Analytical Scientists in Pharmaceutical Product Development

Task Management and Practical Knowledge

Kangping Xiao

• Publisher: Wiley
• Year: 2020
• ISBN:
  9781119547891
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Analytic Chemistry

This book explains task management concepts and outlines practical knowledge to help pharmaceutical analytical scientists become productive and enhance their career.

• Presents broad topics such as product development process, regulatory requirement, task and project management, innovation mindset, molecular recognition, separation science, degradation chemistry, and statistics.
• Provokes thinking through figures, tables, and case studies to help understand how the various functions integrate and how analytical development can work efficiently and effectively by applying science and creativity in their work.
• Discusses how to efficiently develop a fit-for-purpose HPLC method without screening dozens of columns, gradients, or mobile phase combinations each time, since the extra effort may not provide enough of a benefit to justify the cost and time in a fast-paced product development environment.

1
Pharmaceutical Development at a Glance

In the United States, there are two main categories of medicinal products: prescription medicines and over‐the‐counter (OTC) medicines. The prescription medicines are prescribed to patients through appropriate health‐care practitioners, while the OTC medicines are available to the general public through consumers' self‐prescription. Many OTC products are once prescription medicines that are later switched to be over the counter with approvals from the US Food and Drug Administration (FDA). Consumers select OTC medicines based on their knowledge of the medical symptoms; by reading the labels on the product packaging; through their experiences with the products; according to their perceptions about the brand, manufacturer, packaging, product quality; and via their likes or dislikes of the sensational aspects of the product. Attractive dosage forms and appearance, pleasant flavors, soothing tastes, convenience at the time of use, costs, etc. are significant attributes (selling points) of an OTC medicinal product.

The processes for developing prescription medicines and OTC medicines are quite different. Prescription medicinal product development must go through the following steps: Step 1, Discovery and Development; Step 2, Preclinical Research; Step 3, Clinical Research; Step 4, Registration and FDA Review; and Step 5, FDA Post‐Market Safety Monitoring. OTC medicinal product development has more varieties. A pharmaceutical company can commercialize an OTC medicine after going through either most or just a few above steps of the development [1].

1.1 Prescription Medicinal Product Development

The development of prescription medicine is a time‐consuming process that requires a pharmaceutical company to spend lots of resources in both infrastructure and workforce. From infrastructure point of view, the company has to make a lot of investment to (1) build research and development (R&D) facilities with sufficient space that holds various kinds of state‐of‐the‐art instruments and laboratory equipment; (2) build modern manufacturing facilities and the associated waste treatment capacity; (3) build robust and effective document management systems to safeguard proprietary information and secure data integrity to comply with laws and regulations; and (4) build digital/electronic capability for data acquisition, processing, storage, and sharing. From the staffing point of view, the company must be able to attract and retain talents. Besides all the personnel needed to manage and run the business, a number of intelligent scientists are needed to carry out an enormous amount of research/discovery work. The medicinal product development starts from massive and fundamental researches that sometimes are tedious during drug discovery, that hundreds of molecules are studied. The development work then moves on to the safety and efficacy evaluations of the selected molecules. Once human clinical trials are involved, stringent regulations are applied to the studies from the sourcing of raw materials to the release of clinical trial materials to hospitals. High‐quality documentation and noncompromised data integrity are a must for clinical studies. If the candidate molecule is lucky enough to make itself into a final medicinal product, information regarding Chemistry, Manufacturing, and Controls of all the ingredients in, the manufacturing process of, and the analytical methodologies employed to ensure the quality of the product are put together and submitted to health authorities for approval, which itself is lengthy and costly. Averagely a new prescription medicinal product approval in the United States takes more than a decade if counted from Step 2, preclinical research. The overall time is much longer if including Step 1, drug discovery.

1.1.1 Active Pharmaceutical Ingredient (API) Development

An Active Pharmaceutical Ingredient (API) is the molecule that possesses a desired therapeutic effect. During the drug discovery, a promising molecule is identified and studied thoroughly for its chemical nature, potential interactions with a target protein receptor, and its safety and toxicity. Studies regarding how potentially the molecule will be absorbed, distributed, metabolized, and excreted from human bodies are carried out [1]. Knowledge gained from the drug discovery helps the pharmaceutical company to design the clinical studies and begin the Investigational New Drug (IND) application, a process must be gone through before clinical trials can be carried out.

Once upon a time, compounds extracted from traditional remedies were isolated, characterized, and their medicinal efficacies were studied. From those compounds, the working chemicals were identified, purified, and synthesized to become the so‐called active pharmaceutical ingredients. Nowadays, those low hanging fruits have been long‐gone. The modern drug discovery starts with much more in‐depth fundamental research at molecular levels. For illnesses such as cancers, Alzheimer's, and cardiovascular diseases, the knowledge accumulated from the entire scientific community, not just within one or two pharmaceutical companies, regarding the mechanisms behind those diseases is shared and applied in creating new medicinal molecules.

Upon identification of an API molecule, a robust synthetic route has to be established to produce the API consistently with a high purity (e.g. within 99–101% w/w). The analytical laboratories in pharmaceutical or chemical industries equip themselves with many modern technologies to ensure a synthetic route is effective, efficient, economical, environmentally friendly, and most importantly, to ensure the manufacturing of the API material is consistently at a high quality. Those analytical technologies include, but not limited to, high‐performance liquid chromatography (HPLC), gas chromatography (GC), ion chromatography (IC), inductively coupled plasma (ICP), mass spectroscopy (MS), combinations of MS with other detection mechanisms such as LC‐MS, GC‐MS, ICP‐MS, Fourier transform infrared spectroscopy (FTIR), near‐infrared spectroscopy (NIR), Raman spectroscopy, X‐ray powder diffraction, thermal analysis such as thermogravimetric analyzer (TGA), differential scanning calorimetry (DSC), and gravimetric technique such as dynamic vapor sorption (DVS), etc.

1.1.2 Preclinical Research

Before testing a candidate molecule in humans, the pharmaceutical company must demonstrate that the molecule does not cause serious harm. Instead of demonstrating its efficacy in curing the target disease, Do No Harm is the first‐thing‐first in medicinal product development. There are two types of preclinical research: in vitro (Latin for in the glass or in the test tubes) and in vivo (Latin for within the living) studies. Preclinical studies can provide detailed information on dosing and toxicity levels and serve as the decision‐making basis for the next step, i.e. clinical studies in humans.

The FDA requires that good laboratory practices (GLP) are to be followed for preclinical laboratory studies. The GLP regulations are defined in 21 CFR Part 58.1: “Good Laboratory Practice for Nonclinical Laboratory Studies.” These regulations set the minimum basic requirements for study conduct, personnel, facilities, equipment, written protocols, operating procedures, study reports, and a system of quality assurance oversight for each study to help assure the safety of FDA‐regulated products [1].

1.1.3 Clinical Research – Phase 1, Safety and Dosage

After a successful preclinical study, the pharmaceutical company will conduct extensive clinical researches on the interactions between the API molecule and human bodies. Usually, there are four clinical phases. Each phase has a different purpose.

The Phase 1 clinical study is for safety evaluation of the API and for exploring its potential dosage. The study usually involves 20–100 healthy volunteers, and the length of study is about several months. In some cases, people with specific diseases or conditions, such as certain types of cancer, can also participate in Phase 1 trials. The study is more focused on the safety aspect. Evaluation is carried out on the tolerable amount of the drug molecule and what kind of acute side effects the molecule may cause. The Phase 1 trials can also provide some preliminary information about the effectiveness of the drug molecule. Approximately 70% of the studies potentially make their way to the next phase [1].

1.1.4 Clinical Research – Phase 2, Efficacy and Side Effects

The volunteers who participate in Phase 2 studies are patients with the disease or condition for which the drug molecule is targeting to cure. In Phase 2 trials, a placebo, i.e. a mixture of all the ingredients without the API, is used as a comparison to explore the efficacy of the medical product. Although usually a few hundred patients are involved, a Phase 2 clinical trial still is focusing on the evaluation of the drug molecule's side effects. The number of volunteers is yet considered not big enough to conduct a definitive evaluation of benefits versus risks of the medicinal product. The length of study can range from several months to about two years. Approximately 33% of the studies move to the next phase [1].

1.1.5 Clinical Research – Phase 3, Efficacy and Monitoring of Adverse Reactions

A Phase 3 clinical trial, also known as a pivotal study, involves a few hundreds to a few thousands of volunteers. Efficacy is the focus of a Phase 3 study. Drug safety, however, remains a primary focus throughout this phase. Not only the number of volunteers is much larger, the duration of the trial is also longer, from one to four years, which makes it possible for the pharmaceutical drug developer to study long‐term side effects and other uncommon and unwanted reactions between human bodies and the API molecule. Approximately 25–30% of the studies move to the next phase [1]. If we pause and do a simple calculation of the final ratio of the studies that survive from Phase 1 through Phase 3, 70 × 33 × 30%, we find a stunning failing rate of more than 90% of the clinical studies for a new prescription drug product development!

If the API molecule is one of the lucky survivals that make through Phase 3 clinical research, the pharmaceutical company can apply for the right to manufacturing and selling of the newly developed medicinal product. In the United States, the drug developer files a New Drug Application (NDA) to the FDA.

Detailed information and guidance regarding the NDA applications can be found on the FDA website. Since 1938, every new drug has been the subject of an approved NDA before US commercialization. The NDA application is the path through which a pharmaceutical company seeks approval from the FDA of a new drug product for sale and marketing in the United States. The data gathered during the animal studies (preclinical) and human clinical trials (Phase 1 through 3) are in the NDA. The contents of the NDA must be able to enable FDA reviewer to assess whether the drug is safe and effective in its proposed use(s) and whether the benefits of the drug outweigh ...

Table of contents

• Cover
• Table of Contents
• Title Page
• Copyright Page
• Dedication
• Preface
• 1 Pharmaceutical Development at a Glance
• 2 Analytics in Fast‐Paced Product Development
• 3 Effective, Efficient, and Innovative Analytical Development
• 4 Analytical Chemistry and Separation Science at Molecular Level
• 5 Degradation Chemistry and Product Development
• 6 Practical Statistics for Analytical Development
• 7 Thoughts on Conventional Chromatography Practices
• Index
• End User License Agreement