Formerly known as the California Separation Science Society, the CASSS organization has maintained a close relationship with BioProcess International since its inaugural year. In particular, the CMC Strategy Forum series began the same year that BPI’s original staff joined Informa to develop a new international trade publication covering biopharmaceutical development and manufacturing. Beginning with our February 2004 issue, BPI has been proud to publish dozens of reports from this influential series of meetings over the years. Their success around the world — with similar events now held regularly in Asia, Europe, and Latin America — demonstrates the benefits of providing an open forum for scientific and technical dialogue that provides the basis for regulatory evolution.

Early in 2022, CASSS awarded distinguished fellowships to BPI editorial advisor Nadine M. Ritter (president and analytical advisor at Global Biotech Experts, LLC) and CMC Strategy Forum cofounder Mark A. Schenerman (president of CMC Biotech-MAS Consulting, adjunct professor of pharmacology and molecular medicines at Johns Hopkins University, and professor of practice in biotechnology at the University of Maryland in Baltimore). This lifetime appointment is bestowed on <1% of CASSS members. In announcing the honor, board president Julia Edwards (vice president of biologics and pharma technical regulatory at Genentech, a member of the Roche group) noted “the passion of both individuals, who have led many volunteer initiatives over the past quarter century.” She also recognized Ritter’s status as the first female board member, vice president, and president — and now the first female distinguished fellow.

Ritter’s analytical background is well known to BPI readers and conference attendees, with BioReliance, Abbott Diagnostics, and the American Red Cross listed on her resume. Just as familiar to our audience is Schenerman, who spent over 24 years between MedImmune and Novavax before moving into academia and consulting. The recent CASSS announcement prompted me to bring them together for a chat about our past couple decades.

A Shared History
Scott: Earlier this year, you were both named as distinguished fellows in the CASSS organization. What does that mean to you?

Schenerman: It means a lot to me. I began participating in CASSS activities back in 1993 with the “CE Pharm Conference” focused on capillary electrophoresis applications. The US Food and Drug Administration’s (FDA’s) well-characterized biologicals concept began around then, and right after that is when CASSS started the Well-Characterized Biotechnology Products (WCBP) conference series. I have participated in every WCBP Conference except one in 2000.

I led the second CMC Strategy Forum, which was on monoclonal antibodies (MAbs) and held in 2004. I cochaired the WCBP Conference in 2011, and I have been cochair of four other CMC Strategy Forum meetings. The CASSS Bioassays symposium series began with a strategy forum that I put together with Tony Mire-Sluis. (Editor’ Note: Then with Amgen and just as active with CASSS, Anthony Mire-Sluis is now head of global quality for AstraZeneca and another frequent contributor to BPI.) I also cochaired a CMC Strategy Forum on live-virus vaccines and gene therapy products, one on reference standards, one on raw materials, and one on higher-order structure of proteins (which also became a regular CASSS meeting).

After chairing a one-day meeting on immunogenicity at MedImmune, I initiated the DC Area discussion group on that topic. Currently, I’m cochair of the Academic Outreach Committee. I serve as liaison for the CASSS–Johns Hopkins mentoring partnership, and I recently initiated a new CASSS consultants network. Being a distinguished fellow means to me that I am carrying on with CASSS’s mission, spreading the word about CASSS, and expanding the network.

Ritter: I don’t go back as far as Mark does. I attended that first WCBP meeting. I felt like Alice in Wonderland at the time, as a new scientist with Abbott after 10 years in academic R&D. I was surrounded by all these people whose names I had known from influential publications (particularly on the regulatory side, because people in industry didn’t publish as much back then), and I was star-struck just to be watching them. I remember being in awe of Tom Layloff because I’d read his method validation papers.

I got “hooked” by CASSS from there. Like Mark, I worked on various program committees. In 2002, seven of us initiated the CMC Strategy Forum series. Over the years I took on increasing amounts of responsibility, including lead- or coauthoring 10 CMC Strategy Forum reports and serving as scribe for many others.

Although I was the first woman elected to the board, other women were added soon after. There hadn’t been any malicious exclusion before then; I think it was just the recognition that “Hey, half the faces in the audience are female, and none of them are on the board, so let’s fix that.”

When I took over as president of the board in January 2020, I was full of ideas. But with COVID-19, I spent my entire two-year term working with the board and staff to make sure CASSS could adapt and continue. We succeeded, but my term seemed to go by in the blink of an eye.

When both of our board terms expired in 2022, Mark and I each received the Distinguished Fellow award, and that means a lot. Like other CASSS members, we’ve done years of pro bono work. It’s been a passion to communicate and build bridges. This is the organization to which I’ve devoted most of my career volunteer time. I choose CASSS because it’s small nd intimate in terms of the relationships that you build, and because the contributions you can make are very direct. So it means a lot to me that my peers acknowledged my contributions over the past 25 years.

Scott: I’ve noticed a real collegiality in the CASSS meetings I’ve attended. You can talk to anyone.

Ritter: That’s exactly what CASSS was designed for. My understanding is that in 1996, the FDA Center for Biologics Evaluation and Research (CBER) wanted scientists from this new recombinant biologics industry to have a means by which to exchange ideas with regulators so that together they could design scientifically-relevant regulatory guidance.

CASSS is doing it again now with cell and gene therapy. Last week’s meeting was a good example. (Editor’s Note: The Cell and Gene Therapy Products meeting was held in Arlington, VA, on 6–8 June 2022.) We’re all trying to figure out the best CMC strategies for these complex biologic modalities — exactly like we did in the late 1990s and early 2000s, when we were trying to feel our way into what’s appropriate for MAbs. Now, guidance for them is well established and proven successful.

Scott: So the forum series was partly driven by regulatory people?

Ritter: Yes, the founding committee included Tony Mire-Sluis (then at CBER, which had not yet split into CDER and CBER), and every forum program has an FDA cochair and FDA speakers. (Editor’s Note: See the box above-right for the full membership of that founding committee.)

Schenerman: The first CMC Strategy Forum was “Strategies to Establish Release Specifications for Peptide Maps” on 19 September 2002 at Northeastern University. John Dougherty (then with Eli Lilly and Company, now retired) and Rohin Mhatre (Biogen) created the format and pulled off that first one. The idea was to pick a specific industry-wide problem and focus on it in depth over a couple days. A scribe — initially Tony or Nadine — took detailed notes in real-time, then presented an oral summary at the end of the Forum. The speakers generate a manuscript for open-access publication, and that’s how BPI got involved.

Technologies Lead the Way
Scott: Let’s talk about some of those early topics and how things have progressed over the past 20 years.Is structural characterization of MAbs straightforward now?

Ritter: We resolved analytical issues that were considered difficult back then. The industry got as far as it could with the tools we had, licensed a bunch of great products, and settled back. Some companies even closed their analytical development groups. But when biosimilars came along, they upped the ante of analytical capabilities. Biosimilars ushered in a whole new wave of analytics.

Schenerman: Yes, that’s true. And structural characterization capabilities have evolved with the available instrumentation. In 2003, mass spectrometry (MS) was considered to be just for academic settings. These were million-dollar instruments, some actually built in academic laboratories and only run on site. Now MS is an everyday laboratory tool. In fact, some companies use it in routine quality control. That evolution has enabled the industry to characterize protein products much more thoroughly and rapidly, with all the associated posttranslational modifications.

Biophysical analysis methods also have evolved dramatically. In 2003, it would have been laughable to think that you could use nuclear magnetic resonance (NMR) spectroscopy for MAbs. And yet, that’s the reality now. It’s amazing what capabilities we have: We can discriminate almost to the atomic level for very large proteins.

Ritter: In my first foray into consulting, which I did between jobs, I named my company NMR Biotech based on my initials. I used to get calls about nuclear magnetic resonance, and I was like, “Who would do NMR on a protein?” And now that’s a standard characterization tool.

Scott: But test-method qualification — another early CMC Forum topic — hasn’t advanced much?

Ritter: Don’t even get me started! I chaired that forum in 2003, and as of today we still have no codified definition, even though biologics regulators still use the term all the time. In 2003, we asked what a method qualification exercise encompasses. Logistically, how does it differ from method validation? How do you document it, who reviews it, and who approves it? Back then, we teased out a few principles that seemed consistent among regulatory and industry thinking, and those are in the paper we published. I was certain then that we’d have it captured in a guidance by now — but nope, not yet. In fact, guidance documents written in the past 19 years all mention phase-appropriate validation, but only one European Medicines Agency (EMA) guideline offers any clarity on the difference between method-validation expectations for products going into phase 1 and those for coming out of phase 3 (1). New FDA and EMA guidances on CMC for advanced-therapy (cell and gene) products use the term qualified methods with no indication on how that differs from validation.

Scott: Was the 2003 forum a step in the right direction?

Ritter: It was, yes. The FDA representatives told us in that forum that qualification is needed for methods used only in characterization or comparability studies and that quality control (QC) methods used in phase 1 would evolve into validated methods later on.

With forums in 2018 and 2019, we revisited the concept in search of better clarity and alignment on phase-appropriate method validation and method qualification. More regulatory agencies participated in those forums, and discussions highlighted a clearer line between qualified methods run in R&D (which never need to be validated for good manufacturing practice (GMP) but must be proven scientifically sound and suitable for their intended use) and QC methods that are subject to phase-appropriate validation as GMP requirements increase during development. But many companies continue to use the term qualification for early phase QC methods, as do the FDA and EMA guidances for advanced-therapy products.

The next CMC Strategy Forum paper on my docket summarizes those meetings. Even though I’m obviously way behind in my deadline — COVID-19 has kept us all very busy over the past two years — it is still highly valuable information to publish.

Moving Things Along
Scott: Two of the other topics I wanted to touch on may be related: lot-release testing and speeding up development. A lot of people at the forums have been hopeful about the possibility of real-time release testing (RTRT). And speed seems to have become a key theme overall.

Schenerman: RTRT is realistic for [protein] biologicals, but we’ll see more of it with cell therapies. It’s the way we need to operate when patients require very fast turnaround of treatments. When you have to take cells from a patient and transport them and treat them, then bring them back and reinfuse them, the longer that process takes, the more cells will die along the way. So to maximize the benefit to patients, turnaround has to be very fast. I imagine that the cell therapies on the market already include some RTRT testing.

Ritter: Although the speed of RTRT is important for highly labile materials such as cell products, sometimes I hear it invoked like a “magic wand” to eliminate all QC release and stability testing. Speed of test results is always desirable, but it may not be technically necessary based on the timing of process steps. And there are many cases in which forward processing continues anyway, pending test results. But the final decision for lot release is based on QC specification testing of drug substance or drug product.

So having test results faster and farther upstream in the process — with RTRT and process analytical technologies (PAT) — creates a situation in which, if a process step fails a control specification, then it should be “game over” for that batch. You can’t have it both ways. When using PAT/RTRT as a control point in lieu of final QC testing for a given attribute, if a batch fails at that checkpoint, then you can’t just go ahead and process that batch further and invoke QC release testing to find out what happened (in an effort to override the out-of-specification result that occurred upstream). At one CMC Forum in Latin America, a speaker presented a great case study that directly correlated posttranslational modifications (PTMs) measured at the upstream level with a product quality attribute in the drug substance. So the developers proposed putting that checkpoint upstream instead of doing PTM testing later in QC. And I asked him, “Does that mean that if you fail the upstream PTM checkpoint, then the batch dies?” He said, “That’s the way it should be.”

Scott: Our most recent forum paper (May 2022) is on accelerated regulatory pathways around the world. Why is everybody obsessed with speed now?

Schenerman: It was important even before COVID-19 because of the drive to cure oncology diseases in particular. But I think the pandemic has shown what’s possible. It showed the industry that it can do things extremely rapidly. The life cycle of a vaccine before COVID-19 took 10 years to start clinical trials and get through to approval. For the pandemic, basically, it was four to six months.

Ritter: COVID-19 should not be used as a model for how we can develop drugs because, in this case, the only alternative was hundreds of thousands of people dying very soon. This required everybody (including the regulators) to clear their schedules and work at an unsustainable pace. Supply chains and manufacturing sites were cannibalized, and people were overworked: analysts and operators, managers, regulators, and inspectors — everyone.

Supply chains were diverted and manufacturing sites were cannibalized. Other lifesaving therapeutics and vaccines were put on hold. To repeat the speed of SARS-CoV-2 vaccines would mean stopping or significantly slowing  the development of everything else.

Finally, billions of dollars were pumped rapidly into the industry to go immediately from R&D to commercial-scale production. Normally project funding is metered out at defined clinical milestones over years. Here, it was zero risk for the producers who were given, more or less, a blank check on day one. With nearly unlimited personnel, materials, facilities, and funding, no quality corners had to be cut. But resources were prevented from supporting anything else. This was the one time in our career when we could ask, “If money was no object, what could we do?” In an extreme public safety emergency, we showed what could be done. But that kind of speed absolutely is not sustainable.

Schenerman: I agree 100%. Lessons have been learned, and that learning can be applied going forward, but resources have to be freed up to support other indications or other clinical trials will be delayed.

Ritter: One month after pandemic lockdowns started, my younger brother was diagnosed with aggressive cholangiocracinoma. He was two weeks away from starting a clinical trial with a dual MAb cocktail when he developed ascites and cachexia that disqualified him for the trial. He died six weeks later. So I personally know the risks of putting other disease programs on hold. I’ve had people in management ask, “If we can go that fast for COVID-19, then how can we go that fast for our product?” And I say, “First, create an existential global threat, then write a blank check . . .”

Scott: It brings us back to the adage about prioritizing either speed, quality, or money, right? If you can just spend with impunity, then you can do it both fast and well.

Ritter: Even with unlimited money, we couldn’t have achieved that level of speed if industry and regulators hadn’t joined forces and opened lines of communications around the world.

What we can learn from this is the benefit of cooperative discussions with regulators. They aren’t there to punish you; their goal is to get the information they need to make the right decision on your product. Another benefit has been transparency within and across companies. Information was shared at an unprecedented speed and in great detail. CMC data for COVID-19 vaccines were shared at meetings and in open-access publications, partly because it was publicly funded work. I would hope that such a level of communication can continue — at least to an extent that’s acceptable for confidentiality and proprietary matters.

Scott: Right. We all have family and friends — and ourselves — who are in the same sort of situations.

Ritter: In industry, if we make an erroneous decision in our job, then we might get called on the carpet or, in the worst-case scenario, we might get fired. That’s unlike regulators. Congress is not going to call us to testify about a bad day when we made a poor decision because we didn’t think to ask the right question or get enough data. Most people I know in the industry respect regulatory authorities; I just hope that that we remember how efficient it is when we all work toward the same goal. Their job is to protect people; let’s get them all the CMC data they need to help them do that.

Scott: Barb Immel was a consultant who used to write a column for BioPharm when I worked there, and she beat that drum over and over again. I got to edit her great series showing how different regulations had come about in response to things that happened — how all of these exist for a reason.

Ritter: Yes, that’s right.

Scott: We hear people complaining about the baby-formula shortage, and they’re blaming the FDA.

Ritter: I just want to say, “You realize that babies died, and the FDA had to investigate why, right?”

A Larger World
Scott: Over the years, the forum series has expanded to other countries. How did that come about? Are those meetings different somehow, and do you think we might get papers from them someday?

Ritter: In launching CMC Strategy Forums in other regions, we learned that the administrative structure of their regulatory bodies is a factor in authoring publications. FDA representatives participating in our forums are all in the same agency, so administrative approval for publication comes from a single entity. But in Europe, each member state has individual authorities that would have to give approval. So it is harder to generate an attributed forum paper the way we do with the US meetings. We still do real-time scribing and present oral summaries at the end of each forum. But those are published just as summaries, with no named authors.

Also, CMC Strategy Forums in other regions have a different format. The original goal was to focus on a single topic, with the senior-most scientists from industry and regulatory hashing that out for a day of uninterrupted discussion. It was meant to be a senior-level strategy discussion. But when it went into Europe, Japan, and elsewhere, they used the established name for more of hybrid event like both the US forums and the WCBP meetings. The events are small (usually fewer than 200 people), with no vendor presence, roundtables, or workshops. But unlike the US CMC Forums, the global programs are longer and cover more than one topic.

Schenerman: Also they are led by regional volunteers rather than us in the United States.

Ritter: And that’s very important. Global CMC Strategy Forums are organized and led by regional industry and regulatory agencies.

Schenerman: For some time, a Global CMC Steering Committee came up with themes that could be addressed around the world. Each regional forum could interpret those themes in its own way.

Ritter: We didn’t want to impose US-centric issues or regulations on global regions that have their own requirements. Only if requested would people in CASSS work with regional regulatory agencies and industry representatives to launch a forum there.

Scott: That’s the most important thing, it seems — that these meetings have strong regulatory presence and participation. It’s not like one person’s there just to do a presentation and leave.

Ritter: A major goal of CASSS has been facilitating meaningful regulatory interactions of all types. We’ve learned over the years that when regulators attend CASSS meetings, sometimes it’s the first time they get to meet their counterparts from different agencies. It provides face-to-face communication among individual regulators that otherwise might not happen. We now have receptions at the WCBP meetings just for regulators to meet each other. To share even more CMC issues with them, CASSS started a pilot outreach program to global regulators with access to International Pharmaceutical Quality (IPQ). It was suspended during the pandemic because of resource issues, but I hope we can resume and expand it soon.

Schenerman: People don’t realize the work that goes on behind the scenes just to get these meetings off the ground — the struggles John Dougherty had to go through just to get the European regulators to come together.

At the first European CMC Strategy Forum, nobody wanted to say anything. None of the regulators wanted to get up and talk because they were afraid that whatever they said personally would be taken as what their organization represented. Then one fellow from the Paul-Ehrlich Institute stood up and stated his opinion on some topic. After that, you could feel the tension in the room go down, and people were more comfortable talking. The same thing happened in Japan. At the first forum there, it was all US people talking at first, and when eventually a local person did stand up and say something, that broke the ice.

Scott: A lot of meetings go that way: Somebody has to get people talking.

Schenerman: People like John Dougherty, Nadine, and Wasim Nashabeh (Roche) are the catalysts who make that happen. Once it starts, then discussion self perpetuates.

A Vision for the Future
Scott: Do we have a sense of where things are going or what’s next?

Ritter: I believe that the European region now has enough companies and regulatory agencies involved in CASSS that we should create a European version of a full WCBP conference with its highly diverse program of plenaries, workshops, posters, roundtables, and so on. Just like in the United States, industry and regulatory agencies could send their rising scientists to engage at multiple levels. Vendors would have full WCBP-level visibility in Europe. I don’t think we should worry about “cannibalizing” WCBP-US, which was bursting at the seams before COVID-19.

That way, each EU CMC Strategy Forum programs could focus on a single challenging issue with senior-level industry and regulatory scientists. We could let it continue to move around different countries. For me, visiting new locations has been a great bonus for attending EU CMC Forums.

I think that having two regional WCBP meetings at opposite times of the year — with the option for people who can’t travel to join virtually — would serve the needs of both regions very well. It would help with our succession plans. For decades, Mark has championed the cause of mentoring and bringing in students. He established it at WCBP, and CASSS has extraordinary regional discussion groups in which students can participate. But CMC “newbies” in Europe should have the opportunity to engage in WCBP-like interactions and exposure to leaders in the field. They deserve that Alice-in-Wonderland experience that I had.

Scott: It seems that the CMC Strategy Forums and BPI have chronicled the progress of quality by design (QbD) in biopharmaceutical development and manufacturing. Where are we now, and where are we going with that?

Ritter: A number of CMC forums have been dedicated to discussions of QbD, and I think they have helped the industry quite a lot. When regulators first rolled out the concept, it was pretty vague. People wondered what the agency was looking for, exactly. It took a lot of discussion, much of which occurred in our forums,­ to come up with tangible actions that people could execute. Those discussions developed into mock QbD case studies. Many senior people who knew each other through CASSS worked on the “A-MAb” QbD case study (2). Then they generated an “A-Vax” QbD case study (3). Using their model, there’s a now a gene therapy case study (4). And an “A-Cell” case study is on the horizon.

Schenerman: CMC Strategy Forums have enabled people to build those networks and make those case studies successful.

Ritter: I give Mark a lot of credit here because he led the charge for developing a working model for QbD with MAbs. He worked hard to get that going, and it set a benchmark for the other case studies with the level of detail that the team was able to achieve. It was a lot of work for Mark and the team.

Scott: It’s had such a strong presence in the industry ever since it came out.

Ritter: Not only did it launch other modality case studies for QbD, but the BioPhorum group actually launched off of A-Mab for the continued process verification (CPV) model (5). The BioPhorum publication stated that the A-MAb case study was the predicate fictitious archetype on which the CPV model is built.

Schenerman: These are all tremendous teaching tools, and I use them in my course at the University of Maryland.

Scott: So with the benefit of hindsight, let’s consider these questions posed in a 2009 CMC Strategy Forum report (6): Do companies see any regulatory relief based on design-space data? Has QbD been a worthwhile effort?

Schenerman: Regulatory relief is in the eye of the beholder, so I say yes —but not in the sense of “design space.” People were focused on design space early on, but that’s just part of it. Implementation of a QbD approach has enabled the industry to identify and do the right testing at the right times. There’s less of a focus on end-product testing and more of a broad view that all aspects of testing contribute to the overall quality of a product.

Scott: That makes sense. It seems to have enabled a lot of the progress we’ve seen in speeding things up and working efficiently. Has QbD been more of an enabler than just an exercise you have to go through?

Schenerman: Yes. If you compare how MAbs were tested 20 years ago with how they’re tested now — even biosimilar makers have implemented a QbD approach — then you’ll see that it’s a refined control strategy now.

Ritter: QbD has provided the rationale and data sets needed for us to approach process control more thoughtfully. The old concept of “the process is the product” hasn’t gone away. QbD’s value is in providing enough understanding of the variables for each unit operation that you can see which “levers” contribute to which elements of product quality. So you end up with a much more robust control strategy than if you were just hunting and pecking or following a formula.

But I don’t think it makes product development go faster. In my own experience, most companies developing new products or biosimilar products want to get to market as fast as they can. And believe me, patients who need these products want that too. Companies often don’t have the time or resources to invest in doing a lot of QbD early on, so they use the traditional approach. Most will to use it after commercialization when they have more time and money to build out process understanding and continued process verification (CPV). They leverage that QbD/CPV work for future products that are based on the same process platform.

This year the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is introducing analytical QbD. It has many things in common with process QbD but one very significant difference. Similar to process QbD is the concept of scientifically optimizing the way a method functions and generating substantial performance data to establish robust operational ranges for a test procedure. Analytical QbD produces sufficient data to support making changes in the method procedure within its design space without prior regulatory approval — just like process QbD data supports making changes in unit operations within a design space. But the draft of ICHQ14 currently states that analytical QbD goes a step further, and I’m not sure how this will be received by regulators for biological products (7). It is the idea that analytical QbD could be used between methods: So if I design analytical QbD around a target product quality attribute, then I don’t have to specify in my marketing application which method technology I will use to measure that attriute in QC release or stability specifications. From my own experience, I have some concerns about that. It seems like the counterpart in process QbD would be, “I’m going to develop three different downstream unit operations, and QbD design space will allow them to be interchangeable for any batch I make.” I can see the value of the operational flexibility, but in some situations the decision to switch could be made to cover up a problem.

Scott: It shouldn’t be a matter of picking the one that gives you the answer you want.

Ritter: Exactly. And my concern is that different methods have different sensitivities and specificities — that is why we call them “orthogonal” — for measuring biological products. Certainly we hope this QbD analtyical interchangeability concept would be used honorably, but there’s no way to truly guarantee that it won’t be abused. If you set specification limits for a product attribute with a more sensitive method, then switch to a less sensitive method or routine testing, you will never fail a batch. That’s why for biologics our QC specification criteria are linked to measurement methods. A company with a strong product quality specification and sound ethics deserves regulatory relief. But consider what Boeing internal oversight gave us with the 757-Max jetliner. Good people can be forced to make bad decisions under management pressure. As a patient, that is my worry.

Scott: So the industry has to be careful about applying this exceptional circumstance of the past couple of years to make any general rules.

Ritter: Yes, exactly right. We also need to be careful when we put out these guidance documents. They’re supposed to cover all kinds of product modalities, both chemical and biological, and all kinds of different companies. It has to apply for companies that have been around for 100 years, with legacy products and their associated data, with experienced management and senior scientists — as well as for newer “virtual” companies with none of those things. Start-ups have less data to draw on, but the rules have to apply to everyone because they are all treating human patients. And some people don’t read the fine print, or they only see what they want to see.

References
1 EMA/CHMP/BWP/534898/2008 Rev 2. Requirements for Quality Documentation Concerning Biological Investigational Medicinal Products in Clinical Trials. EMA: Amsterdam, 28 January 2022; https://www.ema.europa.eu/documents/scientific-guideline/guideline-requirements-quality-documentation-concerning-biological-investigational-medicinal_en-2.pdf.

2 CMC Biotech Working Group. A-Mab: A Case Study in Bioprocess Development. ISPE: North Bethesda, MD, 30 October 2009: https://ispe.org/publications/guidance-documents/a-mab-case-study-in-bioprocess-development.

3 CMC-Vaccines Working Group. A-VAX: Applying Quality By Design to Vaccines. Parenteral Drug Association: Bethesda, MD, May 2012; https://www.dcvmn.org/IMG/pdf/a-vax-applying-qbd-to-vaccines_2012.pdf.

4 McCormac P, et al. Project A-Gene: A Case Study-Based Approach to Integrating QbD Principles in Gene Therapy CMC Programs. Alliance for Regenerative Medicine: Washington, DC, 2020; https://alliancerm.org/wp-content/uploads/2021/06/ALL-PROJECT-A-GENE-V6-FINAL.pdf.

5 Continued Process Verification: An Industry Position Paper with Example Plan. BioPhorum: London, UK, 2015; https://www.biophorum.com/download/cvp-case-study-interactive-version.

6 Mire-Sluis A, et al. Quality by Design, the Next Phase: Potential Regulatory Implications and Filing of QbD Data. BioProcess Int. 7(1) 2009: 34–42; https://www.casss.org/docs/default-source/cmc-strategy-forum-north-america/cmc-north-america-summary-papers/cmc-summary-paper-cmc-strategy-forum-north-america-summer-2007.pdf?sfvrsn=f863f347_3.

7 ICH Q2(R2)/Q14 EWG. Analytical Procedure Development and Revision of Q2(R1) Analytical Validation. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use: Geneva, Switzerland, 2022; https://database.ich.org/sites/default/files/ICH_Q14_Document_Step2_Guideline_2022_0324.pdf.

Cheryl Scott is cofounder and senior technical editor of BioProcess International, part of Informa Connect Life Sciences; [email protected]; https://www.bioprocessintl.com.