Yingtai: Appearance of Freeze-Dried Products: How to Evaluate It

Yingtai: Appearance of Freeze-Dried Products: How to Evaluate It

With the conclusion of the latest round of national volume-based procurement, reports indicate that the winning bid price for *Metamizole Sodium Injection* has dropped as low as 0.22 CNY per vial. This astonishingly low cost prompts one to wonder: what methods make such extreme cost control possible, and what kind of production line can achieve profitability at this price point? A few years ago, concerns were raised regarding the discoloration and deepening of *Metamizole Sodium Orally Disintegrating Tablets* (ODTs), which posed challenges during regulatory reviews. These issues left me speechless and convinced that convincing domestic regulatory agencies can be far more challenging than convincing overseas ones. Perhaps the limits of science lead to metaphysics, and science alone may not suffice to persuade domestic regulators.

Starting with Metamizole Sodium ODTs

Metamizole sodium exists in two stable crystalline forms—dihydrate and anhydrous—which are well known. However, its hydration properties are far more complex. By deeply studying the structural and thermodynamic causes of hydrate formation and utilizing tools such as X-ray diffraction, spectroscopy, differential scanning calorimetry, and solution calorimetry, a complete structural and thermodynamic description of the hydrate/anhydrous system reveals that metamizole sodium tends to crystallize as a dihydrate. However, the morphology and crystal quality can vary. During phase transitions between hydrates and anhydrous forms, or during the dehydration of dihydrates, nucleation and growth mechanisms cause rearrangement of hydrogen bonds between metamizole sodium and the hydroxyl groups (-OH) of bound water. As water is expelled, nucleation and macroscopic defects occur.

When metamizole sodium is dissolved in water and allowed to evaporate at room temperature, it forms colorless, nearly white rhombic plate crystals. By contrast, dihydrate crystals obtained through slow cooling crystallization appear as yellowish-brown block-shaped crystals. Apart from formulation processes such as dissolution (resulting in an amorphous state) and subsequent freezing, environmental factors like saturated vapor pressure and humidity during production also influence the product. Furthermore, during storage, water molecules released due to changes in the crystalline state of excipients like mannitol can trigger slow phase transitions in metamizole sodium, resulting in color changes unrelated to chemical degradation.

Thus, the color of metamizole sodium ODTs does not indicate changes in chemical stability. Without proper labeling, the appearance alone cannot confirm whether the product is metamizole sodium, nor does the appearance provide a basis for proprietary identification. For metamizole sodium ODTs, the appearance should merely serve as a general description of product integrity rather than an all-encompassing evaluative criterion for all products.

What Constitutes Integrity?

My understanding of integrity focuses more on the usability of the active pharmaceutical ingredient (API) within the product. Taking small vial freeze-dried products as an example, whether the product is in block, powder, or granular form, as long as the reconstituted drug meets quality standards for the active ingredient's content, it should be considered intact. Even if the cake’s appearance is visually appealing, if the reconstituted product fails to meet the content specifications, it cannot be deemed intact. Overemphasizing aesthetic aspects of appearance does not contribute positively to the drug’s pharmacological efficacy.

This reminds me of an older case involving *Esomeprazole Sodium for Injection*. At the lab stage, most of the products showed upper-lower layer separation and poor chemical stability with significant batch-to-batch variation. In this scenario, prioritizing the resolution of chemical stability issues over the appearance of cake fractures would have been a wiser approach. Similarly, for freeze-dried oral solid formulations, occasional mild bottom or wall adherence does not affect the content of extracted tablets, and these products can still be considered intact.

Incorporating Appearance into Critical Quality Attributes (CQAs)

In the domestic pharmaceutical landscape, dominated by generics, most experts focus more on the physicochemical properties of formulations, mechanically applying Quality by Design (QbD) principles without categorizing appearance as a CQA—despite significant attention to appearance. When should appearance be included in CQAs?

The critical quality attributes of drug formulations primarily include safety and efficacy. Any parameter under CQAs must be defined to reflect the safety and efficacy of the product. For freeze-dried oral solid formulations, some suspensions may exhibit sedimentation after freeze-drying, especially if the API is non-white. It is crucial to identify the stage at which sedimentation occurs. If sedimentation occurs during solution preparation or filling, leading to significant dosage content variations, appearance should be included as a CQA. However, if sedimentation occurs during the pre-freezing stage, and each unit dose already contains a precise amount of active drug, sedimentation will not result in adverse outcomes related to safety or efficacy. Such appearance characteristics are acceptable and need not be categorized as CQAs.

Ultimately, concerns about appearance stem from worries over the product's physical and chemical stability. Whether to include appearance as a CQA and how to define “appearance inspection” or “characteristics” requires establishing a relationship between product safety, efficacy, and appearance. Even if quantification is not possible, at least a qualitative relationship should be determined to guide control over product appearance and characteristics.