API, vital part of formulated end product

Chemists design and develop new molecules to use as a potential drug based on new disease, cost effective or better alternative of existing drugs,  better health etc.  Development of a new drug passes through different steps viz. synthesis, purification, testing, approval review, manufacturing and marketing. Once a new drug has been formulated one must take approval of drug administrator for testing which involves different stages. If the drug is for human applications, it must first be tested on small animals. After testing on animals, it goes for stage-wise clinical testing.  At this stage the drug first applies to healthy volunteers, then on patients suffering from the affliction the drug is intended to combat. After extensive testing, the manufacturer must take approval of the drug administrator to sell in the market  The various aspects of drug development are discussed in this paper.

The development of the sulfa drugs in the 1930s and penicillin in the '40s open a new chapter in pharmaceutical industry and the pharmaceutical industry became geared to intensive research on antibiotics, antihistamines, steroid hormones, vitamins, and many other kinds of drugs. The discovery of a new drug triggers an elaborate testing programme, first on small animals such as mice, then on larger animals such as monkeys and dogs

Drugs are divided into two groups: the ethical, or prescription drugs, normally available only through prescription; and the proprietor, or patent, drugs, sold over the counter for relief of minor and temporary ailments. Drugs are prepared from two basic components: Active Pharmaceutical Ingredients (API) and excipients (an inert substance, for example, starch or gum Arabic that is combined with a drug to make it easier to administer). The API forms the most vital part of every formulated end product .First raw materials are converted to APIs. The final formulation of drug is carried out by mixing excipients to APIs. The formulated drug is then converted to tablets or filling capsules or in solutions. The product is then packed sold in the consumer market.

Discovery and development of new drugs
The first step of a potential drug development is the knowledge and understanding of the disease for which the drug is to be developed to bring a safe and effective new treatment to patients. Recent advances in genomics, proteomics and computational power present new ways to understand the illness.

Scientists must understand the disease to be treated as well as possible and the underlying cause of the disease. They should try to understand how the genes are altered, how that affects the proteins they encode and how these proteins interact with each other in living cells, how those affected cells change the specific tissue they are in and finally how the disease affects the entire patient. This knowledge is the basis for treating the problem.

Researchers from government, academia and industry all contribute to this knowledge base. However, even with new tools and insights, this research takes many years of work and, too often ends without success. Even if the research is successful, it will take many more years of work to turn this basic understanding of what causes a disease into a new treatment.

Developing a new drug consists of various stages. The whole process is time consuming and expensive.  On an average a drug development process requires 10-15 years.  The process begins with laboratory experiments resulting in the synthesis and purification of compound as shown in Figure 1.

The compound then goes through a series of tests in animal and human subjects to determine if it is safe and effective against the disease. When those studies are completed, the Food and Drug Administration decides whether to approve the drug for safe in the country. Every country has their drug administration authority.

Testing of new drug
Discovery and development of a new drug depend on many factors. As new diseases are discovered, we need a new drug to combat with. The urge for reduction in production cost of costly drugs also motivates to develop new substitutes.  Whatever it may be, the fact is that drug development requires extensive research, development and elaborate testing programme.  First the formulated drug is tested on small animals such as mice, then on larger animals such as monkeys and dogs. After testing on animals, it goes for stage-wise clinical testing. For this stage approval of drug administrator is a must. In this stage the drug is first applied in 20-80 healthy volunteers, then on patients suffering from the affliction the drug is intended to combat.

After extensive testing the formulation process is once again reviewed. At this stage safety aspect especially side effects and remedies if any of the drug, consequences and various other aspects viz. cost, market etc. are considered. Then the company must apply for approval of drug administrators of a country or of different countries.

Drug delivery
Drug delivery mechanism (the way the drug is to take – by mouth, injection, inhaler) is also an important part of the whole process. Worldwide research is going on for the effective and controlled utilization of drugs.

Good Manufacturing Practices
During mass scale production a Good Manufacturing Practices (GMP) are followed. Every company uses its own quality control procedure and GMP. However, World Health organization (WGO) has laid down guidelines on it.

United Nations (UN) purchase drugs directly from a manufacturer. For this the drug manufacturer has to pass Pre-Qualification (PQ) test conducted by The World Health Organization (WHO). WHO has started its Pre-Qualification (PQ) programme in 2001 to ensure that final drug formulations manufactured by the manufacturer utilizing money provided by the United Nations (UN) would be of acceptable quality.

Only firms that have passed a WHO PQ assessment can bid on UN tenders.  WHO, NGOs, and national regulatory authorities use GMP standards to assess manufacturers; the difference is often in the stringency with which the regulatory authorities apply GMP standards. As a result, WHO PQ of a final formulator is an indicator to the market of quality.

Traditionally, WHO PQ is just applied to final formulations.

Part of the PQ process required final formulators to use GMP procedures to acquire APIs. This ensures a quality API. However, in the late 1990s, WHO became more concerned about the quality of APIs, especially following an incident in 1995 and 1996 when more than 100 children died in Haiti following ingestion of cough-and cold syrup containing counterfeit excipients: a Chinese chemical company sold diethylene glycol labelled as glycerine to the cough syrup manufacturer. The WHO Expert Committee on Specifications for pharmaceutical preparations responded by identifying several activities to control and ensure safe trade of starting materials for pharmaceutical products. In May 1999, The World Health Assembly adopted the Revised Drug Strategy resolution (WHA52.19) which requested WHO to prepare a new WHO Scheme for the Certification of Pharmaceutical Starting Materials Moving in International Commerce, which WHO released in 2001.

The WHO Expert Committee on Specifications for Pharmaceutical Preparations discussed the need for WHO PQ of APIs at its fortieth and forty first meetings (October 2005 and 2006, respectively). The WHO PQ Program then drafted an API PQ procedure, which the Expert Committee endorsed in principle at its 42nd meeting (October 2007), and adopted at its 43 rd meeting (October 2008), subject to approval by WHO Legal Counsel.