Freeze! Avoid Catastrophic Project Delays Caused By Formulation Changes

Transcription

1 W H I T E P A P E R Freeze! Avoid Catastrophic Project Delays Caused By Formulation Changes By John G. Augustine, PhD

2 Introduction The race to bring a novel or improved drug product to market is both exhilarating and frustrating. Each decision along the way (lead candidate selection, dosage form, API manufacturing, fill/finish facility ) is a delicate balance between time and cost. Often smaller pharmaceutical companies outsource many, if not all, of their product development needs to contract research organizations (CROs) whose area(s) of expertise/ services play a vital role in ensuring that ambitious goals and milestones are met. Ideally the relationship between client and CRO is a collaboration in which ideas, as well as data, are shared freely throughout the development program. However, the constraints of time and cost can lead to decisions which save neither time nor money; therefore, it is essential that the CRO identify and properly inform the client of the risks associated with certain decisions. As an illustration, the study presented below describes a formulation of a lyophilized product which was altered by the addition of a different bulking agent (Formulation B). In this case neither sufficient funding nor time was deemed available for carrying out optimization of lyophilization cycle parameters for the new formulation. Rather, it was requested that the lyophilization cycle parameters developed for the original formulation (Formulation A) be used without modification for the lyophilization of Formulation B in a pilot run. Not unexpectedly, the initial run was not successful in producing a quality product. Thus, after further discussions and after less than one week of work, data generated from freeze-dry microscopy and modulated differential scanning calorimetry (MDSC) were used to propose new lyophilization cycle parameters which provided for a suitable cake product.

3 Initial lyophilization run The lyophilization cycle parameters previously designed for Formulation A were used in the freeze-drying of Formulation B samples (Table 1). A fill volume of 1 ml was placed into 10 ml tubing vials. The stoppered vials were then transferred to a Virtis 25L Genesis SQ Super XL freeze dryer and subsequently lyophilized. The resultant lyophilized product cakes were cracked and pulled away from the sides of the lyophilization vial (Figure 1). Thus, the resulting cake products were not suitable for commercial use and additional lyophilization cycle development was called for. Table 1. Initial lyophilization cycle parameters. Step Rate ( C/min) Shelf temp ( C) Pressure (mtorr) Duration (hours) ambient ambient In order to develop more suitable lyophilization cycle parameters, thermal analysis of Formulation B was undertaken using two approaches: freeze-dry microscopy and differential scanning calorimetry (DSC). A basic understanding of the thermal properties of any formulation is crucial to successful lyophilization. Freeze-dry microscopy In order to obtain a visual indication of thermal events such as the collapse of amorphous materials or the eutectic melting of crystalline materials, observations were made Figure 1. Product cake vials from initial lyophilization run.

4 Figure 2. Cake collapse of Formulation B at -35 C under vacuum. using a Linkam FDSC 196 freeze-drying cryo stage in conjunction with a Zeiss Axioskop 40 POL light microscope. A volume of 2 μl of solution was placed within the sample cell and cooled to below -70 C. The pressure of the sample cell was then reduced and the sample temperature was increased 2 C/min to 25 C. As noted in Figure 2, the collapse of the frozen Formulation B material in the cell center during sublimation was observed starting near -40 C. In Formulation A, collapse of the cake material wasn t observed until the temperature was raised to -10 C (Figure 3). Modulated differential scanning calorimetry In order to investigate the apparent cake collapse of Formulation B, modulated differential scanning calorimetry (MDSC) was carried out in a TA Instrument Q200. A volume of 3 μl Figure 3. Cake collapse of Formulation A at -10 C under vacuum. Formulation B was placed into a low mass aluminum pan and hermetically sealed. Test sample was placed into the instrument and cooled/heated at a rate of 2 C/min over the temperature range of 25 C to -70 C using a modulation amplitude of +0.4 C over 60 seconds. The resulting heating thermogram indicated a sharp phase transition near -42 C in the non-reversing heat flow plot (Figure 4). This data

5 Figure 4. MDSC heating thermogram (-70 C to 25 C) of sample Formulation B at full scale (upper panel) and scale adjusted to highlight transition (bottom panel). agrees with the freeze-dry microscopy data, and further indicates the need to reduce the primary drying temperature of the lyophilization cycle to obviate cake cracking and/or collapse. Lyophilization cycle #2 The resulting cake products from the initial lyophilization cycle along with the freezedry microscopy and MDSC data indicated the need for changes to the lyophilization parameters; specifically, a lowering of the shelf temperature during primary drying. In the freeze-dry microscopy analysis, while under vacuum, the frozen product was observed to collapse near -40 C during sample heating. Similarly, in the MDSC analysis a thermal transition was observed near -42 C. Together, these data suggest that the product temperature must remain near -40 C to preserve the cake structure; thus an initial primary drying shelf temperature of -40 C was chosen to obviate the product cake collapse (Table 2).

6 Table 2. Lyophilization cycle #2 parameters. Step Rate ( C/min) Shelf temp ( C) Pressure (mtorr) Duration (hours) ambient ambient The lowering of the primary drying temperature also necessitates a lowering of the chamber pressure as the rate of ice sublimation is related to vapor pressure. In a typical lyophilization cycle, the chamber pressure is set well below the ice vapor pressure to ensure an optimal rate of sublimation. The vapor pressure of ice at -40 C is approximately 96.5 mtorr, which necessitates the reduction of the chamber pressure to 50 mtorr for effective product drying. Note, the reduction of the chamber pressure to less than 50 mtorr is not obtainable/sustainable with commercial scale lyophilizers. Moreover, the rate of sublimation is actually decreased at very low pressures (< 50 mtorr), due to inefficient transfer of heat by convection. The resulting intact cake products are shown in Figure 5 below. The moisture content of the lyophilized cakes was 1.7% as determined by Karl Fischer analysis using an Orion AF8 Volumetric titrator. Furthermore, the cake product was completely reconstituted within 10 seconds upon addition of 1 ml of sterile water for injection. Figure 5. Product cake vials using lyophilization cycle #2 parameters.

7 Conclusion In less than one week, data from freeze-dry microscopy and MDSC experiments was generated which facilitated the proposal of new lyophilization cycle parameters. By lowering the shelf temperature during primary drying, a suitable cake product was formed. Moreover the resulting lyophilization cycle was far from complex, and allowed for the facile transfer of the drying process to manufacturing. Without adequate study of lyophilization cycle conditions, production of the formulation would be problematic and would have slowed commercialization. Therefore, prospective clients and CROs must be cognizant of the potentially cascading effects of simple formulation changes that lead to major modifications in the downstream processing, ultimately affecting project cost and timelines.

8 References Lyophilization: introduction and basic principles, by Thomas A. Jennings, published by Informa Health Care, 1999 About SP Formulations SP Formulations, LLC, a Smithers Group Company, delivers a broad range of formulation services for small and large molecules in a variety of pharmaceutical dosage forms including liquids, solids and semi-solids. As a member company of the internationally recognized research and testing leader, The Smithers Group, SP Formulations has unique abilities to support pre-clinical and clinical drug development for North America and Europe, with the personalized approach of a small contract research organization. Our quality management systems have been inspected by authorities in both North America and Europe, meeting FDA and EU regulations. SP Formulations is able to offer a full-service package for pre-clinical and clinical drug formulations, including analytical and manufacturing support. SP Formulations, LLC 790 Main Street Wareham, MA Phone: Fax: info@spformulations.com 2009 SP Formulations All rights reserved. Printed in U.S.A. Pub 05/09