Industry Viewpoints: Can Sterile Manufacturing Turn the Ship Around?

The past five years have been troubled ones for sterile injectables manufacturing, with key players and contract manufacturers jumping ship, facilities being shut down, and shortages of critical drugs and cancer therapies ensuing.

During this period, companies including Teva, Ben Venue, Hospira, SCM Pharma, and Aesica Pharma have either shut down major facilities or left the market entirely, citing high costs and inadequate funding. BenVenue, which went out of business in 2014, spent more than $350 million to improve its facility in Ohio after receiving an FDA warning letter, but still expected financial losses of $700 million through 2020 had it stayed in business. Hospira spent $375 million in improvements after its Clayton and Rocky Mount, NC plants were cited by FDA, but still decided to close Clayton. Now the company is being acquired by Pfizer.

New companies, including BioTechnique and Symbiosis, are entering niche parts of the business, and AMRI bought OsoBio’s business in 2014. Mistakes and compliance slips have brought new attention to what is needed for compliance. In addition, equipment is now available to automate more of the processes and offer features such as process analytical technology (PAT) to improve quality. What will be needed to invigorate sterile manufacturing? Industry associations, particularly Parenteral Drug Assocation (PDA) and International Society of Pharmaceutical Engineers (ISPE), are examining these issues as they connect to infrastructure and product scarcity.

Experts in the field-James Agalloco, principal consultant, Agalloco and Associates, Inc.; Jacques Navellou, co-founder of Axys Network; and Victor Lee, vice-president of business development at BioTechnique-shared insights and views with Pharmaceutical Technology on the status of the market and needed steps to make corrections in business operations.

Stopping the race to the bottomPharmTech: What has the industry learned from all these issues with sterile injectables? Are conditions improving?

Agalloco: Employees are aging and people are retiring, so there is less mentoring going on, and less talent available. We had a headcount cut 20 years ago and we’re finally feeling the effects of it, because there is nobody left around to keep things going. Companies are running without sufficient technical knowledge.

PharmTech: Does outsourcing affect this picture?

Agalloco: The problem with outsourcing is that, when you outsource, you need two people who know what they’re doing: one on the inside, and one on the outside.

PharmTech: Have companies gotten better at contract manufacturing organization (CMO) oversight in this area?

Agalloco: I think that the problem again is headcount. CMOs want to operate lean. They are not overstaffed, and the processes have not gotten any simpler in the past 20 years. They’ve gotten harder, and we don’t have the knowledge on the CMO side or even the sponsor side to really cover this. We’re doing a good job on the development side, to develop products, but when you bring any new product into a commercial setting, there are all kinds of perturbations that can happen, for instance, changes in materials, in scale of equipment, analytical methods. It’s not as simple as it was years ago. It now requires more, and we don’t have the people.

PharmTech: Has there been improvement in spite of these challenges?

Agalloco: Very few CMOs have really invested in top-of-the art technology. There are a couple that are trying to get there, but it’s difficult for them. Many of the CMO facilities that we see are older. They’re the original innovator plants that were sold off or declared excess. If you’re a major pharma company, you don’t sell your best plants, you sell your oldest ones. So the buyers end up with less satisfactory operations, weaker utilities, less infrastructure, older equipment. It all contributes to the trouble.

Replacing the bandaging approachPharmTech: What types of investments did the industry make in equipment and training after so many FDA warning letters were issued?

Agalloco: Basically, a lot of bandaging was done, and fixing what is here because it is much harder to anticipate and build new and start fresh, which is what should have been done. Today, so many CMOs and generics companies are using older plants. There is a need to invest, but the economic incentive is gone.

I’m very worried. Think about biosimilars. It’s great that all these sophisticated products will now be less expensive, but it will effectively start another race to the bottom, as we saw with generics. It may take another 10 to 15 years to get there, but, again, we will be chasing lower and lower cost without the knowledge and ability to deliver the consistent quality that we should have.

The answer to quality is simple, to me: Having enough qualified people, having the ability and willingness to invest in technology. Consider the smart phone. Electronics manufacturers invested in that. Where is the comparable investment in pharma? Who is challenging the system and saying, ‘We should have better equipment and more reliable controls and instant feedback from our systems.’ Instead we are satisfied with quality that is, at best, mediocre.

We need to rethink our whole philosophy. Is quality about meeting the spec or the test or eliminating defects and reducing variance so we can reduce the testing and improve the reliability of the output? We give lip service to quality, but it’s all about bandaging and fixing and documenting, not about really making the process more reliable and more robust so that the output is better and always meets the needs of patients.

A regulatory culprit?PharmTech: Are regulators helping to change this?

Agalloco: Regulatory agencies help in pointing out problems. They make it clear there’s something wrong. But they are not helping with reviews and institutionalized checks and balances. The time required to get an abbreviated new drug application (ANDA) approved is abysmal.

But if I say that I have a great way to improve the way I make a product, which will need new equipment, or a new test method, another submission will be needed, and it will take months or years to get an answer. No wonder people just say ‘why bother?’

PharmTech: Is regulation in sterile processing excessive, and is it really based on science?

Agalloco: Today, some folks yell about objectionable microorganisms. In the past two to three years, the National Institutes of Health (NIH) funded the Human Microbiome project, sending researchers to do studies, and found that 30% of humans on the planet have staph in their nose. Now I’m going to tell you that you can’t make a tablet that contains trace levels of staph even though 30% of the patients already have it. Who are we protecting and what are we protecting them from?

Maybe FDA’s expectations are too stringent. In some cases, they may be pushing for things that don’t add value to patients.

The light of innovationPharmTech: Where are you seeing innovation in sterile processing equipment?

Agalloco: The equipment side is the only place we’re seeing innovation. Vendors have come up with equipment that provides more feedback, that compresses and contains at the same time, that features PAT. But it comes at a price. Typically, companies opt to use the older equipment that has already been paid for. New technology is only being used for new products.

There have been some stumbles, for example with restricted access barrier systems (RABS), which got a lot of hype in the late 1990s and early 2000s. Now, more people are seeing that isolators are more cost-effective.

If I’ve spent $100 million on a RABS facility, am I going to tear it down and use isolators? I’ll keep going. If manufacturers had made a better decision 12 years ago, we might see more isolator facilities.

PharmTech: What are the biggest lessons that the industry has to learn, apart from the need to invest?

Agalloco: We have to invest in our people first. That’s the key more than anything else. The idea that we can make these really complex products without really well trained and well-qualified people and enough of them is a mistake. We need headcount. Companies in Korea, Japan, Taiwan, and Singapore are moving ahead of us because they are investing in humans and in technology.

PharmTech: How do we solve the problems you’ve cited?

Agalloco: Industry doesn’t know how to fix what’s wrong. I can see why CMOs are desirable and why they are not going away, but our industry has effectively sacrificed its current products for its future ones. Manufacturing has become a backwater in our industry. It’s something we have to have, but we just aren’t good at it anymore.

Recently, a major company recalled sodium chloride for particles. We’re talking about water and salt. How easy can it be? That’s the saddest part of all: apart from the complex compounds, many of the generics on the shortage list are very simple to make.

PDA and ISPE are trumpeting their drug shortage action programs. Why isn’t PhRMA getting involved in some kind of consortium? Why aren’t they looking at the root cause?

Moving to multifunctional systems
Victor Lee is vice-president of business development at BioTechnique, a cytotoxic sterile injectables contract manufacturer (CMO) that recently bought a fill-finish facility in Madison, WI from the Wisconsin Alumni Research Foundation. Lee shares a CMO’s perspective with Pharmaceutical Technology.

PharmTech: What lessons has the industry learned from events in the sterile injectables space over the past few years?

Lee: There is no straightforward answer. Within the past 5 years, there seemed to be more emphasis on enforcement of regulations and rules at FDA, and we saw an increase in 483s, warning letters, and consent decrees. Several factors were at play with selective budgetary spending being a major culprit. In the world of generics, margins are very tight, so cost control is a main driver.

The FDA warning letters pointed out weak quality systems and staffing issues, perhaps because people who are multitasking and overwhelmed are more likely to make mistakes. Also, the degree of microbial contamination reflects the amount of time a company has devoted up front to make its processes as robust as possible.

PharmTech: Have you seen any improvement in the way sterile manufacturing facilities are run since these problems surfaced?

Lee: In 2010, I worked at Teva when the facility received a warning letter. We had to go through a major process to get back into compliance. During remediation we stopped manufacturing, which resulted in exacerbating certain drug shortages.

More facilities recognize that people are the number one source of contamination, and FDA has encouraged industry to automate as much as possible, so there has been an uptick in the design and use of isolators, disposable process equipment, and the development of rapid microbial monitoring systems.

The pharma industry is typically a slow adopter of new technologies, but with isolators and restricted access barrier systems (RABS), early adopters proved to the rest of the industry that new technology is not all that intimidating. But it did take years, and that is how it is with any new technology in the pharma industry.

PharmTech: What should one be aware of when working with sterile injectable CMOs?
Lee: CMOs are typically working in multiproduct facilities. That’s how they generate margins and revenue. So it is essential to ensure that there is no crossover contamination. Cleaning validation has to be robust. This is one reason more people are using single-use technology.

PharmTech: Have design changes in isolators and RABS made them easier to use or more cost effective?

Lee: Basic isolators and RABS haven’t changed much over the past five to 10 years, but there have been incremental improvements in automation. Within the past two to three years, there has been an increase in multipurpose design, using equipment within the isolator that is multipurpose and can handle various processes. Instead of building separate lines, companies can now use one machine; one day, it can be used to fill syringes, another day, bags, and another day, vials.

Communication, and the sharing of new ideas, needed
Jacques Navellou, co-founder of Axys Network, aseptic processing consultants, discussess progress in technology, and the need for improved industry/regulator communication, with Pharmaceutical Technology.

PharmTech: What positive changes have you seen in sterile manufacturing over the past five years?

Navellou: The most important changes have been driven by improvement of the sterility assurance level, including best aseptic practices, better operator training in microbiology and practices, barrier technology design, and automation. The fewer people you have making the product, the less contamination you will have.

Other technology has been validated that will improve quality, including single-use technology, aseptic connectors and tubing, environmental monitoring technologies, and improved sterilization processes, such as pascalization. Regulations are also being improved, on a continuous basis, as evidenced by the European Medicines Agency’s Annex 1.

PharmTech: What will be needed for the future to maintain progress and prevent the supply shortages and other problems we’ve seen over the past five years?

Navellou: We need to see continuous interaction between industry, regulatory agencies, and vendors through technical meetings and working groups, in which they can share their experiences. We also need to work on the concept of parametric release to a point where we won’t need to do traditional sterility testing.

Article DetailsPharmaceutical Technology Outsourcing Resources Supplement
Vol. 39, No. 17
Pages: s48-s50

Citation: When referring to this article, please cite it as A. Shanley, " Industry Viewpoints: Can Sterile Manufacturing Turn the Ship Around?" Pharmaceutical Technology Outsourcing Resources Supplement 39 (17) 2015.