The process of formulating biotherapeutic products is undergoing an evolution. Over the past few years, several trends in biotherapeutic formulation development have emerged. These trends are most evident in companies that presently have biotherapeutic products approved or have products in late clinical trials and healthy product development pipelines. They include assessing the impact of product formulations on marketability earlier in the process, evaluating and selecting potential product candidates based on a systematic evaluation of their solution stability and considering dose and delivery requirements and their effect on formulation stability.

What used to be an afterthought for many companies struggling to get a product into the clinic is now a fully funded and planned effort to arrive at optimal product formulations earlier in the development process. This is good news for the industry as many products have failed or have been compromised as stability issues such as aggregation, loss of activity and the inability to meet specifications have slowed their development considerably. Sadly, there are still too many companies learning the downside of not adequately planning or scheduling a diligent formulation development effort as part of their overall product development timeline.

As discussed in an earlier article (Contract Pharma, “Formulation Development,” March 2000 p. 46-55), outsourcing formulation development is one choice that companies have to access expertise, compress timelines and provide a cost-effective alternative to adding specialized formulation resources. This is true in both larger companies that have the expertise but are overburdened with formulation challenges and smaller or virtual companies that plan to outsource such activities as a way to employ a variable cost structure, increasing resources and spending when necessary and decreasing when demand subsides. Regardless of whether formulation development is an internal or external project at your company, the level of sophistication in formulating biotherapeutics continues to grow due to gains in formulation experience among the scientists involved in formulating biotherapeutics, changes in agency expectations in validating excipient choices and more demanding dosage forms such as outpatient, high concentration (high dose) products.


Challenges in Formulating Biotherapeutics
To fully explain how the formulation development process is changing, it is necessary to take a step back and examine some of the challenges in formulating biotherapeutics. Among the top 20 or so biopharmaceutical products (by revenue), almost all are delivered parenterally. For the purposes of this article, the focus will therefore be on parenteral formulation development. Ensuring a product’s stability during its shelf life is the major challenge. To develop a pharmaceutically acceptable, stable drug, instabilities either inherent or latent within the drug must be explored and stabilized. Instability of protein and peptide therapeutics may be broadly classified as chemical instability or physical instability. Examples of chemical instability are hydrolysis, oxidation and deamidation. Examples of physical instability are aggregation, precipitation and adsorption to surfaces. Therefore, biotherapeutics may be affected by a physical change in structure, a covalent modification, or both.

One of the most prevalent formulation problems is product aggregation. Although aggregation is a physical instability, it can lead to a loss in bioactivity. The addition of excipients may slow the process but may not always completely arrest it. All of the issues above lead to a need to understand the mechanisms of degradation. Biotherapeutics often exhibit multifaceted degradation pathways that do not occur predictably. Activity losses may or may not be detected by physical assays and are only evident in bioassays or potency assays with large (sometimes 15-20%) coefficients of variation, making it difficult to determine actual losses.

In addition to understanding exactly what happens to your product under accelerated stress, there must be a way to monitor these degradation products. For complex drug substances (like most biotherapeutics) multiple stability indicating assays are needed. In looking at the CMC guidance, the language clearly states that a sponsor should develop stability indicating procedures that will detect changes in your product. The focus must be on multiple assays to examine degradation, to detect structural or conformation changes and possibly to correlate a stability indicating assay to a potency assay. Another common problem are assay limits of detection (LOD) that are not low enough to provide meaningful stability data for your product.

Given these challenges including the characterization of the solution behavior of your biotherapeutic, the inability to predict product shelf life from accelerated stress studies and the challenge of adequate analytical assay development, it is easy to understand why a company new to biotherapeutic formulation development may underestimate the time and resources necessary to develop a robust formulation.

Ask the Formulators
When asked how the process of formulation development has changed in their companies over the last several years, many common points arose, including:

• Formulation development is beginning earlier;
• A more systematic approach is used;
• Analytical methods and stability indicating methods
  have improved out of necessity; and
• They are being asked to develop more novel or more
  demanding dosage forms to improve marketability
  or to compete with other products.

When asked what the biggest challenges are in their jobs, their replies were somewhat more diverse:

• Lack of direction from management or clinical as to project goals;
• Inadequate assay development;
• Variable bulk drug substance (cell line or production changes);
• Lack of material to use in formulation experiments;
• Unrealistic timelines for formulation development; and
• Drug candidates that are inherently difficult (insoluble peptides).


How a Robust Formulation Can Save a Product
Several scenarios may move a drug development project into crisis mode. Some examples directly attributable to formulation include a stability failure during a clinical trial or a lack of attention in understanding the product prior to attempting formulation development. A clinical trial may have a slower accrual rate than predicted or the trial may be extended as positive results are achieved. The stability of the formulation thus becomes critical, as does the data supporting that stability. Cutting corners in the pre-formulation phase of development may lead to trouble later, as there is insufficient data to determine what exactly is happening to compromise stability and, therefore, problems are difficult to remedy. Thus, striving for the greatest stability possible for a biotherapeutic through careful and systematic formulation development is ultimately the best insurance for success, given an otherwise efficacious drug.


The ‘Best Guess’ Approach to Formulation
The ever-present timeline crunch taxes the process of systematic formulation. There is a perception that a rational formulation approach will take longer, as it tends to be more comprehensive. While this may seem to be the case, the ‘best guess’ approach often employed by companies may not lead to a successful formulation and may end up taking longer than anticipated. Many companies are tempted to try a set of ‘standard’ formulations, figuring that they may luck out and find a suitable, stable formulation. While there is merit in trying the simplistic approaches first, guessing which excipient combinations may stabilize a biotherapeutic without understanding degradation pathways and solution behavior is highly unlikely.

A typical ‘best guess’ approach involves search-ing the literature or using other general formulations such as phosphate/sodium chloride, various amino acids/ sodium chloride plus or minus tween. The problem with this approach is that the biotherapeutic is formulated and put on a stability protocol for at least two to four months. At the end of that time period, none of the formulations may be ex-hibiting a stabilizing ef-fect on the protein. If this is the case, nothing has been gained in understanding why a stability issue exists. The formulations are often modified to provide another series of ‘best guesses’ that may or may not be successful, possibly wasting another two to four months.

There is a temptation to gamble on a formulation that will be ‘good enough’ to continue to the next stage of development, such as proceeding with a frozen formulation for Phase I studies. Each company must weigh the risk/reward of investing resources in formulation development early in the process, with this decision often occurring before clinical success. Having a non-optimal formulation early in development is certainly acceptable; however, sufficient planning needs to occur to make sure enough time is allotted to revisit formulation concerns prior to pivotal trials. Companies experienced in development seem to be investing in formulation earlier in the process, while others, due to resources or timing, may wait to develop the optimal formulation to just prior to Phase III studies. Regardless of the timing, more and more companies seem to be favoring a more rational systematic formulation development effort.

Why Rational Formulation Development?
What is rational formulation development of a biotherapeutic? It is contrary to the ‘best guess’ approach. Rational formulation development is a data-driven, systematic exploration of a product. Multiple accelerated stress studies, combinations of stability indicating assays and experimentation are used to gain a thorough understanding of the product’s solution behavior. This is the route now favored by formulators experienced in the challenges of biotherapeutic formulation.

In a systematic formulation development ef-fort, the first step is to determine the inherent instabilities of the molecule and work to minimize them. A program of data-driven, biophysical experiments is used to first define the potential pitfalls and then using this underlying data, a systematic screening of excipients combinations is executed. For example, a protein may be subjected to acute stresses such as pH, temperature, shear stress, freeze/thaw stress and combinations of these stresses. These accelerated stress experiments, monitored by diverse analytical assays, are used to gain an understanding of the protein. A protein may be monitored by its ability to absorb, emit and/or scatter light, which may render valuable insight into possible protein conformational changes. The use of qualitative assays in combination with HPLC and other traditional methods can yield a composite understanding of structural stability. Data resulting from these studies include:

• pH, temperature profiles;
• Conformation profiles; and
• Profiles comparing potential buffers, ionic strength, product concentration
  (to detect mass driven instabilities)

Once a biotherapeutic is well understood in its existing formulation, the studies above provide a means for comparing existing formulations to potential new formulations. Thus, excipient screening entails examining not only the effect on stability after a two-month time period, as is usually the case in a ‘best guess’ scenario, but also an understanding of the product’s instability profiles as a function of formulation. This serves to enhance the chance of delivering a robust, stable formulation. Such a process usually takes about three to four months.

The information gained from such studies is particularly valuable when a product is prone to physical degradation such as aggregation. It is also necessary to have such data if the formulation goal is a lofty one, for instance, a high concentration (greater than 150 mg/mL) protein formulation for subcutaneous injection. This basic understanding of the product is also invaluable if more challenging dosage forms, such as controlled release, are desired. According to Gary Gamerman, president of Seraphim Life Sciences Consulting, some common problems in controlled release biotherapeutic formulations are:

• Ability to manufacture the dosage form; and
• Stability

Manufacturability of controlled release dosage forms can be cost prohibitive. Establishing consistent batches at reasonable cost is paramount to product success. Without a full understanding of your product prior to the added complexities of excipients and/or procedures to produce a controlled release dosage form, product stability may be compromised. This is one reason formulation development activities are evolving to become more sophisticated—because they must be to support the increasing complexity of biotherapeutic formulations.

Formulation development is undergoing an evolution as the knowledge base of how to deal with biotherapeutic instabilities grows and as product formulations become more challenging. More and more companies are employing a rational, systematic approach.

Formulation will continue to be a key area of drug development. It affects not only product stability and product presentation, but also a product’s economic success by providing increased patient compliance; marketability verses the competition, patentability and product lifecycle extension. As the biotherapeutic development pipeline continues to grow, there will be an increased effort in rational formulation development necessitated by increasing product complexity, dosage form demands and timeline pressures.