Dr. Krawitz then channeled Votaire stating “Don’t let perfect be the enemy of good”. We all want these methods to be perfect, we want them to be easy and we want them to be a check box. But the methods we’re working with now are not there. When I work with my clients I’m not trying to be perfect, I’m trying to be practical. And what does practical mean? Practical means ensuring product quality and patient safety. My recommendations with HCP’s are meant to ensure those two things. And I don’t always have to have the perfect circumstances in which to do that.

The other thing that came up in the discussion this morning is ‘Does absolute quantitation exist?’. And the answer was it depends on the calibrator. Then the question becomes ‘How was the calibrator calibrated?’. It is hard, and we need to accept, that we’re going to be working with approximations and likely won’t be working with perfect data.

Regulatory Perspective

Nadine Ritter opened the conference with the following statement; “A regulator would rather be burned at the stake than give us a number for what the HCP could be.” I think that’s true! But it’s true for reasons that make scientific sense.

Dr. Ritter also asked ‘Why are we still talking about HCPs?’’

We are, of course, talking about HCPs because our landscape has changed from early biotechnology products. The technology we’re now using and the products we’re making are making the HCP analysis more important and more challenging.

Our North Star for guidance on biotechnology products is still ICHQ6B, (The guidance: SPECIFICATIONS: TEST PROCEDURES AND ACCEPTANCE CRITERIA FOR BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS). This guidance, which is being updated, as we heard from Erika Friedl from the Paul Ehrlich Institut, states “New analytical technology and modifications to existing technology are continually being developed and should be utilized when appropriate”. Sometimes people think ‘why should we do mass spec? It’s not required.’ Well, in a roundabout kind of way, it is. I’ll just say it’s an unwritten rule as Kevin Van Cott, conference producer and U. of Nebraska professor said, but maybe that’s not official.

It took until the third talk of the conference this year to hear “ELISA is still the gold standard for HCP control, but other orthogonal methods, including MS are of increasing importance as part of the overall control strategy.” (We usually get that in the first talk.) You want to really understand the HCP ELISA method that you’re using and the limitations of your method. They all have limitations, all of them. Absolute quantitation of HCPs is hard, especially when working in discovery mode for Mass Spec experiments. You want to clearly explain rationale for HCP risk approach and risk assessment strategy in filings. I believe the concern that we heard from Erika Friedl is that while people are presenting risk assessments, they’re saying ‘well we looked at the top 50 proteins and here’s what we saw’. While that is a legitimate interpretation, why would you stop at 50 and what’s your rational for having done that?

We got an update from the BioPhorum Group as well. They are working on Clinical Risk Assessment for HCPs and there will be a publication coming out from that. I think this is going to be a very important paper for all of us.

Conference Summary

Dr. Krawitz has traditionally given us a summary of the conference as excerpted above. If you can’t attend the conference in person, we recommend that you join the virtual conference and don’t miss the summary talk by Denise! It gives you the opportunity to hear the details, get the feel of the conference and hear about what happened in the interest groups and workshops not available to those listening in from their homes, offices and labs.

The conference had multiple sessions delving deeply into:

• ELISA Development focused on how concentration assignment of the assay calibrator is critical for determining reportable results with an assay. Good coverage is necessary but not sufficient for an HCP immunoassay. As always much discussion about developing antibodies and replacing them in the future. Platform assays were discussed. The bar is still high for demonstrating suitability.
• HCP and Product Stability included case studies for contaminating esterases and polysorbate activity.
• Bioprocessing which highlighted high throughput LC-MS methods and activity-based protein profiling to support process improvements. We also saw the importanc of different DF filters for removing esterases. Also use of a peptide ligand mixture with affinities optimized to remove HCP without impacting product yield or quality.
• HCP Analysis Optimization of proteomic workflow can yield HCP detection sensitivity of analytical flow LC-MS/MS methods comparable to nanoflow
• New USP Chapter 1132.1 will be finalized at the end of 2024 and effective 2025. Long-needed industry HCP standards will be available for industry (proteins, peptides and some cell culture fluid). These can be helpful for a lot but one of the first things that comes to mind is system suitability across labs. To understand if we’re getting comparable performance or the performance that we would expect based on the methods described in the new chapter.
• HCP Challenges
  • If you have an HCP in your product in early-stage clinical development, think and strategize before you panic! Open dialogue with regulators and utilization of a risk-based approach.
  • Orthogonal methods for HCP characterization are critical for less-well characterized systems.
  • HCPs may selectively persist thorough process entangled in HMWS or due to direct product interaction.

In addition to the podium presentations, there were multiple interest groups covering the new USP Chapter, specific new products for HCP ELISA detection, Mass Spectrometry.  Additionally, several posters were available on-line and at the conference, cover topics such as:

• Evaluation of Search Engines for HCP Analysis by Mass Spectrometry
• Case Study on Development of a Platform Process-specific CHO-HCP-ELISA
• Custom Automated CHO HCP ELISA-like Technology for Routine Sample Testing
• Implementation of microfluidics-based immunoassay methods for HCP detection.
• Platform HCP ELISA development for a cell line having a Fut8 knockout
• Development of Platform HCP ELISA for Chicken Embryonic Fibroblasts

Next year, the BEBPA Host Cell Protein Conference is going to be held in Lake Bled, Slovenia. The call for abstracts, titles and topics is out there! If there are things from this meeting that you want to see followed up on, let us know! We want to make sure that the scientific content of the presentations is staying fresh.