Therapeutic Protein Drug Products

Practical Approaches to formulation in the Laboratory, Manufacturing, and the Clinic

Brian K Meyer

• Publisher: Woodhead Publishing
• Year: 2012
• Print ISBN:
  9781907568183
• eBook ISBN:
  9781908818102
• Topic: Medicine
• Subtopic: Pharmacology

Therapeutic protein drug products provides a comprehensive overview of therapeutic protein drug products, with an emphasis on formulation beginning in the laboratory, followed by manufacturing and administration in the clinic. A list of many commercial therapeutic drug products are described and include the product name, dosages, active concentration, buffer, excipients, Ph, container type and route of administration. The laboratory formulation sections focus on the most common buffers, excipients, and Ph ranges that are commonly tested in addition to systematic approaches. A brief section on biophysical and analytical analysis is also provided. Properties of therapeutic protein formulations are described and include opalescence, phase separation, color, and subvisible particles. An emphasis is placed on material and process testing to ensure success during manufacturing. The drug product manufacturing process, which includes the process of compounding to filling, is also covered. Methods of delivery in the clinic are addressed, as well as delivery strategies. Finally, a perspective on the regulatory requirements for therapeutic protein formulations is discussed. - Provides a list and description of commercially available therapeutic drug products and their formulations - A comprehensive and practical overview of protein formulation in the laboratory, manufacturing, and the clinic - Discusses recent topics including high protein concentration, phase separation, opalescence, and subvisible particles

1

Commercial therapeutic protein drug products

Brian K. Meyer and Mohammed Shameem

Abstract

Commercially available therapeutic proteins are formulated as both liquid and lyophilized products. The most common buffer utilized is phosphate, followed by histidine, citrate, acetate, tris, and others. Excipients that are most frequently utilized are sodium chloride, sucrose, and the non-ionic detergents polysorbate 20 and 80. The most common containers utilized are vials followed by pre-filled syringes. These marketed therapeutic protein drug products formulations may be used as a reference point during the development of future products.

Keywords

therapeutic

protein

commercial

formulation

liquid

lyophilized

excipients

salt

sugar

buffer

container

administration

1.1 Introduction

There are over 140 therapeutic protein products on the market. These products consist of monoclonal antibodies, Fc-Fusion proteins, immune globulin, peptides, and other molecules that are generated using cell culture or fermentation. The majority of these products are liquids or are lyophilized. Commercial products have been listed in tables to be found in the Appendix and separated into lyophilized and liquid products. The tables include the name of the protein drug, the dose per container, a description of the drug target, the concentration of the active, buffers, excipients, pH, drug product container, and route of administration. The first table in each section lists monoclonal antibodies, Fc-Fusion proteins, and immune globulin products, whereas the second table lists protein and peptide products that are less than 150 kDa. Lastly, a table summarizing protein products that are utilized as radiologic therapies or as diagnostic tools is included. Only therapeutic proteins that are administered parenterally are included in this text. Biosimilar compounds or follow-on biologics are not included.

A majority of the products listed in the tables are single-use and do not include antimicrobial preservatives. In cases where the products are multidose, the antimicrobial preservative utilized has been indicated. Information on these products was obtained from the ‘Physicians’ Desk Reference and/or the Prescribing Information from the various manufacturers. For additional information, it is recommended that the reader consult the latest edition of the Physicians’ Desk Reference or individual Prescribing Information documents as well as other published lists of therapeutic proteins (Pavlou and Belsey, 2005; Wang et al., 2007; Akers et al., 2002). An attempt has been made to capture the majority of marketed therapeutic protein products; however, it is possible that some may have been omitted unintentionally.

Lastly, the details provided in this chapter and the Appendix are for information only and not for use in diagnosis or treatment in humans. It is not intended as a substitute for the Physicians’ Desk Reference or for the Prescribing Information provided by the manufacturer, but rather as a resource for comparing and evaluating formulations of different therapeutic proteins.

1.2 Lyophilized formulations

1.2.1 Lyophilized monoclonal antibodies and IgG fusion proteins

There are approximately 64 therapeutic proteins that are marketed as lyophilized products. A number of these are listed in Tables A.1 and A.2 in the Appendix. Table A.1 lists a total of eight monoclonal antibodies that are lyophilized (see the Appendix). Of the products listed in Table A.1, two are buffered with phosphate, four with histidine, one with lactic acid, and one with acetate. Table A.1 provides insight as to the most common pH ranges, buffers, and excipients utilized in this class of commercialized therapeutic proteins. These lyophilized products have a pH range of 5.2 to 7.2. The buffers utilized to maintain a pH range of 5.2 through 7.2 are in relative order lactate, acetate, histidine, and phosphate. The products that are at low pH (such as 5.2) are buffered with acetate and lactic acid, whereas products at pH 6 and 7 are buffered with histidine and phosphate, respectively (Table A.1).

The pH in many of these formulations was achieved using the acid and base form of the buffer, for example Herceptin contains L-Histidine and L-Histidine HCl. The combination of these forms in the appropriate ratio will result in the desired pH. The use of the acid and base form eliminates, in most cases, the need to add either HCl or NaOH to the formulation to achieve the target pH. Additionally, buffering capacity may also be achieved from the protein itself, especially at higher protein concentrations (Gokarn et al., 2008). A majority of the products in Table A.1 contain sucrose, which may act as both a cryo-and lyo-protectant. Trehalose, which may be substituted in some cases for sucrose, is also found in one of these products. Mannitol is used as a bulking agent for lyophilized products. Polysorbate 20 is more common in these products than PS-80. These non-ionic detergents have been demonstrated to prevent aggregation of proteins at surfaces and at the air-liquid water interface (Kerwin, 2008). These products are presented in vials, and in one case in pre-filled syringes. The concentrations of these monoclonal antibody products range from 1 to 200 mg/mL and are administered intravenously (IV), subcutaneously (SC), and intramuscularly (IM).

1.2.2 Lyophilized proteins and peptides to 150 kDa

Table A.2 lists a total of 34 therapeutic proteins less than 150 kDa (see Appendix). These lyophilized products have a pH range of 4.2 to 8.5, which is slightly broader than that of the products listed in Table A.1. The reason for the wider pH range may simply be due to the number and properties of products that are in this group. Just as for the monoclonal antibodies listed in Table A.1, the most common buffers are phosphate and histidine. The acid and base forms of the buffers are also used, but not in all cases. HCl or NaOH were indicated as possibly being utilized to obtain the target pH (Table A.2). Many of these products are provided in vials; however, some are provided in pre-filled syringes as well as dual-chamber syringes. The formulations also contain either sucrose or trehalose, which act as both a cryo-and lyo-protectant. Sodium chloride is common among these products. Polysorbates 20 and 80 are also utilized. There were more products containing polysorbate 80 when compared to polysorbate 20 (Table A.2). The concentration ranges of the products listed in Table A.2 following reconstitution are from 1 to 80 mg/mL.

The formulator developing a lyophilized product must consider not only the protein concentration, buffer, excipients, and drug product image, but also understand the principles behind the physical parameters associated with lyophilization. These include freezing and primary and secondary drying, as well as the ramp rates, hold times, and other principles such as annealing. There is a large body of literature on the subject of lyophilization. The formulator is referred to the Recommended Reading section for texts and publications describing how to develop lyophilized products.

1.3 Liquid formulations

1.3.1 Monoclonal antibodies and IgG fusion proteins

There are a total of 18 marketed liquid therapeutic monoclonal antibodies and immune globulin products listed in Table A.3 (see Appendix), which is approximately double the number of lyophilized monoclonal antibody products (Table A.1). These products may be dosed IV, IM, SC, and intravitreously.

The buffer predominantly used in these products is phosphate buffered in the pH range of 6 to 7. Citrate is also utilized at a pH of 6.5 to 7. Sodium chloride is utilized in most of the liquid products. Polysorbate 80 and polysorbate 20 are utilized in the liquid products (Table A.3).

1.3.2 Proteins and peptides to 150 kDa

There are 38 commercial liquid therapeutic proteins less than 150 kDa listed in Table A.4 (see Appendix). A large majority of these products are administered subcutaneously; however, some are also administered IM and IV. The buffers utilized are phosphate, acetate, citrate, and succinate. Unlike the monoclonal antibodies, the active drug may be described in International Units (IU).

The pH values utilized were from 4.0 to 7.8. Sodium chloride is commonly utilized. Sucrose is not as common in the liquid products as in the lyophilized products. Both PS-20 and PS-80 are utilized in these formulations.

1.4 Protein formulations for radiologic and diagnostic use

Products listed in Table A.5 are for radiologic or diagnostic applications (see Appendix). A majority of these products are provided in phosphate-based buffers. All are administered intravenously.

1.5 Summary

Based on a survey of the formulations from commercial therapeutic protein products (see Appendix), it is clear that there are four predominant buffers utilized, which include in order phosphate, histidine, citrate, and acetate. The use of phosphate in these products may have been derived from the use of phosphate buffered saline in the early development of therapeutic proteins. It is a common reagent and has the best buffering capacity at physiological pH, approximately 7. There have been a number of publications indicating the challenges with using phosphate due to pH shifts that may occur with this buffer during freezing, for example (van den Berg et al., 1959; Murase and Franks, 1989; Sarciaux et al., 1999; Pikal-Cleland et al., 2000). This characteristic of phosphate poses a challenge for drug substance lots that ar...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of figures and tables
• Preface
• About the authors
• Chapter 1: Commercial therapeutic protein drug products
• Chapter 2: A formulation method to improve the physical stability of macromolecular-based drug products
• Chapter 3: Properties of protein formulations
• Chapter 4: Material and process compatibility testing
• Chapter 5: Compounding and filling: drug substance to drug product
• Chapter 6: Administration in the clinic
• Chapter 7: Regulatory guidelines for the development of a biotechnology drug product
• Appendix
• Recommended reading
• Index