Good EHS Practice for LC Test of Highly Toxic Drug

[Terry]

Hello guys,

I am assigned to prepare some EHS procedures for the LC analysis of a highly toxic drug (anti-cancer drug containing platinum). I do not have much experience on dealing with toxic drug.

I have the following questions:

1. What precautions shoule be taken in weighing, dissolving and LC running steps?

2. Should we discarded every labware that have been in contact with the drug? Or wash and rinse them throughly, then reuse them?

3. How to deal with the waste?

Thanks in advance.

[krickos]

Hi

Based on an API with a terapephtic dose of 2-10ug (inhalation drug). We do something like this. (once dissloved risk is much lesser as dusting is the worst part)

1. Weighing/dissolving is performed in a "high" risk room with a air lock. Technicians swiths clothes and uses mechanical air breathers.
Once dissolved the sample is carried out to normal LC after cleaning outsides of vials etc.

LC vials and mobile phases are collected and handled/destroyed by external enviormental acredited company.

2. Depend on substance, so case by case. Consider decticating glassware if possible, manual washing procedures before normal washing. But perhaps better safty to wash manually and destroy if few samples.

3. As mentioned above, an enviromental acredited Waste company could handle it.

[Peter Apps]

Hi Terry

Among the first few requirements of all the QC systems I have come across is something along the lines of "staff will be suitably trained and experienced".

So before you draw up the EHS procedures you need some training to compensate for your lack of experience. It is a good thing that you already recognise that you need some expert inputs on this.

And of course the EHS procedure will need to require that whoever puts it into practise has been suitably trained. Toxic chemicals are not a good area to learn by experience.

Peter

[HW Mueller]

On the other hand it is not so easy to find chemicals that are less toxic than Pt comps. What sort of people ask others to do work without training? This seems to become the rule, judging from recent questions.

[DR]

We weigh out powder form OEB2 and higher level items in laminar flow balance enclosures. Once we've dissolved them in something, there's sunstantially less risk of ingestion, aspiration etc. so they are handled pretty well as you would normal solvents & samples.

For powder containers (bulk or standard vials), double packaging is the rule, packages are not opened except in the containment hoods, for dispensing production quantities of powders and working with powder intermediates, we suit up and use supplied air or respirators in special rooms.

[Bruce Hamilton]

Most regulators expect organisations to have safety programmes in place that require an " approval to use/manufacture" release before containers are released to locations. That also covers training.

Generally, the very first step is a risk assessment. That determines several outcomes, because it establishes the hazards and guideline occupational exposure values, as well as resources and training..

As many platinum compounds are also sensitisers, there are stringent safety guidelines already available for pharmacy/hospital dispensing of those compounds..

One obvious effect is that standard protective airflow cabinets etc. may become contaminated and have to be decontaminated or destroyed, especially if the compound is a sensitizer.

Some steps I've followed for larger quantities of cytotoxins ( with mouse LD50 of ~100ug / kg ) include confirming:-
1. You can detect spills/residues down to acceptable concentrations ( ng/swab is typical ).
2. Your decontamination protocol is effective ( if not, then you have to identify the contaminated material, and dispose of it as cytotoxic waste - for example we had to treat ours separately to other medical/chemical wastes - exporting to an approved incineration facility in Europe.
3. What the guideline occupational exposure values will be, eg x ng/m3. What unique labelling all containers will carry.
4. What are the medical indications of exposure.
5. Who can work with the compound - eg females of childbearing age may be excluded.
6. Locations that are unsafe - eg obvious one is nmr where tube break can release aerosols.
7. What regulatory agencies may have to be informed.
etc.etc.

I'm very surprised you are expected to set up systems for such toxins without having been through a risk assessment, and access to appropriate knowledge of dispensing systems.

The obvious step is to minimise quantities, have restricted areas and access whereever th toxin is present, and to use suitable containment ( usually double ) and PPE. Note that inappropriate PPE can be more hazardous than adequate PPE - you become clumsy and knock containers over, and airlines can catch on all sorts of items.

There is a huge amount of literature out there for handling cytotoxins in the medical environment eg cancer treatment, and there are special precautions - such as traps to ensure dust extraction systems are not contaminated. Cytocabinets are usually used - they have HEPA filters on inlet and outlet and traps on outlet.

Many regulators will have requirements for handling such compounds, and "research exemptions" don't mitigate the responsibility for safe working practices.

Note that many toxin solutions can readily travel through the skin and some PPE, so powders are not the only hazard, and PPE has to match the forms of the toxin - risk assessment should identify these issues..

In reality, I'm very loathe to give you any detailed advice, because your organisation should have health and safety protocols in place to ensure that appropriate information is available, and that procedures are prepared by knowledgeable personnel. You should ask for that resource to be made available.

Bruce Hamilton

[Terry]

Hey guys,

Thank you so much for all your input, I really appreciate that.

The company I am working in is at the very beginning stage. Our lab building is still under construction.

As I was told by my boss a couple of minutes ago,
EHS training by the EHS department is right on the schedule. Probably I will be qualified to prepare QC EHS procedures after that.

I was also told that personal protectitve equipments (PPE), such as mask, goggle, containment room, gloves, would be in place.

We would have enough resources, with proper training, I think I could propose QC specific EHS procedures.

I still have a question about the validation of decontamination/spill clean-up procedures:

Is it something like cleaning validation?

Terry

[Bruce Hamilton]

The cleaning validation protocols are a reasonable starting point, however these protocols are established AFTER the risk assessment has established safe GOES ( Guideline Occupational Exposure standards ).

In my experience the GOES establishes far lower limits than cleaning validation calculations will.

The cleaning validation calculations will also be necessary for any facilities that are going to be reused - especially for less toxic
compounds ( detection limits will be lower ).

Ensure that your safety protocols are checked by a qualified Industrial Occupational safety expert - we used specialist consultants..

Bruce Hamilton

[Terry]

I got it.

Thanks, Bruce.

Terry

[freemab]

I suggest that before anyone work with highly toxic substances, he try working with dyestuffs. Try weighing out a pH indicator dye, or some other readily available material. Do this with white paper in the balance hood. Continue at least through the preparation of the first solution.

Now look at yourself, your gloves, the balance, the hood, and the paper in the hood. I'll be the first time anyone does this, he'll find color in at least one of those places. Worse, he may find it on his skin.

It's quite sobering and is a very good exercise for that reason.

[HW Mueller]

Chances are that the dye is more dangerous than the Pt compound, or whatever.

[freemab]

Mueller -

That is a totally unreasonable assumption and contributes nothing to this discussion.

The original post called this Pt compound "highly toxic," which is a fairly extreme toxicity (unfortunately applying to many materials we must handle in the lab). In one lab I worked in, we could not even begin work with a compound labeled "highly toxic" without first thoroughly assessing the hazards of all operations we needed to conduct, and having management sign off on the "job hazard analysis."

Yes, dyes CAN be hazardous too. But all workers should know what an MSDS is and how to determine from that the hazard of a known compound.

There are many dyes that are not hazardous, or scarcely so. Some of these are listed as "irritants". It is this relatively safe class of dyes that I would suggest for a test like this.

[HW Mueller]

What I am trying to say is that all this fuzz about toxic chemicals has the smell of unprofessionality. A chemist has learned to handle these, otherwise he is not a chemist.

[Bruce Hamilton]

Hans,

My issue is that, at least here in NZ, the employer or institution has full responsibility for ensuring relevant safety information and resources are available, includes specialist experts, for all workplace hazards.

I also doubt that many chemists can even locate and identify the relevant toxicity information ( especially for novel compounds ), much less perform the calculations necessary to establish safe occupational exposures and identify the most appropriate PPE and containment. Not many chemists routinely work with cytocabinets.

Down here, chemists are not multi-skilled, hence organisations must provide access to specialist experts to help ascertain hazards and quantify risks. I would expect my institution to provide all the information before working with cytotoxins, chemical/biological warfare agents, radiochemicals, etc.,

Once the hazards have been identified, and the resources provided, the workers have responsibilities to adhere to all agreed protocols, otherwise instant dismissal is an option.

For example, I've worked on several cytotoxin programmes where females of child-bearing age have been excluded from working with any quantity ( even ng ) of the chemicals, and all staff have to undergo special medical examination for any symptoms every few months.

Those decision were made by medial staff and industrial hygienists, not chemists. If the institution had not provided those rules, it's quite likely the chemist and managers would have just continued on.....

I doubt that few chemists would suggest that Karen Wetterhahn was not a oustanding chemist, but using the wrong glove material was fatal.

From another place and time....
" A review of death certificates of members of the Royal Institute of
Chemistry who died between 1965-1975, indicated elevated numbers
cancers, especially lymphomas.

A subsequent review of deaths between 1965-1989 confirmed the increase in lymphatic and hematopoietic cancers, in particular leukemias. There was also increased mortality from some gastrointestinal cancers, cancers of the duodenum and kidney, some skin cancers, mental disorders, and diseases of the nervous system.

A review of the cause of death for 3637 members of the American Chemical Society who died 1948-1967 revealed that chemists die at unusually high rates from suicide, cancer of the pancreas, and cancers of the lymph system (malignant lymphomas).

The study indicated an increased death rate for working age male chemists ( 444 deaths ), when compared to non-chemist professionals of the same age ( 354 expected ) with approx 50% of excess deaths attributed to pancreatic cancer. Older chemists ( 65+ ) had unusually high rates of leukemia, malignant lymphoma, and pancreatic cancer."

There are old chemists and bold chemists, but not many old and bold chemists.

Bruce Hamilton

[HW Mueller]

If people used their sound scientific judgment and experience there would hardly be statistics like that. Rules are ok to try the prevention of criminal acts and that sort of thing. My comments clearly go in the direction to do better than the rules demand.