Outsourcing Lean Quality for Manufacturing Efficiency

Shortening production cycle time with rapid microbial screening

By Tina Sturgill

If you are using traditional testing methods to release your products — or those of your customers — to market, the adoption of rapid screening is one of the most important changes you can make this year to improve your business.

Rapid microbial methods (RMMs) are being adopted by increasing numbers of pharmaceutical companies, contract manufacturers, co-packers and testing operations to reduce lead times. Whether you bring rapid screening in-house or send samples to a lab that offers RMMs, shortening the production cycle can unlock huge operational savings.

The Value of Rapid Methods

Over the past two decades, “lean manufacturing” initiatives have made their way through most industries. By stripping waste and other non-value-add steps out of the production process, lean manufacturing has saved companies billions. But why stop there? “Lean quality” extends the same principles to microbial testing. Instead of holding materials or products for a week or two while awaiting microbiological test results, rapid methods can provide assurance in as few as 24 hours. This translates into an average five-year net present value (NPV) savings of $500,000 or more per facility.

As a contract partner, the same benefits of “leaning” also apply to an operation by reducing the time it takes to produce, package and/or test customers’ products. Taking less time to complete an order means a provider can invoice faster and get paid faster. Since you won’t need as much space to house product in micro-hold, you’ll have extra warehouse space — increasing your capacity for additional business. Plus, the provider will gain a competitive advantage by helping customers be more responsive to changing market needs.

Improved efficiency also reduces recovery time in the event of a contamination. At these times, when so much is at risk, the benefits of rapid methods are doubled. The faster you start corrective action, the faster you recover, reducing the potential impact on customer relationships and the bottom line.

How Rapid Methods Work

Products that are susceptible to microbial contamination but expected to be shipped contamination-free are screened before being released into distribution. That screening adds multiple days to the production cycle and extends lead times. Micro screening typically takes three to seven days for limits testing, and 14 or more days for sterility. That’s a long time to wait when you have a good production process in place that is turning out products free from bioburden almost all the time. The wait time is frustrating and expensive.

Well-validated rapid methods are just as effective as traditional microbiological methods. Most significantly, these RMM results can be delivered in as few as 24 hours using a rapid method featuring adenylate kinase (AK). AK-amplified bioluminescence combines the use of ATP, the gold standard of rapid detection, with a patented enzyme technology to deliver accurate results even faster.

All living organisms contain the compound ATP (adenosine triphosphate) as a vital part of their energy metabolism. In the standard bioluminescence test, when ATP is detected a reaction occurs that generates a photon of yellow-green light, similar to that of a firefly. It is a very sensitive technique, but limited by the fact that an organism can contain only a finite amount of the metabolite ATP.

Adenylate kinase (AK) is another vital part of energy metabolism in all living things. When supplied with an excess of ADP (adenosine diphosphate), AK acts as a catalyst converting ADP into ATP. Because AK is an enzyme rather than a metabolite, it can be harnessed to generate almost unlimited amounts of its product. After 25 minutes, for example, the amount of ATP can be 1000 times greater than what the organism originally contained. As a result of this amplification and the reduced dependence upon microbial growth for detection, AK-amplified bioluminescence provides even faster results when screening for microbial contamination.

Adopting Rapid Methods

As a growth-based method, the assay preparation for bioluminescence technology is already familiar to the lab technician, so it is an easy transition. The additional amplification cycle is integrated into the bioluminescence assay and is transparent to the user. Both methods rely on batch or lot sampling, enrichment and incubation. While the traditional method depends on lab techs visually inspecting hundreds of samples one at a time over multiple days, the rapid method assays up to 120 samples in about an hour’s time using a light-measuring instrument called a luminometer. Results are objectively recorded and presented in clear, color-coded tables and graphics, so lab technicians are free to work on other projects and no “judgment calls” are needed to interpret the results.

Transitioning pharmaceuticals and other regulated products to a rapid release method is straightforward and is, in fact, encouraged by many global regulatory bodies, including the U.S. FDA. The preferred approach is to “tell them what you’re going to do, do it, and then tell them that you’ve done it.” Albeit highly simplified, this is a reasonably accurate description of the FDA’s Comparability Protocol. The centerpiece — or “do it” part — is validating the product or group of products for routine release using the rapid method. This typically entails side-by-side testing to ensure the rapid method is as sensitive as the traditional method. During this stage, lab staff become more practiced and confident in the rapid system so that once the validation data is collected, the RMM is effectively implemented.

Your rapid system provider may have regulatory compliance expertise on staff that you can tap into as well as drug master files (DMFs) accepted by the FDA. The DMFs include data for specificity, limit of detection, robustness, ruggedness, and equivalence, and can be used to supplement or streamline the validation of your rapid system. This may save significant time in both your preparation and in the FDA’s review and approval process. Ask your system provider about its regulatory compliance assistance and additional resources such as white papers and validation guides.

Outsourcing Rapid Methods

A new alternative to bringing a rapid screening system in-house is to partner with a contract analytical lab that offers rapid detection as a service. With overnight shipping widely available, there’s still much to be gained by being able to release products within two days.

Look for an accredited lab that is certified in current good manufacturing practices (cGMP). Such labs will understand the demands of the regulated environment. Ask about their experience with validation services and, if there’s a future possibility of bringing testing in-house, with method transfer. In addition to having a robust rapid screening system, the lab should be equipped to perform follow-up testing on any samples that test positive.

Some labs are capable of mapping organisms at the genetic level. This strain typing process uses rep-PCR to identify and track organisms. Since it can be used to catalog any mutations or seasonal changes over time, strain typing can be a significant benefit to facilities plagued by a recurring bug.

Rapid Methods in Pharma

The pharmaceutical industry is an ideal place for rapid screening. The manufacturing and packaging of pharmaceuticals is done under conditions today that produce a “clean” product 99% or more of the time. With functionally sterile products — those with low bioburden — a positive is rarely expected; therefore there is rarely anything to count or enumerate.

Despite this, some companies are hesitant to adopt an absence/presence screening. It’s at this point I like to ask, “What type of equipment do you need to count to zero?” The most significant time- and labor-saving benefits from any rapid method come from the ability to release products more quickly. That’s 99% or more of your products. If you focus on the <1% of exceptions, rather than the rule, you will not find the return on investment that will make you a hero at your company.

The Cost of Rapid Methods

Rapid methods are not about costs; they are about savings. While there is an increased cost for assay materials, the operational — and thus financial — benefits far outweigh the expense. If you store batches or products awaiting test results, you will benefit by reducing your working capital investment in inventory. By reducing your investment in inventory, you will benefit by clearing out space in your warehouse. If you carry safety stock, you will further benefit from cutting it down to size. If you manage a brand, you will benefit from the faster response time you can offer your distributors and from reducing the risk of contaminated product reaching consumers.

The best way to know if rapid screening will benefit your specific operation is to contact a system provider that can provide a financial modeling tool. Business consultants Arthur D. Little (ADL) conducted a study of the financial impact of implementing a rapid system to release finished goods earlier. Based on the results of this study, ADL developed a working “Value Creation Model” that can quantify the financial value to your business of implementing a rapid screening system at one or multiple facilities and for both in-house and outsourced micro testing.

The Opportunity of Rapid Methods

Controlling costs and operating more efficiently is a priority for everyone in the pharmaceutical value chain. Building on the success of many lean manufacturing initiatives is this newly emerging focus on lean quality — the cornerstone of which is rapid screening. Available as a purchased system or as a contracted (or sub-contracted) service, rapid microbial screening is a significant opportunity for manufacturers and contractors alike to reduce costs, reduce risk and reduce working capital requirements.

Tina Sturgill is senior director of Biological Sciences and director of site operations for Celsis Analytical Services. She can be reached at [email protected].