Shire Monoclonal Antibodies

Meeting the Challenges in Manufacturing, Formulation, Delivery and Stability of Final Drug Product
1. Auflage 2015
ISBN: 978-0-08-100297-1
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 224 Seiten

Monoclonal antibodies (MAbs) are currently the major class of protein bio therapeutic being developed by biotechnology and pharmaceutical companies. Monoclonal Antibodies discusses the challenges and issues revolving around development of a monoclonal antibody produced by recombinant DNA technology into a therapeutic agent.This book covers downstream processing which includes design of processes to manufacture the formulation, formulation design, fill and finish into closure systems and routes of administration. The characterization of the final drug product is covered where the use of biophysical methods combined with genetic engineering is used to understand the solution properties of the formulation. The latter has become very important since many indications such as arthritis and asthma require the development of formulations for subcutaneous delivery (SC). The development of formulations for IV delivery is also important and comes with a different set of challenges. The challenges and strategies that can overcome these limitations are discussed in this book, starting with an introduction to these issues, followed by chapters detailing strategies to deal with them. Subsequent chapters explore the processing and storage of mAbs, development of delivery device technologies and conclude with a chapter on the future of mAbs in therapeutic remedies. - Discusses the challenges to develop MAbs for intravenous (IV) and subcutaneous delivery (SC) - Presents strategies to meet the challenges in development of MAbs for SC and IV administration - Discusses the use of biophysical analytical tools coupled with MAb engineering to understand what governs MAb properties at high concentration

Steven J. Shire is currently consulting and serving as an adjunct faculty member of the USC School of Pharmacy and University of Connecticut School of Pharmaceutical Sciences. He was at Genentech for 32 years where the majority of his career was in the pharmaceutical development department. He retired in June 2013 as Staff Scientist in the Late Stage Pharmaceutical Development Department. He has been responsible for directing research and development of formulations for a variety of recombinant human proteins including Pulmozyme© and Xolair©. Dr. Shire has served as the chair of the American Association of Pharmaceutical Scientists (AAPS) Biotechnology Section, and was elected as a Fellow of AAPS in 1998 and member at large to the AAPS Executive Council in 2001. He has published over 80 reviews and papers dealing with various aspects of formulation and pharmaceutical development of therapeutic proteins.

Autoren/Hrsg.

Shire, Steven

Leseproben

1

Introduction

Abstract

Pharmaceutical development is discussed in the context of the requirement to provide not just a stable formulation, but one that addresses the needs of safety, drug delivery, manufacturability, and patient/user convenience. Much of this information is captured in a document called the target product profile, which is a dynamic document subject to change as development proceeds. The emergence of therapeutic antibodies as approved pharmaceuticals is also discussed. The structure of monoclonal antibodies is reviewed so that ensuing discussion of assays and stability would be easier to follow.

Keywords

Antibody structure; Drug product; Target product profile

Pharmaceutical development

Pharmaceutical development departments are often labeled as “Formulation,” and while this is certainly an important part of creating a pharmaceutical, in reality it is only part of the whole process where the active pharmaceutical ingredient often referred to as the “API” is made into a pharmaceutical. Creation of a robust formulation is critical for the ultimate success of the product. This generally means that the API is formulated in the presence of buffers, excipients, and stabilizers to ensure its physical, chemical, and biological stability over its entire shelf life. However, if the formulation process is done just to achieve the greatest stability possible that may not lead to a successful development of the API into a pharmaceutical. Essentially the formulation, in addition to being stable and maintaining product quality, must be safe, easy to administer, easy and economical to manufacture, convenient for the end users, and ultimately marketable. Development to attain all these qualities requires an interface of many disciplines as well as focus areas. Thus, pharmaceutical development can be envisioned as a Venn diagram (Figure 1.1) where within each focus area there are many possibilities that can lead to a successful outcome for that particular attribute. The challenge is to interface all of these attributes to lead to a pharmaceutical target whereby the key elements from all of the areas meet the needs for the pharmaceutical. In order to successfully “hit” such a target requires a clear understanding of the needs for the pharmaceutical for the chosen indication by all the relevant functional areas in development. Such a document or agreement is often referred to as the target product profile (TPP).

The role of the TPP is to create a clear set of target goals that require input from all functional groups that contribute to the development of an API into the final drug product. Often the TPP is considered a document that meets directly the clinical and marketing needs, but it is important to also include manufacturing requirements. Development of a laboratory-derived successful formulation that is stable, safe, and easy to deliver can become very problematic if an efficient, easy, and economical manufacturing scale-up is not possible. Some of the key challenges in each of the development areas highlighted in Figure 1.1 will be discussed in the following subsections. Although the TPP applies to goals in general for pharmaceutics, much of the discussion will concentrate on the development of biotherapeutics manufactured by recombinant DNA technology, and in particular monoclonal antibodies.

Figure 1.1 Major contributors to successful pharmaceutical development.

Development of the API

Traditional small-molecule pharmaceutical process development begins with a medicinal chemist who generates a synthetic approach for making the small-molecule drug. The purified API, usually a solid phase preparation, is then handed off to the formulation chemist for development of a final dosage form for administration. This overall process is very different for rDNA-derived protein drugs, and the manufacturing of rDNA-derived API, generally referred to as drug substance (DS), has been extensively reviewed and discussed in several books. In particular, DS is manufactured using organisms transformed with the appropriate gene coding for the protein along with genetic control elements to allow for manipulation of protein synthesis during fermentation or cell-culture processing. Although many different host cells have been used, the most frequently used systems have been Escherichia coli and Chinese hamster ovary cells. After centrifugal harvesting of the cells, the expressed protein is recovered and purified from either the centrifuged cells (if expressed intracellularly) or the supernatant (if secreted into the harvest fluid). The resulting purified protein therapeutic DS at this point is in a solution after exchange that consists of all the excipients required for the final liquid chromatography step. Thus, unlike a small-molecule pharmaceutical the development of a formulation manufacturing process that can be efficient and economical resides with the recovery and purification scientists. However, this step cannot be developed until the pharmaceutical scientist creates an appropriate formulation that confers the required stability and compatibility with the administration route. Moreover, the DS also needs to be formulated to allow for long-term storage of bulk DS since several final drug product (DP) lots may come from one manufactured DS lot.

Generally the DS formulation will be similar to the final DP, but there are several challenges that have to be addressed. Often the final dosing required is not known, and thus it is difficult to choose one final volume and concentration of the protein therapeutic for the formulation. Thus, “preformulation” studies to determine a range of concentrations and excipients are required. These studies are facilitated by designing experiments to investigate the impact of external conditions such as pH, temperature, and ionic strength on the solubility and stability of the molecule. It is also important to determine early on in development what route of administration is required for the particular indication. As an example development of formulations for subcutaneous (SC) versus intravenous (IV) routes will have different challenges and will be discussed in later chapters. One important aspect in the development of the DP formulation is whether the biopharmaceutical requires low dosing, such as erythropoietin for generation of red blood cells (µg/kg), or high dosing such as human growth hormone (mg/kg). This book will focus on development and the challenges to address the requirements of the TPP of a class of protein therapeutics, monoclonal antibodies (mAbs), that although are very selective for targets, generally require high dosing for efficacy. The term mAb as used in this book encompasses full length and fragments of mAb as well as radiolabeled and drug-conjugated forms. Antibody drug conjugates have their own set of challenges, which will be briefly discussed in the last chapter, but are not within the scope of this book.

mAbs as protein therapeutics

With the advent of recombinant DNA technology it became possible to express human or designed proteins in a variety of microbial, plant, and mammalian systems. Over the years the development of mAbs as drugs has increased at a large rate. As of 2014 there have been 64mAbs approved (4 of these mAbs have been voluntarily withdrawn from the market) or in review in Europe and the United States or pending (Table 1.1). Of the 64mAbs, 8 are radioisotope-labeled imaging agents and 1 a radioisotope-labeled mAb for treatment. A majority of the approved mAbs (40) are delivered by IV and the remainder by SC (9), intramuscular (IM) (2) (Amevive is given either IV or IM), and intravitreal (2). In addition, there are more than 200mAbs in clinical studies with more than 600 in preclinical development (Reuters, 2014). The market forecast for mAbs in 2014 is $35billion in the United States alone (Frost & Sullivan, 2008).

There are several reasons why mAbs have become increasingly popular for commercial development. mAbs are highly specific, binding to a single antigen target, which leads to fewer side effects than conventional small-molecule drugs. Although mAbs have been created to bind to specific targets on cells or ligands that bind to targets that mediate disease, one of the exciting prospects is the development of mAbs as specific drug delivery molecules, which deliver conjugated toxins or radioisotopes to specific cellular targets (Wankanker, 2010). For conjugated drug toxins, appropriate design of linkers for the drug conjugate minimizes the exposure of nontarget cells to the toxin during circulation resulting in a reduction of harmful side effects (Junutula, Raab, Clark, & Sunil, 2008). Radioisotope-labeled mAbs can also be used as both therapeutic and imaging agents. The latter greatly increases the ability to excise tumors during surgical procedures. Overall these attributes have led to the emergence of mAb therapeutics as a dominant class of biotherapeutics.

Table 1.1

Therapeutic monoclonal antibodies, Fc fusion and Fab conjugates approved or in review in the European Union or United Statesa

Abthrax

Raxibacumab

Anti-B; anthrasis PA; human IgG1

(2012)

Human Genome Sciences/Glaxo Smith...