Are you and your quality teams ready to the challenge what is critical to quality? Are you willing to rethink yourbusiness requirements and business processes to fit the true business, quality, and regulatory gaps and are you prepared to make new alliances within the organization to refocus on quality? This is the first blog presented by ProcellaRX in a series: Quality Shift
Quality is Free, by Philip Crosby, was one of the first books I was given as a new process R&D chemist in 1998. The principles laid out by Crosby are the cornerstone of my entry into the pharmaceutical world which helped instill that everything matters. Everything from the water particulate counts to the types of stainless vessels we qualified to mix reagents. While developing chemical processes for active pharmaceutical ingredients wasn’t my ‘dream’ job, the circumstances of life (such as a failed starter marriage and almost losing my mind) had me fall serendipitously into a line of amphetamines and opioids (manufacturing, not ingesting, mind you) that changed my life for the better and unknowingly launched my career.
In the late 90’s through early 2000’s – during the time when the race to generic formulations was the go-to market strategy for Pharma – re-engineering chemical processes was the ticket for Big Pharma to be more efficient and cheaper, while still maintaining efficacy. To accomplish these goals, Active Pharmaceutical Ingredients (APIs) companies had to reduce cost to pennies per gram and manufacture at volumes that pushed the limits of chemical engineering. It was a challenge, to say the least, but it presented something I came to thrive in…problem solving. System thinking is at the core of who I am. Combined with my hypomania, I had a recipe to deliver some of my best work in chemical process development.
We, API companies, had a collective, singular goal: a molecular structure with a definite set of specifications. We needed to source cheaper yet quality raw materials. We shaved off every possible minute of reactor time and honed milling time to perfection to optimize particle size. Everything mattered! Every second of planning, cleaning, manufacturing time, people time and lab time was crucial. “Do It Right the First Time” is/was imperative. Every scratched batch and deviation were evaluated for lessons learned, continuous improvement, corrective action/preventative action, and risk mitigation plans.
To prepare for API Pre-Approval Inspection (PAI) took hundreds of experiments, tweaking parameters within the process(es) until all its parts of the process were optimized. Ultimately, this led to the Process Validation batches (what used to be the penultimate) consisting of 3 batches produced in production to meet all requirements. While each part of the process lays out specific criteria to be met, such as duration and speeds for agitation, the ongoing manufacturing is where the real fun begins for a problem solver like me. Out of specifications (OOSs) and/or manufacturing deviations happen because no matter how hard you plan for something and monitor input(s)/output(s), something can and will introduce a change and that change ripples. Regardless of how big or small, it’s a race to stop the ripple before it goes too far and reaches the worst-case scenario of having to scrap a batch.
As part of our mitigation strategy, we heavily relied on our vendor management process and raw material sourcing against clear specifications to ensure our quality from the beginning. This included using sample lot testing approaches and pilot scale experiments to make sure lot differences were sufficient for use, i.e., fit for intended use.
In my years on the manufacturing floor, I performed hundreds of OOS and manufacturing deviation investigations. This allowed me to observe trends, often the ultimate root cause of most manufacturing deviations was due to human factors. Training errors, measurement errors, mis-reading times on an analog clock, using the wrong-colored hose (discovered someone was colorblind), high spore counts (human super shedders are a real thing), and paint chips! Oh, the paint chips…a thorn in my side for quite some time till we figured out where they were coming from. In that case, the root cause was due to incompatible gaskets, due to insufficient specifications, due to incomplete review/approve of specifications, which ultimately boiled down to – you guessed it – a very human factor.
In today’s reach for Pharma 4.0/Validation 4.0 and continuous manufacturing methods, process analytical technologies and improving quality from beginning to end must be at the heart of everything we do. Drug safety is paramount and the rapid drug development that has given us Covid vaccines in months instead of years to curb a global pandemic has pushed R&D across the industry. That push and increased velocity to drive innovation must have quality at the center and PEOPLE are at the heart of what drives that quality. Each and every one of us.
So, here’s the big but….
Despite what the book title “Quality is Free” may indicate, the truth is that Quality is not free. We can get close to it as we approach the “do right the first time” model, which is an objective we all should be striving for, it’s not free. There is a cost to Quality. Besides the technology investment there is a cost to getting closer to that “do it right the first time” state. It’s a human cost that we need to choose to invest in, that we need to commit to investing it.
That doesn’t mean buying another piece of software to ‘solve’ a business need. It means digging deeper to truly evaluate and identify what your team needs to ‘do it right the first time’. This requires examination, deep understanding, training, continuous improvement strategies, and, perhaps most importantly, an ability and willingness to change.
“Slowness to change usually means fear of the new.”Philip Crosby
The slowness to change and sometimes the frank refusal to change within life science industry plagues an organization’s human capital and puts more than drug safety at risk – it puts employees day-to-day mental health at-risk. The slowness and resistance to change is particularly fierce in the computer systems validation (CSV) space, while other parts of the same organizations are in ripe with innovation. The collective refusal impacts not just the organization at the sponsor side but reaches the vendor side and inadvertently puts the supply chain at-risk. Why?
Let’s look at parallels between a raw material vendor and a document management system vendor….
From a manufacturing perspective, the raw material vendor goes through a vendor qualification process and provides evidence of that raw material meets specification criteria (customer specifications and/or USP or other standardized criteria). The sponsor then qualifies the raw material through a process of sample testing and verification of certificate of analysis provided by the vendor, periodically ‘requalifying’ and/or using the raw material lots in pilot lot batch trials, etc.
Customer/Sponsor is satisfied = raw material meets specification.
Vendor is satisfied = Customer/Sponsor is satisfied.
Quality Management Process (on both sides Sponsor/Vendor) are in place to deal with non-conformities and address issues with established feedback loops.
At this point, the hand off occurs via the acceptance of material. The Sponsor then uses the raw material as per Sponsors development process and carries out their own testing on final drug product dictated by the Sponsor specifications.
In contrast, let’s look at a generic software application used in support of storing and approving policies and procedures for a Life Science company, a Document Management System. For this example, we’ll assume a vendor that specializes in Life Science companies with a product that contains 99% of all standard features that a Life Sciences would come to expect from a mature software vendor in the market. This would include, but not be limited to, features like the ability to capture audit trails, electronic records, and electronic signatures. Let’s also assume that this is out of the box, configurable software that is available via SaaS with millions of dollars in revenue sold worldwide.
In order to be a software vendor in this space and have a viable application on the market which sells at this volume, you can be assured there is an established and mature software development lifecycle (SDLC) in place. For software vendors, reputation matters most and word of faulty code or faulty features spreads like wildfire. Even if we assume a software vendor that services multiple industries and lacks the same interpretation understanding of regulatory compliance, they will undoubtedly have a robust SDLC and software quality process in place to ensure their product’s reputation and credibility in the marketplace.
In this scenario, can we / should we apply the same validation ‘rules’ from the above raw material example? If we do, what does that look like…
Sponsors perform a software vendor qualification process – Check
Vendor provides evidence of their process in place – Check
That’s the easy part, but now comes the hard part. It’s now the chicken or the egg time. Which comes first?
In the case of software – at least in most enterprise applications – there are a myriad of ways for it to be utilized and almost never one specific way. Software vendors determine features that deliver the best practices/best fit for its intended purpose as an overall solution for target customers. How a consumer ultimately USES the software is solely the responsibility of the sponsor.
Herein lies the rub for Life Science organizations: A general lack of / insufficient understanding and definition of the intended use of the solution. In the raw materials example, this is not the case. Raw materials, even Delta V Process Equipment, all have explicit and clear specifications rooted in good quality engineering practices. So why is it different in the computerized system validation space for the application under test?
Often, key stakeholders lack a comprehensive understanding to define key business processes and critical quality functions per FDA predicate rules. These stakeholders inform and/or become sponsors of a solution. Sponsors that are not able to define critical business and regulatory requirements leave a fundamental rift between software vendors and sponsors. The rift is often met with requesting unnecessary or extremely specific ‘functions’ into the software which are shinny and appeasing or worse perpetuating or enabling a poor business practice. Developers can build a lot of fancy things into their products, but do you really need all those bells and whistles?
I frequently see sponsors want more ‘nice to have’ functionality. Typically, adding overhead and burden to the business process that they were attempting to automate (or semi automate). This carries over to the vendors, as well, to take on features which add unnecessary complexity to core products. This ultimately results in increasing validation costs and effort where there doesn’t need to be. In most cases this is due to a reluctance of change because a) they don’t want to change their non-digital business process or b) they aren’t willing to take an honest look at what’s critical to quality. This is where accountability, trust and education are crucial.
As Joseph Juran stated, “Without a standard there is no logical basis for making a decision or taking action” and “It is most important that top management be quality minded. In the absence of sincere manifestation of interest at the top, little will happen.” Without clear requirements from the business and alignment of values from the top, quality costs will continue to rise exponentially, but this doesn’t have to be the case. In fact, it is not the case with many forward-thinking life sciences organizations. I have worked with numerous organizations to help drive change and I like to break it down, into 3 steps what I call the Quality Shift:
Step 1: Rethink requirements to determine critical to quality requirements
Step 2: Reshape business processes to fit the true business, quality, and regulatory gaps
Step 3: Remake alliances within the organization to refocus on quality
These 3 steps are crucial to approach with critical thought and intention as organizations strive to enhance and modernize their approaches to support the velocity of innovation we see today. Our industry is in a place where we simply can no longer afford to stand in place. Pharma 4.0 is pushing the boundaries of pharmaceutical engineering forward while making way for Validation 4.0 to drive a more integrated, holistic approach to validation that embraces digital maturity and speed. The CSA (computer software assurance) model is officially upon us with the recent release of the draft FDA guidance. We need to understand and incorporate all these things so we can evolve quality mindset to support the incredible things our industry is capable of, rather than act as a bottleneck stuck in time.
I can close this out by bringing it back to Crosby for a moment, his response to the quality crisis was the principle of “doing it right the first time” (DIRFT), as mentioned earlier in this post. Beyond that, he also included four major principles that should be considered when evaluating the 3 steps I outlined above:
- The definition of quality is conformance to requirements (requirements meaning both test product and the customer’s requirements)
- The system of quality is prevention
- The performance standard is zero defects (relative to requirements)
- The measurement of quality is the price of non-conformance
While Quality might not technically be “free” it certainly isn’t and shouldn’t be proprietary. It’s not some secret that companies need to covet, but rather, it’s a way of being. It is everyone’s responsibility to do their individual part – as a part of the whole. No piece of software or manufacturing equipment is going to be used to its full potential if we humans don’t care and use it as such. We should all want quality to be first and foremost on everyone’s mind. We need to be sharing our knowledge and experiences. We need to drive our approach to quality the same way we drive our approach to innovation in our industry. If we can start to embrace the change that’s needed and exchange in healthy dialogue about what works and what doesn’t, collectively we can begin to do better. We can make quality closer to being free.
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