Prioritizing Quality Over Everything
By Tyler Menichiello, Chief Editor, Bioprocess Online
Quality is king in biopharma manufacturing, as it should be; impurities and inconsistencies can harm patients. There’s a reason 483 letters make headlines and serve as learning opportunities for the industry, because product quality trumps every other metric in bioprocessing. It’s more important than process performance, efficiency, or cost.
Yet, despite the widely understood importance of quality control in bioprocessing, regulatory violations still happen, even at respected institutions and established manufacturing facilities.
Why?
During a recent episode of “Better Biopharma,” Matveeva joined me discuss the role and importance of quality in an organization, as well as what happens when it’s compromised.
If I learned anything from our conversation, it’s that GMP violations don’t happen intentionally, and certainly not as the result of any one decision. Rather, they occur from a systemic erosion of quality, the culmination of decisions made without quality at the center.
Below are excerpts from the full podcast episode, which you can find here (and wherever you get your podcasts).
The accompanying transcriptions have been edited for clarity.
Maintaining Quality Unit Independence
If you ask Matveeva, the single greatest way to combat this erosion of quality and to avoid compliance failures is by maintaining the independence of a quality unit within an organization. She believes quality teams should operate with autonomy and retain ultimate decision-making authority — authority that cannot be overridden by management.
Essentially, a quality team needs to have teeth, and all decisions made during bioprocessing operations need to be considered in light of their impact on quality.
What does quality unit independence mean in the context of GMP?
Matveeva: GMP is an all-encompassing term that involves things like operations, manufacturing, environmental control, and quality control, as well as various assays and how you obtain your raw materials. All of these and many more are required for GMP, because together they ensure not only regulatory compliance, but continuous quality oversight. That allows you to capture flaws or vulnerabilities in any part of your process and to design controls around those vulnerabilities, which essentially increase the odds, if not guarantees that quality is preserved throughout the life cycle.
If you imagine any phase of manufacturing (Phase 1 through commercial), you have a manufacturing operations facility; you have your supply chain; you have your validation of all facilities, equipment, and processes; you have your training for all qualified personnel; and so on. Ultimately, you’re making a therapy or drug that is supposed to go into a patient, keep them safe, and help them.
It’s very important during every phase of this process that there’s oversight about whether everything is done according to approved written procedures; whether there have been any incidents or deviations from a set process; and whether all quality control assays have been correctly performed and quality attributes met. All of those things guarantee, at various points in the process, that the therapy you’re sending to a patient or putting on the market is designed and produced according to the highest quality and safety standards enforced federally and internationally.
A lot goes into production. There’s so much at stake, and a lot of infrastructure has gone into setting up facilities that can manufacture according to GMP. A lot of very highly qualified, expert personnel are required, and a lot of special conditions for the production of therapies are required.
The important component of all this is your quality unit, and the quality unit, as contemplated by the FDA and other international organizations, is a unit that must be independent from the rest of the managerial and operational aspects of manufacturing.
Why?
Because you want to have a highly qualified and skilled quality unit whose concern is not to agree with management or just push something out that doesn’t qualify. Their concern has to be whether the data they’re presented with, the product they’re presented with, and the process records all actually meet pre-specified criteria. Then, and only then, can they sign off and say, “Yes, this is a well-made, compliant product.”
When your quality unit is not truly independent — when, whether because of pressure from management or elsewhere, your quality unit has priorities other than singularly and objectively assessing the quality and compliance of your product — that’s very dangerous. You never want to have a quality unit that’s only good on paper (i.e., one that doesn’t depend on the approval of management, isn’t subject to competing pressures, overwritten, or in any other way non-authoritative with respect to the job they have).
So, independence of your quality unit is about as important as anything else in your process, if not more important, because it is the safeguard against pushing a therapy, product, process, or system of processes that isn’t in the best interest of the patient. This is why independence is absolutely imperative, and we’ve seen recently what happens when independence is doubted.
What Happens When Quality Is Compromised?
What happens when organizations lose sight of quality independence and oversight, or when quality teams are kept from actually prioritizing compliance?
Matveeva: It’s dangerous, and sometimes it happens without any malice or intent. I certainly don’t think people aim to breach quality or disable a quality unit, but for various pressures — maybe even knowledge gaps — sometimes authority and responsibility misalign.
Sometimes, the quality unit’s decision regarding any part of the process is overwritten, or perhaps there’s something more urgent and things get overlooked. Or perhaps there’s legitimate pressure from upper management. There’s occasionally the misunderstanding of what the quality unit really should be, relative to other functions in a manufacturing environment.
Management has a lot of responsibility and ultimately are accountable for everything that happens in an organization. Quality is a part of that, but only in the sense that management has an obligation to run with the judgment of an independent quality unit. Management cannot, at any point, consider themselves to have final word when it comes to quality and quality attributes. When that happens, the consequences are very serious.
During an inspection, if that ever transpires, that’s a very big problem. It’s a problem of credibility. It’s much more than a singular violation, because not only does it capture a violation of some regulatory standard, but it also demonstrates a great degree of subjectivity in the way quality oversight works at that organization, which is a big red flag if you’re the FDA — and rightfully so.
When that happens, it’s important for an organization to craft a response that doesn’t just say something like, “We acknowledge that this or that violation was committed, and we’re going to rewrite our SOPs and retrain our people.” That doesn’t address what transpires to be a cultural problem, a problem of authority and management understanding where they need to step back, a problem of essentially having a quality unit that’s dysfunctional or doesn’t work at all.
It’s important that everybody understands why quality is independent. That independence means not only the ability and obligation to conduct independent analysis and issue decisions, but that those decisions are imperative to follow. If that’s broken, then the organization is broken, and the manufacturing culture and quality culture are not working the way they’re supposed to.
Quality-By-Design As An Intentional Philosophy
How do you think organizations should integrate the philosophy of QbD into operations from the beginning? How do you successfully uphold QbD in operations?
Matveeva: The idea that once upon a time, when producing therapies or pharmaceuticals, you have a quality control test at the end and it’s pass or fail, that’s really not a good system. You’re hoping that you get a pass at the end one way or another, but you’re not thoughtfully designing your process or your product with quality integrated already.
QbD is intended to remedy that.
You start with the quality target profile, defining what the CQAs of your product need to be — how it gets to be effective and safe, what that means, and the critical components or properties of the product. Then, you design the process and import materials for production by defining the critical material attributes and properties. Then, you go into things like CPPs, the parts of the process that must be thoroughly controlled and well understood.
You design a system in which you connect CPPs with critical material attributes and CQAs to know you’re designing a production system specifically with product quality attributes in mind.
There are many things in GMP that are difficult to constantly control at the same level of resolution. There are a million systems and a million things going on. So, instead of trying to distribute all resources uniformly to those myriad things that could influence a process, it’s just more rational and scientifically sound to grade where the biggest risks are and to really focus on those.
When you do that, you assess risks with respect to what you want in the end and focus resources there, because those matter the most. It’s economical and reasonable because it’s very well justified.
You design a manufacturing operation that has taken into account and defined well what the settings must be to end up with the best and safest compliant product you can make.
That’s QbD. You integrate controls that enhance and make it more probable that those critical components in manufacturing fall within an umbrella of compliance, and you minimize the risks. That process is iterative; you learn as you go.
I don’t think in GMP it’s possible to come up with a final, perfect system. There’s always going to be a problem you didn't predict, but you need a solid-enough framework capable of capturing the problem and defining it with a very clear path of how that problem will be handled from a quality and compliance perspective.
That knowledge must be very clear and well understood by everyone on the floor, whether it's your process optimization team, management, your QC people, or your manufacturing operators. Every one of them must know the answer about what would happen if a deviation from your protocol happens: What do you do? When would you announce it? How would you escalate it? What would be the next step of control and so on? Do you continue? Those questions are absolutely critical, and everyone in a manufacturing operation must know clearly and confidently what they would do and what they should do.
That's good training.
When things slip is where you start to see a little bit of uncertainty or people who can't remember when they were last trained, or they're not sure if they want to say the thing they think is right because there’s a manager next to them. That's where problems start to happen.
QbD exactly what everybody should be doing. It's a very rational framework. It's a resource-efficient framework, and it's a safety optimization framework.
I think it's important to really spend the time upfront, before a single phase is hypothesized or planned. Spend sufficient time determining all of those components of QbD. Sit down and imagine all the crazy problems and terrible things that can happen. Be imaginative about everything that can go wrong; rank and assess them to understand how they contribute to the various elements of QbD. Define and risk-rank them to understand where you're vulnerable. Design controls, test those controls, and improve them. You do that over several iterations, and now you really have a system that works in the direction of optimizing quality.
You need to have an empowered quality unit. You need to have management with humility to say, "There are problems and quality found them, and so now we're going to follow whatever they say." It's a lot, and there's a lot at stake. There's a lot that’s invested in continuous operations.
It's certainly understandable why disruptions are unpleasant and sometimes terribly destructive, but quality comes first. And if that's not the mana of production operations, sooner or later, problems will begin to emerge more systemically, and then it will be too late.
It's worth an investment on the front end to design processes, to design practices, and to empower the people who are supposed to carry them out in the direction of optimizing safety and quality so that patients really can get what they need safer and sooner.