CURRENT TRENDS IN DRUG DEVELOPMENT

• With the emergence of new technologies including genomics, proteomics, molecular biology, combinatorial chemistry, computer-assisted drug design, robotics, and high-throughput screening—our ability to generate new molecular entities that are high-affinity legends or receptors has greatly increased. However, success in developing these new entities through preclinical and clinical testing has not improved significantly.
• It is estimated that less than 40% of NMEs produced by drug discovery groups in pharmaceutical companies are candidates for preclinical testing. Only about 10% of them actually make it through clinical trials and are approved for marketing.
• There is intense economic pressure on the pharmaceutical industry by those who pay for its products to make the development of drugs more efficient and thereby reduce or at least contain costs.
• Integrated drug discovery and development


  Bringing company researchers from basic, preclinical, and clinical sciences together to work very early in the development of a drug candidate or even during discovery efforts as a project team
• Project team


  • Relies on the collective wisdom of the group
  • Calls upon academic experts when needed
  • Charged with anticipating problems that may be encountered in the preclinical and clinical testing of a drug candidate
  • Develops a drug product with an acceptable pharmacokinetic profile, a low potential for drug–drug interactions, clear-cut efficacy, and a comfortable safety margin
  • Identifies the target population and strives to exclude from clinical trials patients who are unlikely to derive a benefit from the new drug and eliminate those likely to respond to its effects adversely
• Validation


  A planned series of interactive tests and inspection designed to describe and reduce uncertainty in an important process
• Validation activities


  • Studies (tests or qualifications) showing performance (and intrinsic Behaviour) characteristics
  • Proficiency testing which uses the notion of systematic parallel testing of two systems
  • Internal auditing (sample testing) of a process or product
  • External auditing – of suppliers and service providers
  • Challenge testing, where the most extreme 'worst case' is applied
• PDCA process


  1. Plan

  2. Do

  3. Check

  4. Act
• The compliance of a process to the standards set-up by the organization can be calibrated against existing plans or regulations. This often happens as a consequence of enforcement by inspection that involves regulators such as the MHRA, FDA, Irish Medicines Board, etc.
• Validation master plan (VMP)


  Contains the most important of protocols, defining: responsibilities, nature of testing, items concerned, details of operation
• Types of validation

  • Prospective validation mode
  • Retrospective validation
  • Re-validation
• Validation 'fitness-for-purpose' aids


  • System suitability tests, such as accuracy
  • Challenge testing, where the equipment is stressed more than would be customary
  • Method transfer from recent research and development with best practices involved
  • Failure-acceptance-improvement culture (MII, quality control spiral)
• Validation is undertaken in an attempt (a) to provide evidential proof of process compliance but also (b) to provide the ancillary element of an assessment of risk.
• During routine manufacturing of pharmaceutical products, the principal concerns would be: the drug substance – purity and freedom from degradation products, product stability (compositional change) and impact this might have on bioavailability, the correct status of the certificate of analysis (CoA) and the results of laboratory testing of the product
• Quality

  • Degree of excellence possessed by an item
  • Meeting requirements of specific customer needs
  • Reliability contract with potential customer
• Quality assurance (QA)


  A planned system of activities designed to ensure effective quality control
• Quality assurance (QA)


  • Sampling, and good sampling based on solid statistics is crucial
  • Adequate testing, crucial as for sampling
  • Responsibility for errors and decisions, normally a qualified person
  • Checkpoints must be established by way of evaluation of potential risk
• Quality control (QC)

  A planned coherent system of activities designed to provide quality product
• General model of controlling quality

  1. Apply a standard

  2. Implement and check the value or magnitude of the set standard

  3. Check the product for conformance

  4. Institute an appropriate remedy or action

  5. Feed this back into the implementation and checking stage as an iterative improving cycle
• Total quality control (TQC)


  • Quality has to be 'built into' the product
  • No other approach is acceptable except getting the product 'right-first-time'
  • Faults and non-conformance are minimised by using the correct environment
  • The best outcomes derive from a sense of contribution across all sections and team effort
  • Best practice comes from a quality department that is integrated with R&D
• Current good manufacturing practice (cGMP)

  The process of manufacture is clearly defined, testing and processing methodology are assessed and optimised through lengthy validation
• Validation

  An established regimen of activities based around process capability showing that a SYSTEM of PRACTICE does EXACTLY what it is supposed to do