Industry proponents say continuous manufacturing produces better quality pharmaceutical products and at lower cost than those produced by batch processes. Sell the economic benefits to upper management, they say, and don’t be discouraged by the higher initial costs and perceived regulatory roadblocks.

Speakers at an American Association of Pharmaceutical Scientists (AAPS) meeting on continuous manufacturing of solid oral dose products attested to these cost, time and quality advantages of continuous manufacturing. The meeting was held in Baltimore on March 16-18.

Manufacturers are exploring this paradigm in different ways. While Vertex Pharmaceuticals Inc., is embracing continuous manufacturing full throttle for new drugs, Janssen Pharmaceutical Cos., a unit of Johnson & Johnson, will soon be proposing this mode of manufacture for a legacy product.

Pfizer Inc. is exploring the use of a more futuristic model of continuous manufacturing where mobile manufacturing units equipped with continuous technologies are shipped around the world.

Representatives from Merck & Co. Inc. , Eli Lilly & Co. , GlaxoSmithKline PLC , Roche , and Bristol-Myers Squibb Co. also presented case studies showing how they are integrating elements of continuous manufacturing into their operations.

Pharma is lagging

Pfizer’s Phillip Nixon said that despite the need for the pharmaceutical industry to adopt a more efficient model for producing drugs, industry is still mired in the past. He said that the industry manufactures tablets the same way it has since the 1950s with the advent of the rotary tablet press.

“I would contend that other industries are out there more where the pharmaceutical industry is lagging back. … There is a lot we can learn from other industries.”

The microelectronics, food, steel and petroleum industries, faced with the same global competitive pressures as the pharmaceutical industry, have embraced continuous manufacturing.

He said that many of the same manufacturing technologies used by these industries can be leveraged by the pharmaceutical industry as well. This includes the use of computational and predictive methods, and “intelligent” manufacturing that uses continuous processing, in-line sensors and advanced process control.

Nixon said that “most of us know that we can do better.” For example, the industry does not expend as much effort in particle engineering as it should, so characterizing active pharmaceutical ingredient attributes is an ongoing challenge.

“We have old processing equipment that has been around for decades in our plants so we end up formulating to the existing equipment and the API that is available. This is a suboptimal situation.”

Yet in the preferred state “there is process robustness; there is more particle engineering to get the targeted API attributes that we need.”

Nixon said that in the preferred state, a continuous manufacturing platform is embedded with timely analytics and advanced process control. He said that “if we do that correctly … we can get a much better process robustness.”

Continuous manufacturing could help the pharmaceutical industry increase its process capability from the 2-3 sigma range to 6 sigma, he asserted.

Nixon said that in the current state “we go through a couple of scale-up steps and each step involves several unit operations and they are done in different models in different facilities separated by time and place, and when we scale up we don’t have the same equipment so it is very inefficient and higher risk.”

“Let’s contrast that to having the same exact equipment used in development studies through commercial scale to get the same amount of tablets you need.”

PCM&M embodies factory of future

Nixon said that Pfizer has been working on a PCM&M (Portable, Continuous, Miniature and Modular) model, which is a vision of a manufacturing facility of the future.

These are flexible mini-factories that can be installed into existing warehouse spaces. The same equipment can be used for development and commercial manufacturing. Process analytical technology (PAT) and advanced process control (APC) are used in these systems for real-time monitoring.

Nixon explained that the model would dramatically reduce the effort, cost, time and risk associated with manufacturing and technology transfers. Having portable units also makes it easier to respond to local market conditions.

The system has feeders, a mixer and a tablet press all in one unit. It can convert powders to uncoated tablets in minutes.

Daniel Blackwood of Pfizer explained that having one unit make products avoids complicated technology transfers that can occur between sites.

He said that “our efforts are diluted with equipment changes and equipment locations, so what we have in one site is different than in another site so we spend a lot of time realigning these things for tech transfer. The result is a lot of time and effort.”

Nixon said that another benefit is higher quality formulations. “If you have the mixer closer to where you are forming the drug product you can eliminate a lot of the unnecessary things that cause problems such as segregation.”

This model can be used for making large and small molecule products, and APIs.

The first modular unit was just installed in Groton, Conn., and more will follow later. Pfizer partnered with vendors GEA Pharma Systems and G-CON Manufacturing in making the system.

Nixon said that “if we put this all together we can truly have world class commercial manufacturing that is better than what we have today.”

Pfizer is still experimenting with the model and would like to deploy it at the end of the year.

Continuous ideal for breakthrough

Jeff Katstra of Vertex said that having continuous manufacturing embedded with PAT is “ideally suited” for developing breakthrough therapies.

There is early finalization of the formulation on commercial-scale equipment, and the commercial product is equivalent to the product used for clinical development.

Also, a “data rich” commercial design space can be explored using less API than with a batch approach, and a highly consistent product quality is produced with continuous monitoring.

There is no scale-up required, there is no process knowledge gap between development and commercial, and there is limited material demand for process development because it allows comprehensive design of experiments with multiple data points to be executed early in development.

The scale-up involved in batch manufacture is time consuming and often requires significant changes in the manufacturing process and there are high material demands for commercial process development, and drug product is typically not available for Phase II studies.

Three components in Vertex line

There are three components of the Vertex continuous manufacturing line. First, an individual unit develops and manufactures clinical formulations in a discontinuous mode.

The second is a ConsiGma-25 unit for its continuous manufacturing operation and performs all of the necessary operations for manufacturing solid oral dosage forms. The unit has a wet granulation unit, fluid bed drying and direct compression. The ConsiGma unit is made by GEA Pharma Systems of Wommelgem, Belgium.

The third unit is a larger development and launch rig (DLR). The DLR does the raw material blending and the tablet film coating. It houses the ConsiGma-25 unit.

The DLR uses PAT equipped technologies for process monitoring. These include at-line near-infrared spectroscopy (NIR) for measuring incoming material attributes, NIR for measuring the granule uniformity and the water content, laser diffraction for measuring the particle size distribution, NIR for evaluating the blend uniformity and the water content.

Other PAT tools used are Raman for measuring the tablet coat thickness, a tablet tester measures weight, thickness and hardness, and Raman measures the API form and identity.

Vertex has been an early pioneer of continuous manufacturing and has submitted a new drug application for a cystic fibrosis drug. If approved this would be the first facility to produce a new drug using continuous manufacturing ([A#08150326005]).

Vertex, he said, is “fully committed to continuous manufacturing. We want to use this across our development portfolio, we want to have raw materials and blending and all the way to tablet coating. We also want PAT in these systems to allow for real time release. The drivers are highly consistent product quality, data rich submissions, and API savings.”

Myths debunked

Katstra said that while many pharmaceutical companies are experimenting with continuous manufacturing, none have been commercialized using a fully continuous process.

The experimenters include Pfizer, Merck, Lilly, Novartis, J&J and GSK. He said that “we’re trying to be the first with our lead cystic fibrosis compound.”

The pharmaceutical industry is reluctant to adopt this model because of the high cost of purchasing the equipment as well as the fear of regulatory rejection. He said that these are misperceptions that are holding industry back.

The initial investment can be realized with money saved in energy costs. “We all know it is very expensive so that is why GEA is offering buy one and get one free for the next rig.” GEA is the main supplier for continuous manufacturing equipment.

He said there are also cost savings from reduction in use of API for development, reduced energy consumption and higher production yield.

As for the second hurdle, he said that regulators are encouraging the industry to adopt new technology. He also said that for breakthrough therapies, the opportunity exists to work closely with U.S. regulators.

An FDA regulator at the meeting encouraged industry to adopt continuous manufacturing, and said that the agency would work with sponsors in developing the necessary data to support submissions ([A#08150326005]).

Changing business environment

A changing business climate that necessitated reining in costs prompted Janssen Pharmaceuticals, a division of Johnson & Johnson, to look to continuous manufacturing.

Janssen’s Philippe Cappuyns explained that declining prices and reimbursement rates as well as increased competition with generic companies were taking a toll on the company’s bottom line. The company was looking to reduce costs and improve efficiency.

Cappuyns said that “there are a lot of ways to increase that efficiency. One way to do that is to look at technologies and how we develop and manufacture our products and to investigate potential opportunities that lie behind these technologies.”

Yet before making a long-term investment in continuous manufacturing technology, Janssen needed to explore if it was worth the cost.

Janssen decided to undertake a case study investigating whether an existing product made from batch was comparable to a product made from a continuous process.

The manufacturer wanted to compare the stability and the repeatability by performing three consecutive production runs and by monitoring the granule and tablet properties.

The product consisted of two APIs comprising 85% and 9% of the total formulation respectively.

Products were comparable

The case study found that the granule properties and the tablet properties were comparable from batch to continuous.

The granule properties included residual moisture content and particle size distribution. The tablet properties were hardness, friability, disintegration time and dissolution.

An added bonus was that the product from the continuous line had less moisture than the product from the batch line.

Cappuyns said that “overall we saw good repeatability.”

One benefit was the lower cost and greater environmental sustainability of the continuous process. Janssen saved 34% in energy costs and the process level and 30% at the plant level.

Janssen, he said, is at the beginning of this technology journey.

He said that “continuous manufacturing technologies for us is a long journey. It is not free. It will take a lot of time and a lot of resources. … From that perspective it is important to understand what kind of benefit we get from this huge investment.”

The company just installed a continuous manufacturing line at its site in Puerto Rico and plans to submit a manufacturing supplement requesting approval from Japanese regulators sometime in 2016.

Janssen has had “preliminary conversations” for switching this product over with several authorities including FDA and China.

Cappuyns said that “in the long term we want to invest in continuous manufacturing development and to basically copy and paste the continuous line into our manufacturing launch sites.”

How to get buy-in

At a roundtable discussion, one meeting participant asked presenters how they were able to get management support for continuous manufacturing.

The participant said that “we have seen some really good examples of economic drivers and other motivating factors for implementing continuous manufacturing. … What information or advice was most pertinent in getting senior management to buy into the process? Was it an increase in quality? Or better understanding of the process? What was it that tipped the scale?”

Robert Meyer of Merck said that what sold senior management was the visual impact of showing how products can be made with such a small footprint.

He said that “we at Merck have been further behind than almost everyone else on the panel.”

Yet the most valuable thing the team did was presenting the case for continuous in a room with the equipment already in it.

“What really sold it was we built it and we put it in a room and we brought people in and said, ‘this room can supply this blockbuster product for the entire U.S. market just from this 24 square foot space.’ That was where they got it. It was almost like they needed to see it. We had to go beyond the PowerPoints.”

Pfizer’s Philip Nixon advised selling the cost benefits of continuous manufacturing.

Nixon said that “the pharmaceutical industry has hit a lot of turbulence. We have these small volume products and we have lost a lot of drugs that have gone off patent. If you want to talk to your leaders, they are wondering what is going to happen five to 10 years now. … Show them some options. Producing variable batch sizes is a huge benefit on how they can run the supply chain and reduce inventory. There are a lot of economic benefits. Just the option to show small footprint and variable batch sizes helps.”

Marianthi Ierapetritou of Rutgers University in New Brunswick, N.J., said that “the cost is painful at the beginning. I hope this gets less painful as we get more understanding. It is really much easier to launch in a continuous line than a batch line.”

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