Building a Quality Formulation

The challenge of time vs. risk

by Cindy H. Dubin

The objective of formulation development sounds simple enough to a layman: Put an active pharmaceutical agent into a platform that can be properly delivered for therapeutic value. But from the point of view of formulators and pharma companies, this process is anything but simple. Pressure to fill pipelines and get product to market quickly can take their toll on formulation development, as pharmaceutical companies — particularly smaller firms that are struggling to get their feet on the ground — try to hurry through the formulation development process. This can often lead to finger pointing, disappointment and risk.

Photo courtesy of Glatt Pharmaceutical Services

“The greatest disappointments come when attempts are made to short-circuit the process,” said Charles Frey, director of formulations development for Coating Place, Inc. “Often, clients are looking to get their products to market as fast as possible and consider bypassing quality steps. Funding for these companies is based on the revenue they generate and they look for avenues to short-cut the process. There is a risk with that.”

“As a CRO, we have to understand the personality of the client and what their tolerance for risk really is,” said Tom Salus, business development manager at Glatt Pharmaceutical Services. “Some want to skip certain steps based on the type of company they are; emerging/startup/virtual companies are driven by timelines and meeting milestones, so they are willing to forego certain steps.”

Elsie Melsopp, Ph.D., director, Formulation Development, Solid Pharmaceuticals, AAIPharma, agreed: “Our team sits down early with the client to provide in-depth analyses of the risks involved with accelerated programs to our clients. The decision to forego a specific experiment, or conduct a certain test, or move forward with a formulation based on four prototypes rather than 10, these all present certain risks that need to be balanced with the overall objective. And objectives change. While overall both client and AAIPharma have long-term sights set on a product for the market, project timelines are typically segmented into shorter term milestones upon which client, contractor and investors can measure success. Both scientific and business risks must be identified during the course of the development and their impact considered. Short-changing the process can move it along faster at the time, but it can prove to be at the expense of the overall objective later on.”

In an effort to thwart such attempts and ensure quality, FDA did its part by presenting industry with PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. The guidance, intended to describe a regulatory framework (Process Analytical Technology, PAT) that encourages the voluntary development and implementation of innovative pharmaceutical development, manufacturing, and quality assurance, is based on science and engineering principles for assessing and mitigating risks related to poor product and process quality. From a formulation perspective, a variety of analytical tests must be performed, each for a particular quality attribute, to study both in-line materials and end products.

“There is a big push from FDA to perform Quality by Design (QbD); quality is built into every phase of a pharmaceutical product,” said Mr. Frey.

But PAT is not feasible for some. At its optimum, PAT could test the quality of every one of the often one million or more capsules or tablets in a batch,” remarked Michael B. Mackaplow, Ph.D., associate research fellow, Global Pharmaceutical R&D, Abbott. While companies are introducing PAT into their manufacturing processes, they presently mainly rely on statistical testing to ensure quality, explained Dr. Mackaplow. “We test at different stages and test certain amounts of product using mathematical algorithms. This is an extremely conservative method that gives us confidence to make assumptions about the entire batch based on a small portion of the batch. The chances of us accepting a false positive are very low. There is a greater chance of us rejecting a false negative.”

Mr. Salus said that PAT is a great tool for pharmaceutical companies that have inhouse compounds being routinely manufactured. “A CRO such as Glatt, however, turns over its product so it is difficult to implement the benefits of PAT,” he contended.

Hindsight is 20/20

More often than many care to admit, formulators run into thorny situations that can put the breaks on product development. The key to circumventing these issues is communication, both with clients and with the process development team. Orapin Rubino, Ph.D., associate director of Formulations and Product Development for Glatt, said she routinely screens APIs to ensure physical characteristics and the quality of raw material to avoid problems during scaleup. “Additionally, we have a unique development philosophy, working early on in development with the process development team,” she commented. “Formulation and process work should occur at the same time to produce a robust, scalable and repeatable dosage form.”

A similar approach is taken by AAIPharma. Dr. Melsopp said teams are formed around each project with members from multi-disciplines, including formulations, analytical, manufacturing, quality, regulatory and project management. But sometimes that isn’t enough. “We’ve probably seen it all at one time or another, ” said Dr. Melsopp. “But perhaps some of the thorniest issues are related to moving fast early on versus preparing for challenges that will come later. Early on, the initial objective is usually getting into the clinic as quickly as possible and the question is more one of ‘Do we have a product?’ rather than ‘Do we have an NDA?’ Since statistics demonstrate a very high probability of failure early on, there is strong logic for moving ahead through early phases of clinical study with a formulation that may not be commercially viable. This can present some real hurdles later on in the project when clinical results are promising and NDA filing now appears to be a reality. Obviously, having a formulation and the ability to manufacture on a small scale is good. But it is critical to have a formulation that is stable and a manufacturing process that is commercially viable by the time the NDA is filed. We encourage our clients to evaluate project proposals with a long-term view to ensure that early development does take into account several potential commercialization challenges. We identify the critical processing parameters and characterize the manufacturing process, which can be done in parallel with clinical and/or stability studies.”

Mr. Frey recalled one situation when a client was in a hurry to develop a formulation and Coating Place tried to accommodate them. “When it came time for the production run, we identified issues with the process,” he said. In this particular case, seasonal variations were identified as the root cause of the problem. “The initial process development occurred in the summer, but the manufacturing was occurring in the winter months. Although it was a non-aqueous formula, process air dew point was found to be critical to product performance. Product produced with winter process air dew points at and below 0° during a cold snap did not perform the same as that produced at summer dew points near 40°F. In the summer those points rise and we reduce humidity with chiller and in the winter those dew points drop so we have to rehumidify the air. In this case, time did not allow us to identify and adjust for these variations and the client was disappointed.”

For Dr. Mackaplow, one of the more challenging formulation issues at Abbott is that of stability. “We need to see how long a tablet or capsule will retain its quality and sometimes the only way to test this to actually wait three, six or 12 months,” he explained. “We do perform accelerated methods to estimate real-time results, but these methods are not always predictive. More accurate, accelerated stability methods would be very useful.”

Take Your Time

According to FDA, the key components of building quality into a pharmaceutical formulation are:

• Establish a robust formula — if process parameters are too narrowly defined, the formula will lack robustness.
• Demonstrate formula feasibility — It is important to use acceptable excipients to ensure stability.
• Repeat the formulation steps — Formulators wants to ensure that the product is made consistently every time.
• Perform pharmacokinetic and bioavailability studies.
• Scale-up the product to verify that the same product is being attained at different scales.
• Repeat the scale-up process.
• Perform a parameter range study. If this is not done, Mr. Frey said, the process may not be robust and batches might fail.
• Validate the process.

If these components are addressed, a more robust and successful manufacturing process will be achieved. It really comes down to slowing down and taking the time to instill the quality.

“The industry is fraught with milestones and there is pressure to get product to market fast, but time must be taken upfront during formulation to achieve an optimal manufacturing process,” said Dr. Mackaplow. “Companies need to look at the entire process, not just the smaller milestones along the way.”

Dr. Melsopp agreed: “Time is the biggest challenge. Generally, companies always will spend more money and take more risks to cut the time from concept to market whenever possible. The pharmaceutical business is highly competitive and patients and the healthcare community want newer, safer, more effective medicines brought to market as quickly as possible. But while developing a quality product that delivers the pharmaceutical active ingredient in the most biologically effective way, and doing it as quickly and cost efficiently as possible is of primary importance, doing it in a way such that investors can earn a return on their investment from the long and expensive process of bringing a new drug to market is also a challenge.

“To the formulator, this means not only making a tablet, capsule or some other dosage form, but also looking to wrap that delivery system around some unique intellectual property. Protecting a new product with some innovative and patentable technology that will not only deliver a quality, safe and effective new medicine, but also protect its market life to allow an appropriate return to be made on the cost of development, can be key to a company’s long-term survival.”

Cindy H. Dubin has written about the pharmaceutical industry for several different magazines. She wrote about Analytical Testing in our September issue. She can be reached at cindydubin@att.net.