Risk Managing Through The Void Of ATMP Visible Particle Guidance

A conversation between Diana Colleluori at Biologics Consulting and Life Science Connect's Jon O'Connell

A visible particle control strategy gap anywhere along the production line and up until infusion at the patient's bedside can trigger a clinical hold. Regulators expect a clear and rational explanation for visible particle control even when the drug itself looks like it might be a contaminant.

Unlike clear injectable solutions, many cell-containing products are turbid, short-lived, and difficult to inspect using standards written largely for conventional parenteral medicines.

Current guidance, including USP General Chapters <790> and <1790>, provide important expectations for visible particulate control, but they do not offer a straightforward playbook for products in which particles may be inherent to the therapy itself.

Diana Colleluori, a principal CMC consultant at Biologics Consulting Group, has been thinking about how sponsors can use risk assessments, material controls, visual standards, and in-use compatibility studies to build defensible particulate control strategies. We met up with her at Cambridge Healthtech Institute's Bioprocessing Summit where she filled us in. Our interview has been edited for clarity.

Can you talk more broadly about the origins of visible particles and why it is important to ID them?

Colleluori: There are generally three different contributors to particles or particulates in drug product formulations. Some are inherent, which occurs in a cell therapy. You would expect to see particles present. And the same is true in other gene-modified cell therapies or gene therapies where you have lipid nanoparticles and things like that. So, there are products in this space where particles would be expected to be present. The ones that we're most concerned about are the intrinsic and extrinsic particulates. Intrinsic particles would be something from within your process. You're maybe seeing glass fragments, metal sheared fragments, sometimes perhaps some plastic. These are particulates you don't want to be present in your product, but you can determine the root cause of where it's coming from within your process. The extrinsic particulates are probably the worst of all; it might be hair, fibers, paint chips – things that are outside of your process that somehow got into your product. Being able to identify visible particles or particulates in your product is important so that you can determine where they’re coming from and then put mitigation in place to either remove them or minimize the chance that they would be present in your product.

With intrinsic particles, at least you know that the particles are coming from somewhere within your process. If you have hair or something from the outside environment, that's indicative of a gap.

Colleluori: A lot of cell therapy processes, for example, do have open processing. It may be single system, but it may not be fully closed. So, it is possible to get something extrinsic into your final product. That's the worst case, but it also would help you figure out the parts of your process that bring the most risk so you can fix the process steps that are leading to something like that happening. And I wouldn't say that it's incredibly common to have extrinsic. I think the problem in talking about cell-containing products in particular is that it's very difficult to do visual inspection of a cell therapy for lots of different reasons. They have short shelf lives. They are turbid or opaque in some way. So, being able to do 100% visual inspection of a cell-containing product is challenging in and of itself. And then to be able to actually see something that should not be there is an added challenge.

USP <790> and <1790> are not explicitly written for turbid or partially opaque solutions. How do guidelines address that particular challenge?

Colleluori: I don't think that they do. Currently, there really is no clear guidance on how to handle products like cell therapies. What I have seen sponsors do is create a standard of what their product is expected to look like visually.

And then if there are known contributors of intrinsic or extrinsic particles in their product, they also have standards of what that would look like when an operator is doing a visual inspection, so they know what should be there and what should not be there.

You have a case study from one of your clients. Can you describe the problem and how they addressed it?

Colleluori: Client X had a cell therapy product that they intended to deliver intrathecally, which is injection directly into the cerebral spinal fluid. Obviously, there is a huge safety risk there. And for the most part, these are single-use for single-patient products.

And the complication of the route of administration in this particular case was the biggest issue. You need to obviously do your visual inspection of your final product, which is turbid. But then you also need to do in-use compatibility with your product in the drug delivery system for administration.

And this is where my client got into some trouble. They came to us after they were put on clinical hold because they did not demonstrate that their product was free from visible or sub-visible particulates before and after being pushed through the delivery device.

To be released from the clinical hold, they needed to come up with a study to prove that their product has no visible foreign particles in it but also that  the delivery system – the syringe and infusion kit that they're using – doesn't introduce any additional particles, visual or sub-visible.

How do you test sub-visible particles in a cell therapy? The answer does not lie in any guidance; there is none. There's no chapter out there for how to handle this.

So, we suggested they do a sham run of the delivery device with their formulation buffer minus cells to prove that the delivery device did not introduce any additional visible or sub-visible particles into the final product. That was essentially how we were able to prove, minus the cells, that the compatibility was acceptable for intrathecal administration.

In the case of your client, there were no visible particles detected, but regulators were simply saying, 'You haven't shown us that you're controlling for particles. You haven't proved it'?

Colleluori: Yes … and it set them back several months because you have to then design a study, execute the study, and report on the study.

Hopefully, everything works out in your favor and then you can submit that back to the agency to get their blessing to release you from clinical hold. It's challenging when there are no clear guidelines, but I think there are cases like this where there may never be an exact guideline for every situation.

Some of it's going to have to be using your smarts, the scientific rationale and justification, doing risk assessments, having a control strategy in place for where particles could come into the process — from the beginning of manufacturing all the way through to something being injected into a patient.

Do you have any pointers on developing that control strategy in relation to your case study?

Colleluori: A risk assessment for particulates, whether visible or sub-visible, should be performed to identify what is touching your product. Having a control strategy around the raw materials, consumables, and ancillary materials that are touching your product that go through to the final drug product is really important.

I'm very big on raw material control strategies, which aren't just buffers and media but also the consumables, the plastics, all the things that your product is touching. There could be particles in those. Having a control strategy around where you're purchasing those materials and ensuring that you're getting the best quality materials to go into your process or your final product is pretty critical.

I would say once you have a good process and you're minimizing your risk of introducing particles into your product that should not be there, you try to lock that down as early as possible because any changes down the road could lead you to reassess the risk of introducing something new into your process.

As far as Client X is concerned, I think part of the problem was that they were ill-prepared for needing to do the in-use compatibility study. That was one issue. But also knowing that the administration of the product is also something they have to control — not just getting to your final bag, freezing that bag, and then handing it off. What happens after that has to be part of the control strategy as well, including controlling what materials are being used for infusion or injection, whatever those devices may be. Whatever your cell therapy is touching could introduce intrinsic or extrinsic particles to your final product.

About The Expert:

Diana Colleluori, Ph.D., MBA, is a principal CMC consultant at Biologics Consulting Group Inc. She received her Ph.D. in biochemistry from Temple University School of Medicine and MBA from the University of the Sciences in Philadelphia. She has over 20 years of industry experience in CMC and quality control. Her experience includes technical and executive roles in biologics product development, from pre-IND to commercial stages. She has direct global experience developing numerous biological products, including monoclonal antibodies, vaccines, and cell and gene therapies.