of your DHT study is to prove the capability of your cleaning method by holding of equipment in rusted condition for specified time and to prove that your cleaning method is capable to remove the residue up to acceptance level. Here identification of degraded product is not in objective. But Identification of degraded product can b useful to improve your product knowledge. So to identify degradation is not mendetory but helpful to improve product knowledge