Pharmaceutical Drug Manufacturing

 

In pharma plants, age definitely matters.

 

Ironically, there’s no shortage of new equipment that biotech manufacturers can purchase to replace their older machines. Walk the floor of any HIPAA industry trade show and you can easily get lost in the sea of snazzy new isolators, tablet presses, packaging robots, fill and finish machines — the list goes on. But in a pharma manufacturing plant, this is much more complicated than replacing machinery and plugging in new units out of the box.  In fact, the process can be a regulatory quagmire that companies aren’t likely to emerge from for at least a few years. 

 
 

Manufacturing equipment is also a major investment. It’s no wonder pharmaceutical companies want to put off replacing them to get as much mileage out of their equipment as they can. On top of that, there can be uncertainty involved in trying a new kind of equipment and a learning curve that could lead to production disruptions. Overall, this slow timeline for regulatory approvals and a fear of the unknown creates an environment that makes pharma companies wary of change.


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“When it comes to new Big Pharma tech, no one wants to be the first to implement it — but everybody wants to be the fastest second,” says Maik Jornitz, president and CEO of G-Con Manufacturing, and co-chair of the Parenteral Drug Association’s (PDA) former Aging Facilities Task Force.

 

Yet, there are plenty of compelling reasons to give your aging facilities a needed facelift. Although the regulatory challenges biotech is facing are very real, they’re not insurmountable and can be conquered in a way that’s faster to realize. Also, putting off the process only delays the inevitable breakdown or a regulatory citation that’s likely to be more costly in the long run than an upgrade would have been.

 

Here, we’ll explore the critical link between these manufacturing issues and widespread drug shortages, provide real-world tips on how companies can improve quality control in aging plants, and explain why it pays to update older facilities.

 

Pharma Tech & Drug Shortages

 

The number of drugs and medical supplies in short supply is certainly not a new issue — in the past, the U.S. Food and Drug Administration launched a Drug Shortage Program to help conjure up solutions for keeping a healthy supply of the country’s high-demand medicines. Yet, the problem continues to vex regulators and the industry.

 

Manufacturing technology hiccups that hamper product quality have been shown to be a much bigger culprit of supply problems. The issue is particularly acute in aging facilities where the use of legacy equipment instead of automation often leads to higher rates of contamination.

 

A recent survey conducted by the American Society of Health-System Pharmacists (ASHP) asked pharma manufacturers to identify the cause of shortages, the most-cited known reason was “manufacturing” issues (30 percent). The FDA has also estimated that over half of injectable drug shortages are due to quality problems such as particulate contamination. According to ASHP, the rate of shortages is increasing and “severely impacting patient care and pharmacy operations.”

 

Medicine Manufacturing Compliance

 

Of course, biotechnology companies take calculated measures to remove any deviations that lead to contaminated products. But unfortunately, the economics of producing some types of drugs doesn’t provide incentives for making the needed investments that could help avoid problems with impurities.

 

The product on the FDA’s drug shortage list include a wide range of treatments. They often are the most basic elements for everyday patient care in a health care system (e.g. sterile water, lidocaine, saline, and bupivacaine). These high-demand, older products tend to sku lower on the profit margin scale — making investments into production lines for the drugs less attractive.

 

Pharmaceutical Manufacturing Age

 

There’s no easy way to define what makes a pharma plant officially over the hill. Some experts have estimated that most pharma facilities are designed to run well for about 20 to 25 years. And because all plants are in various states of aging — in regards to both equipment and the facility — it’s difficult to get a handle on how many plants in the U.S. have passed the 20-year mark. But Sue Schniepp, a distinguished fellow with Regulatory Compliance Associates, has seen plenty of first-hand evidence that operations in some plants look like they’re from a bygone era.

 

“The oldest line I’ve seen was about 50 years old,” she explains. “The company had a completely open line, and the only protection was a shower curtain.”

 

 

According to Jornitz, lines that are operating with frequent interventions, such as those susceptible to glass breakage, are at the highest risk of contamination.

 

“It’s important to take the human factor out of the equation,” he says.

 

Jornitz says that the fill lines are often the most vulnerable to contamination issues, but that older utilities, such as outdated water systems, can also put products at risk. Schniepp agrees that contamination risks go beyond equipment.

 

“It’s also in the floors if they’re not state-of-the-art,” she says. “You have to also look at the ceilings — anywhere you’re bringing the walls and ceiling together there’s a gap that could harbor microbes. It’s one thing to put in a restricted access barrier system (RABS). But if there is microbial growth in some of the plant’s older joints, what good have you really done?”

 

Anti-aging for pharma plants

 

Naturally, regular maintenance and upgrades can go a long way in preventing some of these problems.

 

“All facilities are aging,” Jornitz says. “However, when the company is reinvesting funds into the facility and have rigid maintenance or technology improvement cycles, the facility can age much slower.”

 

One of the challenges, however, is that companies are often reluctant or unable to shut down their line to perform maintenance updates.

 

API for Pharma

 

Per the FDA, all APIs are subject to Section 501(a)(2)(B), which requires all drugs to be manufactured in conformance with CGMP. 

 

“When you’re a contract manufacturer especially, sometimes you’re running around the clock,” Schniepp says. “But you have to shut it down to see what’s wearing, what’s tearing — and jump on it before it becomes a problem.”

 

Despite the one-week shutdown that’s typically required for a maintenance check on a company’s line, Schniepp points out that it’s better to spot cracks in the system when it’s down because when it’s running, operations can start to “go awry.”

 

“Look at the line holistically and make sure the equipment is working together,” she says.

 

Jornitz also recommends that companies use predictive maintenance to proactively improve the most important parts of the process steps. Additionally, he says that companies often neglect the importance of their equipment supplier relationships and don’t keep track of the availability of spare parts for their machines.

 

“It’s very important to get early warnings from the supplier that one of their equipment pieces is turning obsolete, so the end-user can act accordingly,” he explains.

 

Pharmaceutical Product Development

 

And putting off these kinds of assessments is likely to haunt pharmaceutical manufacturing companies in the end. Ronald Berk, chief technology officer and principal consultant at Hyde Engineering + Consulting, says that about half of the companies he’s worked with on updating aging facilities are in some kind of regulatory trouble.

 

“We worked for a company that constructed their pharmaceutical manufacturing facility in the late 90s, and the drug they produced was in such high demand that there was a capacity shortage, and they never upgraded the facility,” he recalls.

 

According to Berk, the company didn’t want to slow down production of the drug, so it “hit the snooze button for 20 years,” and never stopped to maintain and improve quality at the facility. Then, after the FDA inspected the facility, the company ended up in a consent decree situation (where the company enters an agreement with the FDA to improve parts of their line that are in violation of regulations). It’s exactly this kind of regulatory scrutiny that should motivate companies to upgrade.

 

Pharmaceutical Manufacturing Success

 

One of the major challenges companies face when dealing with aging facilities is navigating the landscape of regulatory requirements. In particular, companies are reluctant to install new equipment that the FDA could consider a major process modification under its Post Approval Change (PAC) rules. When this occurs, companies often have to revalidate their line, or go through all the tests needed for completing a prior-approval supplement (PAS), which can take as long as four years.

 

In the past, the FDA set out to address this major regulatory hurdle by offering alternative avenues to updating technology. Now, the agency will allow companies to make updates to their operations without a PAS if the new technology is considered a “like for like” change with the older equipment. It’s this route that Schniepp used to completely overhaul the line of one CMO where she worked — a major process she was able to get to the finish line in about two years.

 

“By doing ‘like for like’ you still have to do media fills and qualifications of the line, but you can do it without going through the PAS — as long as you don’t change the footprint of the line,” Schniepp explains. “It would be like upgrading the vanity in your bathroom.”

 

Quality Culture 

 

Here are the major challenges Schniepp faced and how she worked with the QA team to overcome them:

 

Culture and communication: While working as the vice president of Quality for the CMO, Schniepp was tasked with updating a line that was the workhorse of the company, about 30 years old and produced 75 percent of its products. But in the depyrogenation tunnel, the cooling piping was above the products, which was causing fluid to sometimes drip into the vials. The contamination had cost the company approximately $28 million in lost products and triggered an FDA inspection. Yet, Schniepp still faced resistance to change.

 

“When you’re a CMO, your culture is to please the client,” Schniepp says. “When we wanted to upgrade the line, we had to coordinate between about 15 clients that had products on the line and get them all to agree on one approach.”

 

According to Schniepp, not all of the clients thought the “like for like” approach would work. While some were worried about the downtime involved in undergoing a potential PAS, others believed the changes could possibly be communicated to the FDA on an annual reportable. To get everyone on the same page, Schniepp made sure that she wasn’t just talking to the quality department of every pharmaceutical manufacturing client. She also brought each company’s regulatory head into the discussions to get their input and help company leaders feel confident in her plan.

 

Schniepp also ran her plan past the FDA to make sure the agency didn’t have any major concerns with the approach

 

“What regulators really want to see is: Have you thought this out? Can you defend your case? And is your product going to be as safe and effective as it was before? That’s how you win this game,” she says.

 

Working in stages: Once it was time to implement the upgrades, Schniepp says it was all about planning ahead to make sure the company had adequate supplies of its products to offset downtime in operations. The company worked to replace the entire line during a four month period using the comparability protocol specifying before-and-after results for the product requirements for the manufacturing line being replaced.

 

Pharmaceutical Manufacturing QA Training

 

All told, Schniepp says it took a total of two years to update the aging pharmaceutical manufacturing line. Although the company had to deal with about four months of downtime during the process, it was much less of a burden to operations than it would have been to change the entire line under the PAS paradigm.

 

Training: Importantly, Schniepp says the company made sure to adequately train employees with the new equipment so that they could hit the ground running.

 

“We set up the line in a warehouse so the operators could work with it without making any products, because it was so different,” she explains. “They had to learn how to clean the RABS and change out the parts. All of that was going on while we were developing the comparability protocol for shutting down and restarting the line.”

 

Pharmaceutical Manufacturing QA Process

 

Just like when you’re making updates in your home, Berk says that pharma companies often fail to plan for unexpected bumps in the road when revamping their processes and procedures.

 

“One thing that gets underestimated is that if you have an old facility and you start trying to fix things, you might discover other things that need to be fixed or some equipment might break,” he says. “So some kind contingency plan for that is good.”

 

According to Berk, pharmaceutical manufacturing companies also often overlook the life expectancy of their automation and control systems, which can be much shorter than mechanical systems. Changeover to a new control system can also be more challenging than companies realize.

 

“The reality is that you need to spend quite some time testing and qualifying your control system, which can be very time consuming, and inevitably leads to a long downtime,” he explains. “I’ve been at sites where clients wanted to switch overnight. But the process can take up to a month — or half a year if it’s a large facility.”

 

Pharma Tech Outlook

 

There is hope on the horizon in the form of the industry’s newest technologies, if pharma manufacturing companies are willing to adopt them. The rise of automation and single-use equipment, for example, could help lower contamination rates. These advanced technologies allow companies to forgo much of the water utility systems needed to clean stainless steel parts.

 

There could also be changes on the regulatory front and the FDA has demonstrated a commitment to helping companies make needed upgrades.

 

PDA disbanded its Aging Facilities Task Force years ago, but the organization has since launched a new task force aimed at addressing the challenges of Post-Approval Changes. One of the group’s main efforts is to encourage the harmonization of the global regulatory approach to PACs so that companies don’t have to undergo separate approval processes for upgrades in different countries. If other countries accepted an FDA approval, for example, it could shave years off of the process.

 

“The No. 1 question is: How can new, robust technology be implemented faster?” Jornitz explains. “But also, how can we help harmonize global regulations?”

 

Continuous Improvement

 

But for too long, Jornitz says that the industry has used this regulatory hurdle as an excuse for not updating their facilities.

 

“Ultimately, running assets until they break down will cost much more than continuous improvements,” Jornitz argues. And when it comes to dealing with the red tape, Jornitz says that companies that are updating aging tech have a strong case to make with regulators. If they can show that new technology improves patient safety and avoids drug shortages, I think regulators will listen,” he says.

 

About RCA’s Pharmaceutical Services

 

Regulatory Compliance Associates (RCA)® has helped thousands of pharmaceutical companies meet regulatory, compliance, quality assurance, and remediation challenges. With more than 20 years of experience with FDA, Health Canada, EU and global regulatory agencies worldwide, RCA offers leading pharmaceutical consultants that can help you navigate through the challenges associated with evolving industry regulations.

 

Our team of over 500 seasoned FDA, Health Canada and EU compliance consultants and regulatory affairs experts can understand the complexities surrounding the pharmaceutical industry and the unique inner workings of the regulatory process. 

 

Client Solutions

 

Whether you’re in the product planning, development or pharmaceutical lifecycle management stage or need a remediation strategy for a compliance crisis, RCA® Inc. will guide you through every step of the regulatory process and create a customized approach depending on your product and your pharma company’s individual needs. Our clients include:

 

  • Companies new to FDA, Health Canada or EU regulations and the pharmaceutical industry
  • Start-up organizations with novel submissions to 510(k) submissions from multi-national corporations
  • Investment firms seeking private equity due diligence for pre-acquisition and post-deal research
  • Law firms seeking expertise in the remediation of warning letters, consent decrees, 483’s or import bans

 

Regulatory Affairs

 

Regulatory affairs is Regulatory Compliance Associates® Inc.’s backbone and we fully understand the complexities of the pharmaceutical and biopharmaceutical industries. Our expertise spans all facets and levels of Regulatory Affairs, from Regulatory Support for New Products to Life Cycle Management, to other services like Outsourced Regulatory Affairs, Submissions, Training, and more.

 

As your partner, we can negotiate the potential assessment minefield of pharmaceuticals with insight, hindsight, and the clear advantage of our breadth and depth of knowledge and experience. We offer the following four regulatory affairs services for pharmaceutical companies.

 

  • New Product Support
  • Product Lifecycle
  • Other Regulatory Services

 

Compliance Assurance

 

The regulations process surrounding pharmaceutical companies can be tricky for even the most experienced industry veteran to understand, and just one misstep could mean significant and lasting consequences for your business. At RCA® Inc., we offer the experience and resources necessary to guide you in quality compliance.

 

  • Assessments
  • Audits
  • Regulatory Agency Response
  • Preparation and Training
  • Inspection Readiness

 

Quality Assurance

 

Regulatory Compliance Associates® Inc.’s Quality Assurance services include assessments, strategy, implementations, staff augmentations, and identification of quality metrics to ensure continuous improvement, aligning with your business needs and goals. Our consultants are quality experts with experience spanning major corporations and start-ups. We know firsthand how to achieve, maintain, and improve quality, and we excel in transferring this knowledge to your organization.

 

  • 21 CFR Part 11
  • Data Integrity
  • Manufacturing Support
  • Facility Support

 

Remediation 

 

Regulatory Compliance Associates® Inc. has significant experience and a proven approach to managing FDA Warning Letters, Consent Decrees, Remediation and other serious regulatory situations. We know how to partner with executive, legal, and communication teams, and will assist management with a response that will be accepted by the regulatory agency and be realistic to execute. We can develop a comprehensive proof book of documented objective evidence demonstrating the corrective actions taken to remediate non-compliant issues. In addition, RCA can help prepare a comprehensive strategy to assist in your remediation efforts, drive continuous improvement, and maintain compliance with the regulations.

 

  • Regulatory Action
  • Warning Letter
  • 483 Observation
  • Oversight Services

 

About RCA

 

pharmaceutical consultantsRegulatory Compliance Associates® (RCA) provides healthcare consulting services to the following industries for resolution of compliance and regulatory challenges:

 

 

We understand the complexities of running a life science business and possess areas of expertise that include every facet of R&D, operations, regulatory affairs, quality, and manufacturing. We are used to working on the front lines and thriving in the scrutiny of FDA and globally-regulated companies.

 

As your partners, we can negotiate the potential minefield of regulatory compliance and regulatory due diligence with insight, hindsight, and the clear advantage of our unique expertise and experience.

 

  • Founded in 2000
  • Headquartered in Wisconsin (USA)
  • Expertise backed by over 500 industry subject matter experts
  • Acquired by Sotera Health in 2021

 

To begin the RCA® scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage. 

 

 

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