DRUG DISCOVERY

Pre-discovery

1. Disease Identification

Before any potential new medicine can be discovered, scientists work to understand the disease to be treated as well as possible, and to unravel the underlying cause of the condition. They try to understand how the genes are altered, how that affects the proteins they encode and how those 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.

2.Target Identification

The definition of "target" itself is something argued within the pharmaceutical industry. Generally, the "target" is the naturally existing cellular or molecular structure involved in the pathology of interest that the drug-in-development is meant to act on. However, the distinction between a "new" and "established" target can be made without a full understanding of just what a "target" is. This distinction is typically made by pharmaceutical companies engaged in discovery and development of therapeutics. In an estimate from 2011, 435 human genome products were identified as therapeutic drug targets of FDA-approved drugs.

"Established targets" are those for which there is a good scientific understanding, supported by a lengthy publication history, of both how the target functions in normal physiology and how it is involved in human pathology. This does not imply that the mechanism of action of drugs that are thought to act through a particular established targets is fully understood. Rather, "established" relates directly to the amount of background information available on a target, in particular functional information. The more such information is available, the less investment is (generally) required to develop a therapeutic directed against the target. The process of gathering such functional information is called "target validation" in pharmaceutical industry parlance. Established targets also include those that the pharmaceutical industry has had experience mounting drug discovery campaigns against in the past; such a history provides information on the chemical feasibility of developing a small molecular therapeutic against the target and can provide licensing opportunities and freedom-to-operate indicators with respect to small-molecule therapeutic candidates.

In general, "new targets" are all those targets that are not "established targets" but which have been or are the subject of drug discovery campaigns. These typically include newly discovered proteins, or proteins whose function has now become clear as a result of basic scientific research.

The majority of targets currently selected for drug discovery efforts are proteins. Two classes predominate: G-protein-coupled receptors (or GPCRs) and protein kinases.

3.Finding A Lead Compound

Armed with their understanding of the disease, scientists are ready to begin looking for a drug. They search for a molecule, or  “lead compound,” that may act on their target to alter the disease course. If successful over long odd sand year soft testing, the lead compound can ultimately become a new  medicine.

There are a few ways to find a lead compound

• Natural sources ( plant, animal, Micro-organisms etc)
• Synthetics ( Using Chemical Banks)
• Enhance the side effects of other drugs. e.g Sulphonamide used as diurectics
• Seredipity ( By chance e.g penicillin discover
• Use structural similarity to a natural ligand
• Computer-Assisted Drug Design

4. Lead optimization

Structure of lead is altered to improve its properties.This is called as lead optimization.

Now drug development process starts.

 

Click here for drug development

Drug Product Development

Introduction

Active pharmaceutical ingredient (API): component that produces pharmacological activity (drug substance).  May be produced by chemical synthesis, from natural product, enzymatic reaction, recombinant DNA, fermentation, etc.

New chemical entity (NCE): drug substance with unknown clinical, toxicological, physical, chemical properties.  According to the FDA, NCE is an unapproved API.

Drug product: finished dosage form containing API and excipients.

Generic drug products: after patent expiration of brand drug.  Therapeutically equivalent to the brand and has the same drug amount in the same dosage form.  Must be bioequivalent (same rate and extent of absorption) à same clinical results.  May differ from brand in excipients (tablets only unless safety studies are done) or physical appearance.

Abbreviated New Drug Application (ANDA): submitted to the FDA for approval of generic drugs.  Preclinical safety and efficacy studies are not required.  Human bioequivalence is needed (on healthy human volunteers).  Chemistry, manufacturing and controls for generics are similar to the brand. 

Specialty drug products: existing products developed for new delivery system or new therapeutic indication.  Safety and efficacy studies are not required.  Example nitroglycerin transdermal patch after sublignual tablets.

New drug approval

Preclinical (animal safety / pharma) à IND à Phase I (healthy human safety) à Phase II (↓no.of patients) à Phase III (↑ no. patients) à NDA à FDA green light for marketing àPhase IV (scale up) à Phase V (continuous improvements).

Preclinical stage: animal pharmacology and toxicology to determine safety and efficacy.  Formulation is not final. 

Phase I: Submit an Investigational New Drug (IND) à clinical studies on healthy volunteers to determine toxicity and tolerance.  For oral drugs à simple hard gelatin capsule. 

Phase II: small number of patients under close supervision.  Dose-response studies to determine optimum dosage for treatment.  Determine the therapeutic index (toxic dose/effective dose).  Develop final drug formulation (bioequivalent to that used in initial clinical studies).  Start chronic toxicity studies for 2 years in 2 species.

Phase III: large-scale multicenter clinical studies with final dosage form (from phase II) to determine safety and efficacy in patients. Watch for new, rare, toxic or side effects.

NDA submission: FDA satisfaction with safety and efficacy for marketing.

Phase IV: scale-up in preparation for marketing. Only minor modifications on the formulation are allowed. 

Phase V: continuous drug product improvements after marketing. 

Product development

New chemical entities

Preformulation:

Physical and chemical characterization of the drug and dosage form during preclinical phase.  Includes general properties (particle size / shape, polymorphism, crystalline structure, density, surface area, hygroscopicity), solubility (dissolution, pH-solubility profile, various solvents), chemical properties (surface energy, pH stability profile, pKa, temperature stability, excipient interactions), stability analytical methods. 

Formulation development: continuing process.

Injections: final formulation is developed in preclinical phase, stability in solution is critical, few excipients allowed, no bioavailability for IV.  

Topicals / local: final formulation developed in phase I, study release in in vitro diffusion cell models, local irritation and systemic absorption are the issues.

Topicals / systemic: drug delivery through skin / mucosa / rectum, final formulation in phase III. 

Oral drugs: final formulation in phase II. 

Final product considerations: size, shape, color, taste, skin feel, viscosity, physical appearance, production equipment / site.

Product line extensions:

Dosage forms with change in physical form or strength but not use or indication.  Usually occurs during Phases III, IV, V.

Regulatory approval: based on stability, analytical / manufacturing controls, bioequivalence studies, clinical trials

Solid products:

Different strength in a tablet or capsule form à only bioequivalence required (simplest case).  Easier if in vitro dissolution / in vivo bioavailability correlation exists.

Modified release: clinical trials required.

If new indication à new NDA and new efficacy studies.

Liquid products:

If an extension of a liquid à same as above for solids

If an extension of a solid à if big difference in extent / rate of absorption à new clinical trials.

Preapproval inspections

Manufacturing facility is inspected prior to NDA / ANDA approval or after a major reported change to NDA / ANDA.

Includes: general cGMP inspection, reviews documentation, verifies traceability of information to documentation, consults the chemistry / manfucaturing / control (CMC) section of NDA / ANDA, make a final recommendation.

Scale-up and post-approval changes (SUPAC)

Guidelines to ¯ no. of manufacutring changes that require preapproval by the FDA. 

Examples: minor formulation changes, change site of manufacture, batch size ­ or ¯, change manufacturing process / equipment. 

1. Very minor changes not requiring approval are reported in an annual report. Examples: compliance with guidance, label description, deletion of colorant, expiration date extension, ∆ container / closure type (not size), analytical method

2. Changes being effected supplement: minor changes but require some validation, documentation.  A supplement but no pre-approval is required.  Examples: new specs, label changes on clinical info, different cGMP manufacturing facility but same process.

3. Preapproval supplement: major changes require specific preapproval.  Examples: adding or deleting an ingredient, relaxing specs, deleting a spec or method, method of manufacture, in-process controls.

Therapeutic and Bio-equivalence: must be shown for any change.  Minor change à comparable dissolution profiles.  Major change à in vivo bioequivalence study. 

GMPs

Minimum requirements for manufacturing, processing, packing, or holding drugs. Include criteria for personnel, facilities, processes to ensure final product has the correct identity, strength, quality, purity.

Quality Control (QC): department responsible for establishing process and product specifications. The QC dept test the product and verifies specs are met. This includes acceptance / rejection of incoming raw materials, packaging components, water, drug products, environmental conditions.

Quality Assurance (QA): a department that determines that the systems and facilities are adequate and that written procedures are followed.