Solid-Dose Pharma Manufacturing Roundtable

Contributors:
Barry Regan, director of manufacturing, Abbott Laboratories, Global Pharmaceutical Operations Division (Abbott has been providing pharmaceutical contract manufacturing services for more than 25 years and is recognized as a global leader in biologics, potent and small molecule API manufacturing, as well as drug product manufacturing and packaging.)

Thomas Mauritzen, business development manager, Robert Bosch Packaging Technology, Inc. (Bosch provides filling, process and packaging technology for pharmaceutical products, including sterile filling and packaging processes, as well as isolator technology.)

Fred Cooley, VP Global Operations, Capsugel (Capsugel provides dosage forms and solutions for the healthcare industry, including an array of products and services, from hard gelatin, liquid-filled, and vegetarian capsules to R&D equipment and liquid formulations.)

Tom Tappen, director of business development, Fluid Air (Fluid Air is a manufacturer of solid-dosage processing equipment and controls for the pharmaceutical, food, cosmetics, and fine chemical industries.)

How has solid-dose manufacturing evolved in the past 10 years?
Barry Regan, Abbott: Technology plays a more significant role in solid-dose manufacturing than ever before.
Equipment has become more sophisticated with integrated in-process controls requiring fewer manual interactions. These in-process controls and feedback from the equipment help ensure quality, efficiency, and consistency throughout the manufacturing process.

Another trend in solid-dose manufacturing is the use of multi-use equipment on one platform. Quick changeovers allow one piece of equipment to replace what typically was three or four pieces.

New technologies in formulation, which expand the solid-dosage portfolio and give distinct advantages in ease of use, stability, and processing, also continue to be seen.

Thomas Mauritzen, Bosch: On the machine side, solid-dose manufacturing has evolved quite quickly in the last few years. As capital budgets were slashed during the financial crisis, Big Pharma went from dedicated machinery for blockbuster products to needing flexible equipment that can be used for a large variety of products. As capital budgets have expanded again, the requirements have not changed. Machinery uptime has also seen renewed focus. Any design improvements or features that allow for quick and easy assembly, disassembly, and cleaning have become a staple of technical specifications for new machinery. There has also been a huge increase in attention to quality assurance in the last 10 years. In the manufacturing arena, this has taken the form of 100% checkweighing, visual inspection, and increased sampling frequencies. The ultimate goal, however, is real-time-release of product. This means that a product is deemed good during the filling/pressing process through process analytical technology (PAT), and any bad product is immediately rejected.

Fred Cooley, Capsugel: First, filling and tableting equipment has become much faster, more automated, and more accurate, which has improved the overall process for manufacturers and suppliers alike. We’ve also seen many cases where blockbuster drug runs have been replaced by high-value therapies for smaller patient cohorts, yet these ingredients don’t always optimize in traditional tableting venues. Finally, quality by design has required simplification and reduction in production steps where variability can interfere, a spot where hard capsules have excelled.

In the area of hard capsule manufacturing, there have been a number of advances in quality, and a much broader range of applications are now available, such as capsules for delayed release, dry powder inhalers, and lipid-based formulations. In addition, hard capsules are now available in a very wide array of sizes and colors, allowing manufacturers to create a unique and customized appearance and ultimately giving them a means to improve patient compliance and reduce polymedication errors.

Tom Tappen, Fluid Air: Solid-dose delivery forms have become more and more sophisticated and complex in the last 10 years. Equipment manufacturers are now required to build machinery to accommodate these new delivery systems.

Tablets and capsules formerly came in two basic forms: immediate release and modified release. Now we see both forms in one tablet, orally disintegrating tablets, solids delivered in rapid dissolving film, minitabs, and capsules containing both liquid and solids. Another form is sustained-release delivery systems, which are increasingly complex: a layer for immediate release, a buffer, and a layer for 2-6 hours.

A second phenomenon is increased regulatory influence. We see a paradox where the large pharma companies and the FDA are promoting initiatives like PAT, QBD (quality by design), and continuous manufacturing, yet the regulatory morass of approval frustrates attempts by pharmaceutical producers to take advantage of technology advances.

What is the future of solid-dose manufacturing?
Barry Regan, Abbott: Solid-dose manufacturing will continue to be a prevalent method for delivering therapies. Customers are comfortable and familiar with solid-dose tablets as a method of delivery for their medications. Consolidation and optimization of solid-dose networks will continue as Lean principles are expanded to find the most efficient method for manufacturing.

Thomas Mauritzen, Bosch: The future of solid-dose manufacturing will continue to see the optimization of filling/pressing systems to be as widely applicable as possible and to have the greatest uptime and yield. Quality assurance will mandate PAT systems that allow for implementation of real-time release of solid-dose products, allowing for the quality levels of 100% of products to be guaranteed before the products are sent to the consumer.

Fred Cooley, Capsugel: We will continue to see an increase in dosing alternatives that allow for multiple APIs targeted to various points in the digestive tract with increased accuracy. In the hard capsule space, we continue to advance our use of alternate polymers to provide even more specific targeted release profiles.

Capsule design has also changed to include features that make capsule filling equipment much more productive and efficient. I think we’ll continue to see advances in this area in the future.

Tom Tappen, Fluid Air: If this question refers to whether solid-dose tablets/capsules will remain the primary drug delivery form into the future, the answer is a resounding YES!

Tablets and capsules will continue as the preferred delivery system for a number of reasons:

• proven, accepted, predictable performance
• cost efficient
• easy to administer
• able to achieve predictable dosage delivery
• stable
• relatively tamper proof
• established methods for monitoring

 

There are a number of new and very interesting forms of delivery coming into the market, but when measuring pros and cons, tablets and capsules will prevail.

What are some of the most common misconceptions about solid-dose manufacturing equipment?

Barry Regan, Abbott: One common misconception is underestimating the need for continued maintenance and engineering support for solid-dose manufacturing equipment. Appropriate preventive and predictive maintenance needs to be performed on all solid-dose equipment to ensure it operates at peak levels. Continued engineering support ensures that the equipment’s utilization can be maximized throughout its lifetime. Systems integration, control optimization, and productivity enhancements help ensure the performance of equipment for many years.

Thomas Mauritzen, Bosch: One common misconception is that solid-dose manufacturing equipment hasn’t changed over the years. Equipment that is 30-40 years old is considered to be a “workhorse,” and deservedly so if it still runs everyday production. When replacing this type of equipment though, there are a lot more features to consider than there were 30-40 years ago. Make sure you get educated on what is out there and what new technologies could help benefit your production. Equipment vendors are always more than happy to provide you an overview of new and developing technologies.

Fred Cooley, Capsugel: I think many people still believe that solid-dose manufacturing equipment is slow and often wasteful of fill material. In fact, today’s equipment and capsule design provide highly automated processes that maximize speed and minimize waste.

Tom Tappen, Fluid Air: One of the most common misconceptions is that a single machine can be designed and purchased to do any number of things well. Bad idea. Choose a machine and model that is best-designed to handle the primary task at hand. If possible, design the equipment to be able to incorporate features which can be added later, but do not buy a machine expecting it will do everything.

Many believe machines for pharmaceutical manufacture are simple. Most are not simple. Customers want more of the latest technology, custom features, etc. This makes them more complicated.

Finally, just about everyone complains that the machines should be cheaper. Maybe they can be made cheaper when the regulatory standards permit the use of more modern technology. The old maxim “you get what you pay for” still applies. So, many times we hear from customers who got a “fabulous” deal and price on a new machine, only to find out that there is no service or parts available in the United States and no one around who can be of help.

What are some common mistakes pharma companies make when purchasing solid-dose manufacturing equipment?
Barry Regan, Abbott: When selecting equipment, one mistake is to think only about the immediate needs. Equipment is built to last for many years. Therefore, the value that the equipment can deliver years later must be considered. The design and maintenance needs of the equipment as well as support from the vendor, large or small, is a key factor in equipment selection and should be well thought-out prior to purchase.

Thomas Mauritzen, Bosch: One of the most common mistakes is not to consider the aftermarket support of a machine. Is the equipment vendor responsive after the machine is delivered? If I have any warranty issues, will they be handled promptly? How quickly can I get a set of size parts if I have a new product to run? These questions, among others, are things to ask around about. Don’t hesitate to ask your equipment vendor for reference contacts at other companies that you can pose these questions to.

Fred Cooley, Capsugel: Pharma companies really need to do their research before purchasing solid-dose manufacturing equipment, and if they are working in emerging markets, environmental controls have put a whole new set of demands on equipment. As you know, it can be costly, and they need to look to get the most use and life out of what they invest in.

There are a lot of alternatives on the market today, and they can improve the usefulness of their equipment if they opt for machines that can fill a wide range of applications. Some of today’s capsule-filling equipment can fill liquids, beadlets, or pellets and perform over a wide range of powder densities and granularity of the fill materials available today. Companies should look for versatile equipment that will address both current and future needs.

Tom Tappen, Fluid Air: Failure to adequately define what is needed in the way of process, batch size, controls, data logging, changeover, maintenance, validation requirements, etc. is common. Operations, engineering, QA, and regulatory cannot agree on what will work and what is unacceptable.

Another problem we frequently encounter is the customer who will buy equipment with more sophistication and features than will be utilized. Engineers and educated technical personnel have input on these decisions, but the actual operation of the machine is left to production personnel, many of whom have no interest in learning about the operation of the new equipment. This leads to what we refer to as “reluctance to take ownership” of the new machine. Our start-up personnel train customer personnel, but there is reluctance to come forward and really learn how to manage the equipment. Many of the advanced features provided for the machine are disabled or neglected because no one took the time to learn and use them.

How should a pharma company evaluate what type/size/quantity solid-dose manufacturing equipment they need? Barry Regan, Abbott: The first point to consider is whether or not there’s a need for solid-dose equipment based on what is available within the current manufacturing network. Current capacity, processing capabilities (long- and short-term) and regulatory requirements should be considered when determining what equipment is needed. When these questions have been answered, then the primary driver for equipment selection is the manufacturing process itself. The process, more than anything, dictates the type of equipment needed. The requirements of performance (speed, capacity, quality, longevity of the process, and return on investment) will ultimately drive the specific model and quantity needed.

Thomas Mauritzen, Bosch: Generally, the determination of what solid-dose manufacturing equipment is appropriate for a given application is based on the batch size to be run and how many batches per month or year are to be run on the equipment. The bigger the batch, the more dedicated the equipment tends to be. In this case, the production speed equipment is generally appropriate, as changeovers will not be executed as often. If you are running lots of different products in smaller batches on a piece of equipment, make sure that you are selecting a flexible machine that allows you quick changeovers. When comparing machines, if a piece of equipment has a quicker changeover time than its competitors, it can have a huge potential output advantage over the lifetime of the machine. Don’t take the equipment vendor’s word for it; ask for a reference contact.

Fred Cooley, Capsugel: See my previous answer.

Tom Tappen, Fluid Air: This is a question dictated by product mix and the development work done in R&D and pilot-plant operations. Customers generally do a good job in planning what products they are going to make, how the products will be made, and in what quantities.

Unlike many industries where manufacturing and manufacturing methods are very secretive, the pharmaceutical industry is much more open to disclosing information. Companies should, therefore (whenever possible), study the methods of others making similar products to learn what works and what does not work.

What advice would you give to end users searching for solid-dose equipment?
Barry Regan, Abbott: Performing the necessary research and prework is essential in selecting solid-dose equipment. It’s important to explore the options available before committing to specific equipment. Begin with understanding the technology available and defining the current and future process needs in order to match the equipment with the manufacturing needs. Consider whether an off-the-shelf or customized model is needed. Clearly defining the equipment size, capability, and controls will help optimize the equipment for current and future applications.

Leverage vendors’ knowledge and the experience of their customers. Ask to visit sites where the equipment is installed, and seek advice from current users about the value the equipment provides. Understanding users’ experience with the equipment is a good measure for predicting what your experience may be in the future as well.

Thomas Mauritzen, Bosch: I would advise end users searching for solid-dose equipment to conduct processing/filling tests at the manufacturer’s site, ask for references for your specific processing or filling application from the vendor, and contact those references to get direct information on machine performance. If your specific product application is not considered standard, then make sure to have the vendor prove to you that they can handle it. This testing tends to be beneficial to both parties, as prepurchase testing will illuminate any potential trouble-areas before the machine is built, allowing for easy fixes through the design and construction phase of the project. Equipment vendors are generally pretty forthcoming in providing reference lists, as well as contact information for the key users at those companies, if you don’t have your own contacts at those companies. This will often be the best way to find out if the equipment you are looking at is accepted by the market. Remember to ask the reference contact, “Would you recommend this machine to my company?”

Fred Cooley, Capsugel: Look for equipment from a company that has a wide range of experience with proven technical support. Today’s solid-dosing machines are very high-tech and often need upgrades to the software as well as the hardware, so it’s important to choose a company that will be there when you need support and help with any issues you may encounter in the manufacturing process. Ask what type of technical support is provided and how quickly it can be provided.

Tom Tappen, Fluid Air: Lots of suggestions for this one:

• Evaluate the depth and talent of the company technical staff. Are they experienced? Have they been with the company for some time? Do they appear to have a vested interest in the enterprise? Do they like their jobs and their company?
• What is the company’s reputation for prompt, competent service? Check it out. Does it tend to cater to large companies and neglect the smaller companies? Take a representative sampling. Do not just rely on hearsay from one or two sources.
• Is the prospective vendor open to customize and later retrofit the equipment, or does it just want to sell the specified model and available options only?
• What kind of spare parts inventory does it stock? Is it local, or does it ship from overseas?
• Check out the designs of the equipment. Why does one manufacturer differ in design from another. What is the reason for the design difference? It is easy to buy a “Ford or Chevy.” Why not check out what innovations others made to enter the market?