Jack Zheng, PhD, is Research Advisor and Team Leader in the Pharmaceutical Sciences R&D Division of Eli Lilly and Company and Adjunct Professor at Beijing University. Dr. Zheng is the author of more than thirty articles and several book chapters. He has been invited to present his work at numerous national and international scientific meetings. He was involved in more than ten new drug product development and regulatory filing with the Food and Drug Administration.

Formulation and Analytical Development for Low-Dose Oral Drug Products

John Wiley & Sons

Copyright © 2009 John Wiley & Sons, Inc.
All right reserved.
ISBN: 978-0-470-05609-7

Chapter One

AN OVERVIEW

JACK Y. ZHENG Pharmaceutical Sciences R&D, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 40285

U.S. law defines a drug as any substance, other than a food or device, either (1) intended for use in the diagnosis, cure, relief, treatment, or prevention of disease or (2) intended to affect the structure or function of the body. The mission of pharmaceutical scientists is to continue developing safer and more effective new drugs to conquer various human diseases. However, successfully developing new medicines for patients requires significant collaboration of many interdisciplinary sciences, including:

molecular biology;

medicinal chemistry;

pharmacology;

toxicology;

preformulation;

formulation;

clinical evaluation;

synthetic chemistry;

quality assurance/control;

regulatory affairs;

sales and marketing.

The objectives of formulation and analytical scientists are to develop new drug products for human use that are chemically and physically stable, bioavailable upon administration, manufacturable, cost-effective, elegant, and marketable.

Pharmacologically, a drug should demonstrate its ability to:

target the intended site or receptor (selectivity);

remain attached to the receptor (affinity);

show its effectiveness (efficacy);

show its safety (adverse/side effects).

Ideally, a drug should be highly selective for its biological target, so that it has little or no effect on other physiological systems. The drug should also be very potent and effective, so that low doses of drug substance can be used, even for disorders that are difficult to treat. Finally, the drug should be administered orally, not only for patient compliance, but also for ease of production, distribution, and administration.

Drug product development is a process of transforming concept into reality. The process is not only science, but also art. After selecting a new drug candidate, drug development moves from preclinical studies to critical clinical investigation, and then to various stages of clinical and commercial product development. A drug candidate can become a drug product only when the compound is clinically efficacious and safe, and the developed product is bioavailable and stable, produces the desired pharmacological effects, and can be manufactured consistently with the identity, strength, quality, and purity it is represented to possess.

During development of an oral solid dosage form, dose strength is one of the critical product attributes that may have a significant impact on formulation and analytical development. Especially for a low-dose drug product, pharmaceutical scientists face great challenges in formulation, manufacture, analytical chemistry, and regulatory requirements.

This book addresses the challenges and strategies in developing low-dose oral solid drug products (i.e., less than 1 mg per dose unit), and aids development scientists in improving research and development productivity with a scientific and structured approach to product development. The information presented in the book is based on the extensive experience of the contributors, all of whom are actively working in the pharmaceutical industry and/or regulatory agency and have gained significant knowledge from their practical experience.

1.1 THE DRUG DISCOVERY AND DEVELOPMENT PROCESS

Drug discovery and development is a time-consuming and unpredictable process as well as an expensive venture. Today the average cost to research and develop each successful drug is estimated to be somewhere between $1.2 billion and $1.5 billion. The whole adventure is highly innovative, highly risky, highly regulated, and highly technology- and information-intensive. Typically, it takes 10-15 years to develop a safe and effective new medicine from the early stage of discovery until the drug is available to treat patients. This process, as illustrated in Fig. 1.1, is normally divided into two key phases: discovery and development. During these phases, scientists have to:

understand disease status, hypothesize “targets” that new drugs might be able to affect, and validate the targets;

discover the molecule(s) to interact with the target hypothesized;

assess the new compound (drug candidate) in the laboratory and clinic for safety and efficacy;

develop the right drug product/dosage form for the intended use;

gain regulatory approval and get the new drug into the hands of physicians and patients.

1.1.1 The Discovery Phase

Before discovering any new drug, scientists strive to understand the disease needing treatment and unravel the underlying cause of the condition. To do this, they investigate:

how the genes are altered;

how that alteration affects the proteins they encode;

how those proteins interact with each other in living cells;

how those affected cells change the specific tissue they are in;

how the disease affects the patient.

This knowledge is the critical foundation for hunting a new medicine and treating the disease.

In 2001, scientists completed the sequencing of the human genome. They found that the genome of Homo sapiens consists of 24 distinct chromosomes (22 autosomal and the sex-determining X and Y chromosomes). There are approximately 3 billion DNA base pairs containing an estimated 20,000-25,000 genes. Each gene codes for a protein, and these proteins carry out all the functions of the human body, laying out how it grows and works. These genes and proteins can also be involved in disease. Hence, scientists are able to understand the inner workings of human disease at both the tissue level and the molecular level.

Once scientists understand the underlying cause of a disease, they can select a “target” for a potential new drug. A target is generally a single molecule, such as a gene or protein, which is involved in a particular disease state. Scientists call this earliest step in drug discovery “target identification.”

After identifying a potential target, scientists must demonstrate that it actually is involved in the disease and that a drug can act on it. This process is called “target validation.” Target validation is a crucial step in the drug discovery process that helps scientists minimize research paths that look promising, but that ultimately lead to dead ends. Target validation involves proving that DNA, RNA, or a protein molecule is directly involved in a disease process in vitro and in vivo, and that it can be a suitable target for a new therapeutic drug. Scientists use several methods to validate a target.

One type of target validation uses computer models. They are a fast, relatively cheap option for initial screening of both targets and potential drugs. The models usually focus on how the two types of candidate structures interact with each other. Sense reversal is another route to target validation. It hinges on disrupting gene expression to reduce the amount of the corresponding protein, thereby identifying the physiological role of the target. Examples of this technique include gene knockouts, antisense technology, and RNA interference (RNAi).

One disadvantage of doing target validation at the genetic level, however, is that many genes produce several different protein isoforms that can have subtly different functions. Post-translational modifications can also give protein variations. To address these issues, a developing approach in target validation, proteomics, focuses on manipulating the activity of the potential target protein itself. Proteomics investigates and manipulates the protein make-up of a cell so it is easier to distinguish and target just one specific form of a protein.

In vivo target validation involves more complicated experiments in animal models of diseases. However, animal models for certain diseases, such as psychiatric illnesses, are extremely difficult to develop. The alternative is to use gene knockouts, in which genes are deleted or disrupted to halt their expression in vivo. This can be a powerful method of predicting drug action. This method is based on the assumption that knocking out the gene for the potential target has the same effect as administering a highly specific inhibitor of the target protein in vivo. Once the target is validated, it can then be used for screening potential new drug candidates.

Scientists screen thousands of compounds (either by synthesizing or choosing from libraries) to find a molecule, or “lead compound,” that may interact with the target to alter the disease course. De novo and high-throughput screening are methods commonly used to find a lead compound. Promising lead candidates are called “hits.” Hits go through a series of tests to provide an early assessment of the safety, efficacy, and pharmacokinetic properties.

Lead compounds that survive the initial screening are then “optimized” or altered to improve their drugability and developability (that is, they are developed to achieve better physicochemical and biopharmaceutical properties and more effective and safer profiles in animals). Scientists make and laboratory-test hundreds of different variations or “analogs” of the initial lead compounds to evaluate the structure-activity relationship (SAR) of the hits.

New techniques have revolutionized the ability of scientists to optimize potential drug molecules. These new techniques include magnetic resonance imaging, X-ray crystallography, and powerful computer modeling capabilities. These tools allow scientists actually to “see” the target in three dimensions. This allows them to design potential drugs to bind more powerfully to the active sites of the target where they can be most effective.

After optimization, scientists test the lead compounds in more sophisticated models including pharmacokinetics, pharmacodynamics, and toxicity. The optimal molecule selected from these assessments is then declared a new drug candidate and moves on to the next phase (development). If a program is successful, it may take a total of 3-6 years from target selection and validation through lead generation, lead optimization, and preclinical evaluation in animals to candidate selection for a potential new medicine.

In recent years, biologists have explored more therapeutic targets related to human diseases (for example, nuclear hormone receptor resources). This exploration led to the discovery of many drug candidates that are more highly specific and more active, and, consequently, can be delivered in lower doses than before. Examples include ligands for peroxisome proliferator-activated receptor, thyroid hormone receptor, mineralocorticoid receptor, and glucocorticoid receptor. The clinically efficacious dose for these compounds could be as low as a few milligrams or even micrograms. As expected, this leads to more challenges to pharmaceutical scientists during product development.

1.1.2 The Development Phase

A potential new drug candidate faces a well-defined clinical and product development process that has been refined over several decades. The development phase of a new drug product usually consists of two main activities: clinical evaluation (safety and efficacy), and product development (drug substance and dosage form). As shown in Table 1.1, the process can last as long as 7-9.5 years and the cost can be approximately 50% of the entire expense for development of a new medicine. At this stage, some programs would be terminated for various reasons, such as lack of clinical efficacy, clinical toxicity, or drug developability.

Clinical investigations are clearly the most critical and demanding stage in the new drug development phase. When a drug company believes it has sufficient preclinical testing data to show that a new drug candidate is adequately safe for initial small-scale clinical studies, the company assembles and submits an investigational new drug (IND) application in the United States or a clinical trial application (CTA) in the European Union. The IND or CTA is the prerequisite for a company to obtain regulatory permission to begin testing a new drug in human subjects. Although there is no regulation that mandates a specific clinical trial structure and design, clinical evaluation of a new drug most often proceeds in at least three phases:

Phase I-phase I trials consist of the cautious use of a new drug in 20-100 normal human volunteers to gain basic safety and pharmacokinetic information. The trials include a single-dose safety study (SDSS) and multiple dose safety study (MDSS). The main goal of a phase I trial is to discover if the new drug is safe in humans. These studies help scientists determine toxicity, absorption, metabolism, elimination, and other pertinent pharmacological actions, and to find the safety dosing range. Recently, the U.S. Food and Drug Administration (FDA) endorsed “microdosing,” or the “phase 0 trial,” which allows scientists to test a small drug dose in fewer human volunteers to quickly weed out drug candidates that are metabolically or biologically ineffective.

Phase II-during phase II, the drug candidate is given to a small number of patients-100-500-who have the disease or condition under study. Phase 2 trials give additional safety data, and provide the first indication of a drug’s clinical effectiveness in its proposed use. Clinical researchers strive to understand some fundamental questions about the new drug: Is the drug working by the expected mechanism? Does it improve the disease condition? What are the effective dose range and dosing regime? If the new drug continues to show promise, the new drug moves into much larger phase III trials.

Phase III-in phase III trials, the new drug is used in a significantly larger group of patients (about 1000-5000) who suffer from the condition that the drug is proposed to treat. This phase of clinical evaluation is key in determining whether the drug is safe and effective. It also provides the information for labeling instructions to ensure proper use of the drug. Phase III trials are both the costliest and longest trials. Hundreds of clinical sites (centers) around the United States and the world participate in the trials to get a large and diverse group of patients. Certain phase III trials, called “pivotal” trials, will serve as the primary basis for the drug approval. These studies must meet more rigorous standards, such as having a randomized, double-blind placebo-controlled study design, or having a comparator. Two pivotal clinical trials are required for a new drug application (NDA) with a regulatory agency.

The formulation, manufacturing process, analytical development, and long-term toxicology studies in animals are parallel to the clinical investigation (Table 1.1). Clinical trial materials should be developed, manufactured, tested, and released before conducting a phase I clinical trial. Process chemists may redesign the synthetic route for the drug candidate to meet the requirements of large-scale production in a pilot plant. Preformulation scientists complete the activities of salt selection, polymorphism studies, and physicochemical characterization. Formulation scientists develop less time-consuming formulations, such as drug-in-bottle or drug-in-capsule, for the first human dose (FHD) clinical trials.

If a drug candidate survives phase I trials, the process chemists start to optimize the synthetic process for the drug substance and the formulation scientists develop near-market-image dosage forms for phase II clinical trials. Preliminary control strategies for both drug substance and drug product are developed.

Following successful phase II clinical trials, the manufacture of the drug substance is scaled up to meet commercialization needs. In addition, the prototype formulation and process is optimized and scaled up to greater than one-tenth of the commercial batch size.

The optimized formulation then is prepared for phase III pivotal clinical trials. Followed by manufacturing process optimization and scale-up, the three batches of the drug product are manufactured for primary stability evaluation at product launch sites. The information on the manufacture, scale-up, control, and stability is used for product registration with regulatory agencies.

During development, pharmaceutical scientists work to achieve an ideal drug product-one that is bioavailable after administration; physically/chemically stable through its shelf-life; and able to be manufactured reproducibly and reliably with high quality.

Upon completion of preclinical, clinical, and drug product development, the drug company submits to the FDA for approval an NDA containing a meticulous, well-indexed, comprehensive, and readable document. The document should satisfy the requirements of the Food, Drug, and Cosmetic Act and the code of Federal Regulations (CFR) used by the FDA in the review and approval of safe and effective drug products in the United States. The FDA’s NDA review process may last approximately two years. Multiple review teams are involved in the review process including:

clinical reviewer;

pharmacology/toxicology reviewer;

chemistry reviewer;

statistical reviewer;

microbiology reviewer;

biopharmaceutics reviewer.

(Continues…)

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