Yingtai: Freeze-dried Powder Injections—Can Formula Deficiencies Be Compensated by Process?

Yingtai: Freeze-dried Powder Injections—Can Formula Deficiencies Be Compensated by Process?

In new drug development, one can freely select a formulation that ensures the stability of the product’s physicochemical properties and maintains its efficacy based on the material’s physical, chemical, and biological characteristics. However, for domestic generic drug requirements, it seems not that simple. Even though there are excipients that can enhance the stability of formulations and similar products on the market internationally, the reference listed drug (RLD) formulation in the Chinese public reference drug list is often not the same. This creates a dilemma: while a formulation may have excipients that improve stability, the domestic reference formulation does not use these excipients, and thus, following the domestic reference formulation feels like the chemical stability is not optimal. Is it really necessary to "compensate for formula deficiencies with process" or is it more accurate to say that "appropriate processes haven’t been found yet"? In other words, can process alone truly save a product with a defective formula?

Following the traditional approach of maintaining competitive fairness, let’s take two examples from at least two years ago: Injection Terlipressin and Injection Acetate Octreotide.

Injection Terlipressin

Let’s first look at Injection Terlipressin, which fits the situation described above. The publicly listed domestic reference formulation comes from Huizheng Pharmaceutical, while the FDA Orange Book RLD formulation has not been included in China’s generic drug reference list. Both use terlipressin acetate as the active ingredient, but Huizheng’s formulation uses hydrochloric acid to adjust the pH, while the FDA RLD formulation uses acetic acid. When consulting on Injection Terlipressin, one unit expressed: “We control the related substances at day 0, but they increase very quickly under 40°C and 60°C, and the batch-to-batch degradation products vary, some just below the limit, others exceed it, but the original formulation barely shows any increase in degradation. How can we adjust the freeze-drying curve to improve stability?” When it was suggested that formulations using acetic acid to adjust the pH should show better stability, the consultant pointed out that China’s listed reference formulation uses Huizheng’s Injection Terlipressin, not the FDA Orange Book's MALLINCKRODT IRELAND's TERLIVAZ (N022231). Since using hydrochloric acid to adjust the pH was a must, improving chemical stability could only be considered by reducing the free energy of the product through process adjustments, putting it in a metastable state. A preliminary approach was to add annealing during the early stages of primary drying. The idea was to rapidly cool the glassy terlipressin acetate to form a long-range disordered arrangement, thus increasing entropy while achieving a lower enthalpy than it should have at that point. The specific operation was to increase the shelf temperature using the maximum heating power of the freeze dryer to 45°C for 3 hours, then rapidly cool the product to -0°C using the freeze dryer’s maximum cooling power, and then increase the shelf temperature to room temperature and continue primary drying for another 2 hours. A month later, the consultant described the results as “dramatic” after applying the annealing adjustment. Two batches of products using this process showed no increase in degradation products under 40°C or 60°C after 5, 10, or 30 days. Thus, the process adjustment successfully solved the stability problem.

Injection Acetate Octreotide

Injection Acetate Octreotide is a much older product, and the issue mentioned occurred over 10 years ago. Now, acetate octreotide microspheres have been approved, offering not only sustained-release long-term effects but also improved chemical stability compared to the earlier formulation. When a generic version of Injection Acetate Octreotide was approved before strict regulations for generics were established in China, the formulation used acetic acid as a pH adjuster, but the stability over time was unsatisfactory. After regulatory guidelines for generics were introduced, changing the formulation became costly, so the original formulation was retained, with numerous attempts to improve stability by adjusting the amount of acetic acid used as the pH adjuster. Despite various stability tests with different pH formulations, the results showed that products with acetic acid as the pH adjuster could only be stored for up to 18 months. The original developers of acetate octreotide used lactic acid as the pH adjuster, combined with sodium bicarbonate, to maintain a stable pH environment. The developers believed that since the acetate salt form of octreotide was chosen, using acetic acid as the pH adjuster didn’t introduce additional substances. However, acetic acid and lactic acid differ in their ability to ionize hydrogen ions, and the activation energy of their reaction with these ions also differs, which affects the stability over time. Additionally, during the pre-freezing process, the change in hydrogen ion concentration might accelerate the reaction between hydrogen ions and acetate octreotide, consuming some of the hydrogen ions, leading to an increase in pH and requiring more acetic acid to maintain the desired pH. From a process perspective, since acetic acid could not be altered, the first step was to minimize the impact of hydrogen ion concentration fluctuations during pre-freezing, reducing the time of interaction between high hydrogen ion concentrations and the active pharmaceutical ingredient (API). Though the dose was only 1mL, the pre-freezing was performed by undercooling and controlling the freezing rate to quickly freeze the product. Then, the drying process was tightly controlled to ensure the product temperature stayed below the glass transition temperature. The process aimed to make the API metastable, further improving product stability. Ultimately, while chemical stability was somewhat improved, the result was limited, and after 27 months, the degradation products were close to acceptable standards.

Conclusion

Comparing the two products, it is clear that process adjustments cannot always compensate for formula deficiencies. The composition of the formulation plays a decisive role in the chemical stability of the product, and freeze-drying processes only serve as limited optimization or enhancements. Once the freeze-drying process cannot reduce the free energy of a product to below the activation energy needed for chemical reactions, the freeze-drying process cannot fundamentally affect its chemical stability. On the other hand, when the freeze-drying process significantly improves chemical stability, it is often because the original freeze-drying process was not suitable for the product in the first place.