Quality Adds Empathy To Outsourcing

By Louis Garguilo, Chief Editor, Outsourced Pharma

Vinita Kumar, VP, QA/QC, Versartis, might be called an empathetic quality expert when it comes to working with contract development and manufacturing organizations. But don’t interpret that as a descriptor for relaxed standards or a lenient approach; it’s actually just the opposite. Reaching a level of shared experience between drug sponsor and service provider requires adhering to specific tenets and a heightened commitment — on both sides. If attained, Kumar says, “Never does that importance of real collaboration reveal itself more than in hard times for your program when you need it most.”

Unfortunate for experiencing some of those “hard times” but fortunate for also having those close CMO relationships, Kumar’s philosophy has been field-tested. An example comes from last year when Versartis did not meet a priority endpoint of a Phase 3 trial for Somavaratan, a novel, long-acting form of recombinant human growth hormone (rhGH) for growth hormone deficiency (GHD). “I can say that all those working on the project at our CMOs were genuinely sad, and I mean emotionally as much as in a business sense,” recalls Kumar. “There’s no other way to put it; there was a real grieving process on both sides.”

She says Versartis and its service-provider organizations worked together throughout the process, including cancelling some and altering other contracts, charting out various tasks, and thinking through future planning. “Through difficult times like this,” explains Kumar, “it’s evident mutual trust and understanding between the CMO and drug sponsor is of utmost value.” She says at Versartis, this feeling comes from her CEO, Jay Shepard. “He’s always been a strong advocate for relationship building.” Shepard also was the CEO of Relypsa for part of the time Kumar was at that company prior to her joining Versartis. She also acknowledges two other former Relypsa CEOs, Gerrit Klaerner and John Orwin, as important contributors to her maturing as a quality head.

A physical organic chemist by training, Kumar started her career in preformulation at Syntex, which integrated into Roche in 1994. She subsequently moved on to positions including analytical development and sterile manufacturing. In 2000, she had her first experience directly in quality, where she has stayed put since. She experienced working at a CMO when Roche sold Syntex’s pharmaceutical development capabilities to OREAD. “That’s where I learned what it feels like to be on the other side,” she says. She joined Relypsa at its inception (2007) and became part of its successful development and commercialization of Veltassa, a prescription medication to treat high levels of potassium in blood (hyperkalemia). These experiences — both successes and setbacks — have shaped what she calls a “consensus approach” to outsourcing in the quality function.

Data Integrity And Intent
On the desk in her Menlo Park, CA, office, Kumar keeps “quality coins” — shiny tokens imprinted with a “Q” that her children used to play with — to remind her that her quality team and those at partner organizations are “two sides of the same coin.” She also has a quote on one wall: “Quality By All.” When asked by her colleagues about it, she elaborates, “Quality is as much your responsibility as it is mine.” She starts our conversation by discussing how recent FDA guidance (more on the FDA later) regarding contract manufacturing, aimed at further instilling in drug sponsors the idea they are responsible for what happens in all aspects of their programs (including at CMOs) reinforces the need for the close sponsor-service provider relationships she supports. She uses the recent hot topic of data integrity as an example of both this taking and sharing of responsibility. “Even for areas like data integrity,” she explains, “creating quality agreements is the optimal phase. That’s when you have the most leverage in setting clear and realistic expectations. And when quality fully participates in the initial CMO qualification audits, it becomes the time to really look at all the details of their systems. The partners also should be looking closely at you, the sponsor, to understand how to work together.”

Her empathetic side then surfaces. “Subsequently, as work is ongoing between the sponsor and selected partner, I believe you can back off a little. Trust has been built,” she says. “CMOs need some space to breathe.” Kumar sees an immediate outcome to this. “The sponsor’s initial resource drain for overview, typically very taxing on small drug developers, can abate. Being the sponsor, yes, we are ultimately responsible; that remains a full requirement. What I’m suggesting is we also need to make operating decisions so that both sides can actually be productive.” There’s a clear prerequisite, though. “For this relationship to really work with integrity, the two-way flow of that data between sponsor and CMO is paramount.”

I interrupt Kumar here to ask if she’s experienced problems with data not fl owing between partners. As she most always does, she bookends her comments by saying most CMOs she has worked with do things well, and negative examples are the exceptions. With that mitigation in place, she relays this story. “At one CMO, we had difficulty getting data down to the level we needed. In this type of situation, the sponsor first needs to take full ownership of the problem. Maybe the quality agreement wasn’t clear enough, or some of the needed documents weren’t shared or were contradictory. In this particular case, we were looking for analytical data for QC review on a specific development run. Information about how a buffer was prepared was kept in a separate notebook at the CMO and was hard to gain access to. We also wanted to look at some chromatograms. They said their system wasn’t suited for providing that information. I have to say, in their defense, they were receptive to us if we made an appointment to go on-site to check; yet, for us to get the data in-house was a difficult experience.”

After a reflective pause, she recalls another “very rare,” case where her group received data indicating a purity value was within specification, but the chromatogram “didn’t look right.” Kumar’s team asked more questions of the CMO and received an updated chart. “It appeared the timing of a certain peak was still the same,” she says, “but it looked like the chromatogram was cut and pasted, and copied. We initiated more conversations, and finally our CMO informed us, ‘It has been taken care of, and that person no longer works here.’ So, I have seen that, but only one time.”

I ask Kumar for one more cautionary tale for our readers. She starts to recall a “misinterpretation” that a product color was within a specification range. “We kept asking the service provider to send us more pictures, and each time we’d say, ‘No, the material looks too dark.’ When we sent people on-site, sure enough, the color was out of spec, but the CMO still saw it as being okay. Subjectivity was involved, so I would not really call it bad intent, just a difference in judgment. However, we needed to take a stand and reject the material. And as important, it was incumbent upon us to then improve our methods to minimize that subjectivity.

“In fact,” she sums up, “for all these cases, there’s a shared responsibility. I never take an ‘I-caught-you’ attitude. If you drop a nail in a batch, nobody will ask you to release that. Those are easy calls. The gray areas are the ones where that synergy and understanding needs to be in place.”

Trust, Communication, And Synergy
Kumar says the above situations may not have perfect solutions. However, here (in her own words) are three areas where the quality team’s approach can help avoid issues from developing and overcome them when they do arise.

1. BUILD TRUST WITH COMMON GOALS – NO “I-CAUGHT-YOU” ATTITUDE
“I have been through four process validations in the past couple of years. The common goal was to have successful validations with corresponding documentation that can hold up in a pre-approval inspection [PAI]. During one of the process validations, a major deviation occurred; after initial investigation, the CMO determined it to be a process problem, but later the root cause was attributed to human error. The investigation was conducted jointly, and there was no finger-pointing. The goal was to identify the issue, get back on track, and work cohesively to recover some of the lost time. When the CMO and sponsor work in unison and both teams only have to worry about the project problems, the outcome is extraordinary.”

2. CLEAR COMMUNICATION – DETAILED MEETING MINUTES AND ACTION ITEMS
“When the CMO and sponsor have to overcome distance, time zones, and not being able to meet in person as frequently as one would like, clear communication is of utmost importance. That means both sides need to speak the same language; mutually understandable terms need to be used. Detailed meeting minutes outlining action items and documenting decisions made take the guesswork or ambiguity away. The timeliness of issuing minutes after a meeting is extremely important. Not everyone can be in every meeting, and these minutes become the source of truth for the extended cross-functional teams.”

3. THE SPONSOR’S OPERATING TEAM MUST BE ON THE SAME PAGE – SYNERGY IS IMPORTANT
“It is important that a ‘one and the same’ message is passed on to the CMO from the sponsor. There are situations where different functional teams at the sponsor are not in agreement on the priority for the CMO. This becomes dysfunctional if the various sponsor teams are communicating different tasks as being ‘the highest priority.’ Internal discussion at the sponsor site needs to take place, and a unified message needs to be communicated back to the CMO. There was an instance where the same team at a CMO was supporting both the release and stability testing. The sponsor QC team communicated to the CMO that for the submission of an investigational new drug amendment, the stability data was the highest priority task for the laboratory. At the same time, the sponsor manufacturing team was instructing the CMO that releasing the drug product lot was the highest priority, because clinical supplies were running low. The CMO reached out for clarification, and the sponsor teams worked on setting the unified priority that was best for the company.”

Shepard values Kumar’s quality approach and leadership. The CEO told us, “The process of meeting product needs such as efficacy, safety, strength, reliability, durability, and quality is a nontrivial task. Over the years, I have witnessed Vinita establish phase-appropriate quality systems and processes. She is very technical and pragmatic in her approach, and her judgment regarding the ‘must haves’ and ‘nice to haves’ is practical and dependable. She has maneuvered well through challenges regarding spearheading, spreading, and auditing the quality ‘must haves’ across various stakeholders in the company.”

And, we’ll now hear how those stakeholders include the FDA.

Empathy Spreads To – And From – The FDA
The trouble with many guiding tenets is they break down at the rocky shores of reality. That is, ideals meet with too many exceptions to regard them as cohesive in application. For the quality function in a biopharma outsourced model, that shoreline is often the regulatory body. Does Kumar’s belief in an empathetic approach, for example, work with the FDA?

That question was addressed at a recent Outsourced Pharma San Francisco conference, during (a rather remarkable) discussion in a session titled, “Teaming Up For Regulatory Advancements.” A dialogue ensued between Kumar and Umar Hayat, who were colleagues at a biopharma during an important product approval/ launch. (At the time, Hayat was senior director of pharmaceutical development and manufacturing; he is currently Principal, Hayat Pharmaceuticals Consulting.) Below is some of that back and forth.

HAYAT: When you’re conducting clinical studies for unmet medical needs, particularly, the FDA will often begin to demonstrate a teaming-up aspect with you. Smaller companies may understand the teaming up between CMOs and sponsors, but what is not so evident is that the FDA is also willing to join. This is increased for breakthrough technologies or fast-track programs. Vinita and I worked for a small company on one such program, and I can tell you the FDA made us feel like a big corporation. We wanted to launch immediately after approval and could not have that if the FDA and our CMOs were not proactively cooperating with us.

KUMAR: Yes, the FDA was almost navigating us. They actually suggested a path that would allow us to keep the PDUFA timeline. We thought a bigger study might be required, but they said we had the necessary data. Our regulatory team was sending emails to the FDA frequently; amazingly, we would get responses by the next morning. It was incredible to see how empathetic they were for getting this new drug out to patients as soon as possible.

HAYAT: The quantity we needed to ship to patients got changed, so that meant the box size, carton design, and even the printing had to change. We had version A as the first labeled content we filed with the FDA. That went to version B, C, D, E, F … I think G was the last. Of course, the validation batches already had been manufactured and were in our CMO’s facility. Some of the lots were already printed, but there was a statement not included on those that became important. The FDA was open enough to tell us we could inkjet the short statement manually on the preprinted labels. [This elicits gasps of surprise from the audience.] Well yes, when you think about it, the FDA really has two objectives. One is to set and ensure full regulatory compliance for manufacturing and safety for patients. But secondly, to make sure that the drug is available to patients in need as soon as possible. I think it also shows the FDA is concerned about the resources you have already spent — in this case, 7.5 metric tons of material.

KUMAR: So let me insert that Umar is, of course, the manufacturing guy. [Audience sends up a collective laugh.] This all came about as a result of our working closely with the FDA. We already had processed material, as Umar described. But from a strictly quality, regulatory, and safety perspective, we asked the FDA what we could do. They suggested that if we could clearly demonstrate that this additional printing would be strictly controlled, and effectively limited for a defined period of time, we could use the material with a printing solution. In the end, the partnership we saw among the sponsor company, all our partners who remained responsive, and in this case, particularly the FDA, was remarkable.

A Final Understanding
Exceeding all the “empathy” shared by the drug sponsor, the service providers, and regulatory bodies outlined above is that for the patient. If ultimately patients do not benefit from the outsourced model, the model would not be worth pursuing. So let’s end with a comment from former Relypsa CEO John Orwin, whom Kumar mentioned at the beginning of our article as one of her formative mentors: “Quality is at the heart of a biotech or pharmaceutical company. We work to advance science and to provide for our shareholders, but we exist for the benefit of our patients. We can only serve them well if we place their interests above every other goal. Quality is the essence of serving them well, whether it is in the design and conduct of clinical trials or manufacturing product. An executive team must ensure that a commitment to quality is given the highest priority, but to be truly effective, quality must be a commitment every employee and contractor to the company shares.”