Product Quality and Formulation

The final product quality attributes are strongly related to the level of optimization of the composition of the liquid formulation, which is a multidisciplinary and challenging problem usually solved by tedious experimental approaches in the development of freeze-drying cycles. The topics of formulation that involve complex knowledge of physical chemistry, biochemistry and biology are outside the scope of this chapter. However, general concepts that are generally applied are summarized hereafter. 

The vitrification concept relies on the experimental observation that efficient stabilizers are always convenient glass-former materials with very high viscosity at temperatures below the glass transition temperature. Several experimental studies have pointed out a sharp decrease in mobility (chain fluctuation and chain rotation) and a consequent decrease in reactivity when the glass transition temperature is approached. 

The water substitute concept states that the stabilizer replaces the water and forms hydrogen bonds with the protein, like water also does. These bonds maintain the native protein conformation and, in this way, stabilize the protein. The water substitution hypothesis has been confirmed either by spectroscopy studies (FTIR), or by experimental observations that have shown that the most efficient stabilizers are sugars which form strong hydrogen bonds with the protein. Indeed, freeze-dried systems with loss of activity present notably altered IR spectra. 

Nevertheless, some exceptions exist and not all additives which are good stabilizers show chemical and bonding properties similar to water. Many experimental data have shown that the stabilization of fragile and thermosensible pharmaceutical proteins requires a lyoprotectant that is a good glass-former, leading to a single amorphous solid phase, with a moderate interaction with the protein surface to avoid phase separation (crystallization, etc.). 

As already indicated, nudeation temperature, nucleation rates and solvent crystal growth rates are of crucial importance for the morphology and for the structure of the resulting freeze-dried product. Freeze-drying generally leads to an 

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In the past decade, significant advances have been made in the selection of environmentally acceptable alternative PBAs for a given polymer to comply with government regulations and local codes. However, there has been very little change in the use of CBAs except that much improvement has been made in the areas of product quality and formulation flexibility. 

Tsotsas, E. Mujumdar A. Modern Drying Technology, Vol. 1 - Computational Methods (2007), Vol. 2 - Experimental Methods (2009) and Vol. 3 - Product Quality and Formulation (2011) Wiley-VCH... 

Modem Drying Technology Volume 3 Product Quality and Formulation, First Edition. 

Volume 1 Computational tools at different scales Volume 2 Experimental techniques Volume 3 Product quality and formulation Volume 4 Energy savings Volume 5 Process intensification... 

The first two volumes of this series have treated Computational tools at different scales and Experimental techniques that can empower Modern Drying Technology with the aim of producing superior products with better processes. Now, it is time to turn from the means to the goal, treating "Product quality and formulation in Volume 3. This emphasis on the product is deliberate, because even the most efficient process is not of real value, if not able to fulfill - if not push - the requirements of the market. The topic is presented in seven chapters ... 

Walzel, P., Furuta, T. (2011). Morphology and properties of spray-dried particles. In E. Tsotsas A. S. Mujumdar (Eds.), Modern drying technology. Product quality and formulation (Vol. 3, pp. 231-294). London Wiley. 

We start with a definition of the problem and based on this, we identify the candidates (such as, molecules, mixtures and formulations) through expert knowledge, database search, model-based search, or a combination of all. The next step is to perform experiments and/or model-based simulations (of product behavior) to identify a feasible set of candidates. At this stage, issues related to process design are introduced and a process-product match is obtained. The final test is related to product quality and performance verification. Other features, such as life cycle assessment could also be introduced at this stage. 

Over the last quarter century the dissolution test has emerged as a most powerful and valuable tool to guide formulation development, monitor the manufacturing process, assess product quality, and in some cases to predict in vivo performance of solid oral dosage forms. Under certain conditions, the dissolution test can be used as a surrogate measure for bioequivalence (BE) and to provide biowaivers, assuring BE of the product. Dissolution test has turned out to be a... 

This description reflects a view from the manufacturing side— beginning with the end in mind. Therefore, the goal Product quality and performance achieved and assured by design of effective and efficient manufacturing processes is placed before Product specifications based on mechanistic understanding of how formulation and process factors impact product performance. ... 

Risk based regulatory scrutiny that relates to the level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance and the capability of process control strategies to prevent or mitigate risk of producing a poor quality product. 

The guidance specifies the application information that should be provided to the Center for Drug Evaluation and Research (CDER) to ensure continuing product quality and performance chacteristics of the sernisolid topical formulation for specified changes. The guidance does not comment on or otherwise affect compliance/inspection documentation defined by the Office of Compliance in CDER or the Office of Regulatory Affairs at FDA. 

The true benefit from molecular models is that they permit the quantitative structural description of complex feeds. As noted above, this allows for easy extrapolation to unstudied systems and also permits product quality and properties issues to be addressed. The kinetics, while formulated at the molecular level, are nevertheless still implicitly tied to the mechanism. The CPU demands, however, are relatively small compared to those of mechanistic models. 

The chemical systems for RIM all have one characteristic in common they require a RIM machine to convert liquid raw materials into quality plastic products. Assuming a properly formulated chemical system, the quality of the end product results from the ability to measure, control (Chapter 3), and adjust temperature, ratio, pressure, and other essential process parameters of the RIM dispensing machine. Such exacting control leads to a reduction in start-up time, minimal rejects and touch-up work, reproducible product quality, and the ability to pinpoint changes in product properties. 

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