Minimizing the Risk of Cross Contamination in a Pharmaceutical Central Chemicals Dispensing Room

GOOD VALIDATION PRACTICE (cGVP) PROCESS VALIDATION
1

In a non pen non sterile pharmaceutical production facility (producing many pharmaceutical products) in which there is a central chemicals dispensing room

The central chemicals dispensing room has the following characteristics:

1- The dispensing room has a LAF weighing booth in which preparation chemicals are manually weighed using scoop and balance

2- Certain amounts of preparation chemicals are weighed from the raw materials containers to obtain a cage containing certain amounts of chemicals (active & inactive) to be dispensed for the preparation of a certain batch of a certain pharmaceutical product

3- The rest of the chemical remaining in the original raw material container after weighing (e.g. inactive ingredients e.g. diluents such as starch) can be weighed and dispensed in the future for the preparation of a batch of another pharmaceutical product, i.e. the inactive ingredient is common for more than one product

I believe that after weighing the API of a certain product, certain measures should be conducted before weighing an inactive ingredient of the same product (but this inactive ingredient is common for more than one product) such as:

1- the whole weighing booth and the balance should be wet cleaned

2- the scoop used for weighing the API should be cleared from the area

3- secondary gowning of the weighing person should be changed

These measures should be conducted to minimize the risk of contaminating the original raw material container of this inactive ingredient with traces of the previously weighed API, because if it is contaminated this contamination may be introduced in the future into another pharmaceutical product since the rest of this inactive chemical remaining in the original raw material container (e.g. diluents such as starch) can be weighed and dispensed in the future for the preparation of a batch of another pharmaceutical product

Am I right ?

Another question:

If the production department demands that chemicals for 5 batches of a certain product are weighed,
Call no.s of batches (1,2,3,4,5) and call the names of chemicals (A, B, C, D)

I believe that the best approach to minimize the risk of cross contamination into original raw materials containers should include some procedures such as:

1- Not to weigh the chemicals for batch no. 1 then weigh the chemicals for batch no. 2 and so on , but the right approach is to weigh the 5 amounts of chemical A for the 5 Batches consecutively then weigh the 5 amounts of chemical B for the 5 Batches consecutively and so on

2- Chemicals are weighed in ascending order of chemical risk, i.e. first inactive ingredients are weighed e.g. diluents followed by weighing colorants & flavors if present , and finally API is weighed

3- Weighing booth clearance & dry cleaning and convenient time interval should be present between each inactive chemical and the following chemical

4- After weighing the API, the previous step is performed in addition to wet cleaning, even if other batches of the same product are required to be weighed after weighing this API, as previously illustrated

Am I right ?

Thanks a lot

2

I agree with everything that you said (if I understand it), it sounds like you are taking a conservative approach.

You might do a risk calculation to determine the possible effects of an inactive in another product. You might be able to get away without cleaning after a benign filler/inactive, as the small carryover you get might have no impact on any other product. In this case you might do a quick clean but nothing too invasive.

Overall, I think you have thought through the risks and have a risked based approach outlined.

3

Thanks for your response

I know that the question is very long, but I did not find any other way to ask the question, because the reader needs to imagine the case with all its aspects so as to understand the question therefore I wrote a very detailed descriptive question

4

This approach will require the presence of 5 cages for 5 batches of the same product in which chemicals for each batch are distributed, i.e multiple Batches of the same product are present concomitantly in the same dispensing room,

I think that further measures will be required to ensure absence of mix up between these batches of this product, so that the measures conducted to minimize cross-contamination do not lead to high risk of mix-up ???

5

While I was reading your post, I wondered if it would be possible to dedicate some cages for various activities. For example, you could get
(a) one cage for excipients and other low/no toxicity components; and
(b) one dedicated cage for each API which has high volume
© one shared cage for APIs with low volume

Cross contamination could then be mitigated based on risk assessment based on material type.

6

all Products batches dispensed by this dispensing room, The chemicals of each batch are contained in one cage or put on 1 plastic pallet which is then shrinked , i.e. Batch kit so that all the chemicals on 1 pallet or 1 cage are used for the preparation of one batch of a product

7

OK. It sounds like your remaining question is that further measures are required to ensure there is no mix up between products.

I think you’ve laid out a few activities to be done to ensure there is no cross contamination. They all seem reasonable.

I do have a question, do your questions come out of an effort for continual improvement, or are they the result of an audit finding. If it is an audit finding, make sure you specifically address the audit finding comments directly. I believe all continual improvement is looked upon favorably and therefore you have more leniency to do things, while an audit should be responded to directly, and without deviation to their audit findings.

8

It is continual improvement,
I think that to prevent mix-up between contents of cages (of batches of the same product) in which chemicals are distributed in the dispensing room, the further measures could be:
1- SOP instructions for operators that should be followed strictly to avoid occurrence of mix-up
2- Continuous triple check on the application of these instructions and on the absence of mix-up during dispensing process, by dispensing room supervisor and QA personnel.

9

How do you document use/cleaning of the cages? Is this done using logbooks for each cage?

10

After using Batch chemicals (which are inside the cage (each chemical in a double polyethylene bag)) in the preparation of that Batch , the cage is washed before reusing it in the dispensing of another batch chemicals, i.e. the cage is washed whatever the next batch is of the same product or of different product

  • no cages are dedicated for certain products (there is no direct contact with chemicals since each chemical is in a double polyethylene bag))
  • no log book for each cage, only a clean label is affixed on the cage after washing & before sending to the dispensing room
11

I think with training, procedures, and the clean label affixed to the cage, that you will pretty much be covered for cross contamination control.

The only other thing I can think of would be to install air flow devices (hoods, horizontal flow areas, etc.) that help pull powders away from the product in a safe manner. Hoods are difficult for large quantities of powder being dispenses, and horizontal flow areas are more suitable for larger quantities being dispensed. I’ve never had personal experience with horizontal flow areas, but I know the World Health Organization discusses a horizontal air flow mechanism, which pulls all powders away from the product horizontally.

In the diagrams, it actually shows a dispensing operation - so maybe this is something you might consider. I wonder if it would be possible to avoid cleaning if it can be shown that there is no risk to cross contamination using air flow this way??? Disclaimer, without further evaluation, I cannot recommend for or against these activities.

Also, if you decide to go down this path computational flow dynamics (CFD) is a resource to predict how particles proliferate in a ventillated area. It might be helpful to show possible powder proliferation.

12

Thanks a lot for your assistance
Unfortunately our weighing booth (LAF) (under which the operator, the solid balance (on a perforated table) and original raw material container are present) is of vertical flow and dust presence is not optimal i.e. our weighing booth reduces turbulence but not to a sufficient extent and so we can not rely on it totally and therefore cleaning is essential to minimize cross contamination

13

Examples of these SOP instructions are
1- to put movable partitions between each cage (pallet) and the adjacent one of another Batch and putting a large ID Label containing Batch No. at each one
2- If there are modified Batches of the same product (of modified Batch size) the chemicals of these batches are weighed in a separate campaign , not with ordinary unmodified Batches

14

I want to ask, cage is made up of which material??
For 5 batches u have 5 cages for each dispensed batch??
Cages secured in lock and key??
Cages are placed outside the dispensing room??
Size of cages??