Pharmaceutical Quality Assurance : Past, Present and Future

  
History of Pharmaceutical Quality System

• ·        Pharmaceutical Regulations - A GMP requirements has to be created and put in place as responses to tragic circumstances and to prevent future tragedies.

     A GLANCE TO THE PAST.......

• 1901 - Children who received antitoxin for diphtheria treatment died of tetanus because the horse serum that had been used to prepare the antitoxin was contaminated with tetanus. 

•  1906 Pure Food and Drug Act – First Act required selected dangerous ingredients to be labeled on all drugs.

• 1930s - The wrong raw material and an elixir of sulfanilamide, anti-infective drug used in 1935. One company used diethylene glycol, a poisonous solvent and chemical analog of antifreeze, in an oral “elixir of sulfanilamide.” Before the problem was discovered, 107 people died, many of them children.

• In 1941, nearly 300 people were harmed some of them died by one company’s sulfathiazole tablets, a sulfa drug tainted with the sedative phenobarbital.

 

• 1960s - Thalidomide was marketed in Europe as a morning sickness pil and to treat morning sickness. When regulatory agencies gave permission to sell the drug for that indication, they had no knowledge of its serious side effects. It turned out to be teratogenic: It caused serious deformities in developing fetuses.

•     In 1982, Poisoned acetaminophen capsules.12-year-old Mary Kellerman died after taking an extra-strength Tylenol acetaminophen capsule, Six other people died after taking the same drug. Johnson & Johnson announced a nationwide recall of 31 million bottles of Tylenol. 
      
      The investigation revealed that a criminal tamperer had opened up and laced some capsules with cyanide. The company destroyed all 31 million bottles of the largest-selling over-the counter (OTC) medicine in the country.

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    PRESENT PRINCIPLES OF PHARMACEUTICAL QUALITY SYSTEM
    
    
  • WHAT IS GMP (GOOD MANUFACTURING PRACTICE)?
    
    
    • ·   The part of quality assurance which ensures that products are consistently produced and controlled in accordance with the quality standards appropriate to their intended use and are in compliance with their marketing authorization specifications.
      
      

    •   GMP involves also Production and Quality Control of Pharmaceutical products Quality assurance (or Quality Management) is a wide-range concept covering all matters that individually or collectively influence the quality of a product. 
      
      
        It is the totality of the arrangements made with the object of ensuring that pharmaceutical products are of the quality required for their intended use (WHO). 
      
      
      
      
    PHARMACEUTICAL QUALITY SYSTEM (PQS)
    
    
    
    
    
    
    
    • Manufacture of medicinal products with appropriate quality attributes. Product and process knowledge is managed throughout all lifecycle stages;
    
    
    1.     Pharmaceutical Development
    2.     Technology Transfer
    3.     Commercial manufacturing
    4.     Product Discontinuation
    
    
    • Good Manufacturing Practice is always taken into consideration through design, development and manufacture of products with clearly specified manufacture and control operations. 
     
    • Deviations during manufacture or control should be investigated, Root Cause should be found and appropriate CAPAs should be undertaken in order to avoid potential deviations occurring in the future. Effectiveness of CAPAs.  
    
    
    • Implementation should be evaluated through Quality Risk Management Principles (QRM). 
    
    
    • Evaluation of planned changes and their approval prior to implementation, taking into account regulatory notification and approval where required through Change Control Management. 
    
    
    
    
  •        PERSONNEL:
   
  

• • Personnel should have the necessary qualifications and practical experience.
    Personnel in responsible positions should have specific duties recorded in written job descriptions and adequate authority to carry out their responsibilities.
  • • PREMISES AND EQUIPMENT:
    
    
    • Premises and equipment must be located, designed constructed, adapted and maintained to suit the operations to be carried out.
     
    • Their layout and design must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt.
     
  • DOCUMENTATION:
      Basic types of GMP documents required in Pharmaceutical         Quality System:
    
    

    
    
    • • ·         Site Master File (SMF)
      • ·       Quality Manual
      • ·        Quality Policies
      • ·        Standard operating procedures (SOPs)
      • ·        Specifications
      • ·       Manufacturing Formulae, Processing, Packaging and Testing Instructions
      • ·       Protocolsements
      • ·        Technical – Quality agreement 
        
        
  • DEVIATION INVESTIGATION AND ROOT CAUSE ANALYSIS (RCA):
    
    
    
    
    
    • ·   Root cause analysis work should be applied during the investigation of quality defects. In cases where the true root cause(s) of the quality defect cannot be determined, consideration should be given to identifying the most likely root cause(s) and to addressing those.
      
      

    •       Appropriate CAPAs should be identified and taken in response to a quality defect. The effectiveness of such actions should be monitored and assessed.
      
      
      
      
        
  • QUALITY RISK MANAGEMENT:
   
  • OVERALL RISK = S x O x D  
    
    

    
    

    
    

    S = Severity of the consequences of the harm

    O = Probability of occurrence of the harm

    D = Detectability, ability to detect the hazard (Source and origin of harm)

    
    

    
    

    FUTURE OF PHARMACEUTICAL QUALITY SYSTEM – THE NEW APPROACH

    
    

    • QUALITY BY DESIGN (QBD)

    
    
     
              
    
    
    
    
  • The pharmaceutical Quality by Design (QbD) is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management. 
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    •  QbD development process include:
      
      
      • Begin with a target product profile that describes the use, safety and efficacy of the product. 
        
        
        • Define a target product quality profile that will be used by formulators and process engineers as a quantitative surrogate for aspects of clinical safety and efficacy during product development.
      • Gather relevant prior knowledge about the drug substance, potential excipients and process operations into a knowledge space. Use risk assessment to prioritize knowledge gaps for further investigation.
        
        
        Design Space:     
              
      • Design space is a scientific concept used in the pharmaceutical/biopharmaceutical industry to support and assure product quality. The culmination of the information and knowledge gained during product development provides the foundation for the design space.
      
      
      • Key areas of focus are materials — active pharmaceutical ingredients (APIs) and inactive components (excipients) — manufacturing process, and the desired quality target product profile (QTPP) tolerances and process variation variables.
        
        
      • When defining design space, your approach should include target product critical quality attributes (CQAs), prior scientific knowledge, and risk assessment. Critical quality attributes are the properties or characteristics that should be within an appropriate limit, range, or distribution to ensure the desired product quality.
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