Here is a familiar demand: “Show me where in the regulations it says to do that!” If you’ve spent any time in Quality, working on a facility or equipment project in the pharmaceutical industry, you have certainly had that put to you at some point. And why not?
Far and away, what most people (including our industry engineers, technicians, and operators) think about when they think “Quality” is “Compliance with Regulations.” Compliance is certainly an issue of vital importance, but Quality does not stop there, and there is no time when that is more clear than during a Quality Audit. This article will show that understanding the potential audit outcomes in the future can serve as powerful design criteria today.
For many companies today, the majority of their external quality audits will not be performed by regulatory agencies, but by other companies. This company auditor has a day or two to assess the overall “quality culture” of a potential supplier or contractor. Unlike the FDA that has a free pass into all FDA-regulated facilities in the U.S. at any time, a company auditor performs the audit at the discretion of the company being audited. After this audit is complete, and provided that the auditor says everything is okay to link his company to the manufacturing processes of the other, the auditor’s company will have little to no direct experience with day-to-day processing. In short, that’s a couple of days to make a full assessment of all quality systems in a unique facility that will have to be valid for a year or more. This is a challenge for non-sterile raw material suppliers, which only grows more challenging as cleanrooms and sterility claims are added to the mix.
With so little time to assess a facility and a manufacturing process (or many of them!), how is it that auditors can effectively and thoroughly measure the strength of all Quality Systems? It is here that a large part of non-Quality personnel would answer something along the lines of “directly measure the facility against the regulations using a checklist or other tool.” Though compliance with regulations is absolutely required, measuring against regulations is a very small part of an audit. Furthermore, it is difficult to do so “directly.” How would one measure “Appropriate measures should be established and implemented to prevent cross-contamination from personnel and materials moving from one dedicated area to another”1 directly? And how would it be done for every possible combination of personnel, materials, and products in a contract formulation and sterile liquid filling company, for example? In short, it can’t happen. Alternatively, there must be a way to achieve solid and defensible results.
The alternative is this: in order to be effective, auditors focus on two things:
- How is the system controlled?
- How is the system monitored?
Superficially, these two questions appear to provide a very narrow perspective. On the contrary, they comprise a far more expansive view of facilities and processing than most, including the normal view of design, for example, which is to design for a specific production volume. The first clear outcome of designing a facility or process with these two questions in mind is that design decisions will be made knowing that the final design must be auditable. A simple example would be to imagine an airlock that does not have any sort of air pressure gauges. The original design intent may be to have 10 Pa over each door, but without data provided by monitoring devices, how could it be proven that the airlock is behaving as designed? Without data, how could adjustments to controls be justified to an auditor? The fact that an audit trail must be available may be very influential, which will be seen through some examples below.
Now it is great that we understand that systems of control and monitoring will be the way an auditor approaches the facility once it is built and the process is running, and it’s also great that we understand that the final facility or process must be auditable. But these facts are not very useful to design engineers and architects if they cannot be leveraged to inform design of projects in specific ways up front. Having a holistic, “eyes of the auditor” type quality influence in the design phase of a project would be incredibly valuable since all projects in the pharmaceutical industry will eventually be production facilities or manufacturing systems, which will go for Pre-Approval Inspection and then biennial inspections by the FDA and international regulatory bodies, and also countless supplier audits for as long as that that facility or process exists.
Some people may balk at the notion of using the potential results of future audits as design criteria as it is commonly held that “regulations keep changing.” I deny that. What happens most often is that over time, the rest of society continually develops more sophisticated technologies like computers, advanced materials, and precision equipment. As the rest of society keeps progressing (or in production lingo, “continuously improving”), our industry is expected to do the same. Thirty years ago, a daily monitoring of room pressure on a written log was the norm. Today, it is very common to see Building Management Systems monitoring room pressures constantly. Physics didn’t change. Air itself didn’t change. Over time, technology advanced and the Pharmaceutical Industry just kept up with it.
Furthering that idea, better data monitoring reduces business and quality risk overall, so these advancing technologies are implemented as companies’ assessment of risk changes. The written regulations also change—usually pretty slowly—to keep up with changing technology and risk perceptions. As an example, consider a smartphone. These devices have incredibly simple user interfaces and are powerful enough to let the user do almost everything a laptop does. With that level of simplistic technology available to anyone, why should a confusing Operator Interface on a process skid be acceptable?
What does it really mean to focus on systems of control and monitoring? Said another way, it means an auditor will focus on systems that will assure product will continuously meet specifications, that any issues with that production are identifiable, and that all activity is traceable. So the auditor focus on control and monitoring systems is truly a focus on “assurance” and “reliability.” Here, it seems that the goal of the design team and the auditor are the same. In project development, no design team aims to create a facility or a process that is unreliable; an auditor merely seeks to validate those efforts. Approaching design from this perspective of “assurance” and “reliability” is obviously constructive and helps projects in our life-saving industry come to the best decisions for our products and our patients. The area where this is most clear is cleanroom design, which will be the focus of the examples below.
Consider a situation in two different ways. In each of these scenarios, the product has some specific requirements, such as sterility throughout the process as the product cannot undergo any downstream sterilization steps. Also, for clarity, these processes are in a single-product facility:
SCENARIO 1: AN OPEN PROCESS
In an open process for a sterile product, the space required is a Grade A with a Grade B background. Personnel in that space are fully gowned. In Grade A, there is continuous particulate monitoring, minimal per-process microbial monitoring, and a lot of air being pumped into the space (laminar in Grade A to boot!).
SCENARIO 2: A CLOSED PROCESS
In a closed process for a sterile product, operations are in Grade C, D, or maybe even unclassified (depending on risk and the way the process is set-up). Personnel are wearing dedicated clean-area clothes and shoes, EM is radically reduced from an aseptic area, and the air change rate is maybe half of that in aseptic areas.
Now, both of these process scenarios have the potential to be completely compliant. For one, though, compliance is far more costly, challenging, time consuming, labor-intensive, and complex, which means that there are many more tools required to control the environment, many more items to monitor, and far more opportunities for failure. Each of these additional failure modes adds another parameter to the process that must be auditable and increases the number of people required to audit. There is nothing in the regulations that would state one of these approaches is completely wrong. And maybe with more information available, the system with fewer parameters to control and monitor is actually the best choice for the production material. What if the product in question here is experimental, unproven, and therefore in need of the developmental flexibility that comes with multi-use Grade A areas? What if product volumes are so vanishingly small that product hold-up (potentially greater in the closed system) is critical? This may come into greater relief with another example:
POTENTIAL SYSTEM A:
The production system is fully stainless steel. Everything was engineered, with measured and exact slopes for all piping. In between uses, all parts must be washed and, before that, the cleaning cycles had to be validated. Their control is automatic and also validated, so repeatability is almost certainly assured.
POTENTIAL SYSTEM B:
This is a completely disposable system. The disposable components can be purchased from multiple vendors (some of which are not as reliable as others), have some potential variability in tubing length, and since they come coiled in sterilized bags, the tubing often sags when outstretched, leading to variability in holdup in the system. The disposable components need no cleaning validation or cleaning cycles. These systems are sterilized by an outside vendor, but are never put through a validated cleaning cycle to remove any particles introduced during assembly at the vendor.
Knowing that outcomes like purity and yield are critical parameters, which system should be selected? What if the product is moderately sensitive to materials used in a disposable system? What if cleaning chemical residues have an exponential negative effect on potency? Again, understanding the way the entire process will be audited quickly digs into many details not always at the forefront of a facility design.
Similarly, across the industry, room air quality must be monitored. But monitoring a Grade A space means continuous particle monitoring, whereas Grade C monitoring may be only weekly or even monthly. For a critical product-contact utility, an auditor will review every document from Design Qualification through routine monitoring over the previous year or two in detail. For a Grade C EM program, the procedure will be reviewed and enough data to show compliance will be reviewed.
In all of these examples, different teams will come to different final selections and it is highly unlikely that any selection will be “wrong.” The unfortunate potential is that for either path taken, the selection will be made, designed to, and built from a single perspective: the perspective that comes with budgets and schedules, that moves in one direction from original concept to construction and validation, and that is ultimately inflexible because it was scoped and designed to meet a specific need (throughput or production volumes, for example) without including the need to control or monitor the process and be fully transparent in an audit, regardless of the volumes.
This is perhaps the best case for viewing projects from an auditor’s perspective. Ten years from the initial build, an auditor will be in that facility. In those ten years, dozens of changes will have happened, production volumes would have increased (hopefully), and systems would have been updated. Cleanrooms designed to hold one production lot at a time might now hold multiple lots. It is here where controlling and monitoring systems for multiple quality systems come together to form an overall quality assurance program. It is here where an auditor could look at the initial design and aid in recognizing how, over the long term, systems to control and monitor different aspects of production can be stressed to the point of failure.
At a minimum, the products of the Pharmaceutical Industry improve the quality of life and, in many cases, save lives or prevent disease entirely. Competition in this field is inevitable and tenacious. Increasing production and lowering cost cannot result in products of lower quality with unreasonable risk to patients.2 For successful products, processes and facilities are asked to increase production over time as demand increases and lower costs as patents expire and competitors come to market. These pressures are as inevitable for a production facility as is the fact that it will be audited dozens of times. We would all do well to employ the tools of an auditor in the design of facilities and processes.
- FDA Guidance for Industry / ICH Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, Section D(4.4), August 2001
- See Eudralex, Annex 11, Principle section
Scott Overton is a Site Compliance Specialist for Merck & Co., Inc. He is the Site Quality lead for Viral Vaccine facility improvement projects. Merck & Co., Inc., 770 Sumneytown Pike, PO Box 4, West Point, PA, 19486 (mail stop WP38M-7); firstname.lastname@example.org; www.merck.com