Water for Pharmaceutical Use Part 2: Water purification engineering

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Water for Pharmaceutical Use Part 2 Water
purification engineering

• Supplementary Training Modules on Good
  Manufacturing Practice

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• Objectives
• To examine the basic technology and requirements
  for
• Water treatment systems
• Storage requirements
• Sampling and testing
• Different types of water used in pharmaceuticals
• Microbial limits, disinfection

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• Water system design
• Pipes sloped so water does not pool and can drain
  easily
• Sanitary fittings connections
• Constructed of suitable materials such as
  stainless steel
• Circulate the water
• Incorporate non-return valves (NRV)

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• Further water treatment purification stages
  downstream of the pre-treatment system
• Filtration
• Disinfection
• Reverse osmosis or de-ionization
• Distillation or ultra-filtration

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• Water system design (1)
• There should be no dead legs

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Water system design (2) 1. Ball valves are
unacceptable
2. Bacteria can grow when the valve is closed
3. The water is contaminated as it passes through
the valve
Stagnant water inside valve
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Water system design (3)

• Sanitary pumps
• Clamps and O rings versus threaded fittings
• Heat exchangers
• Side arm level measuring devices are
• unacceptable

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Reverse osmosis (RO) theory
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• Use of reverse osmosis
• Advantages
• Disadvantages
• Many uses
• purified water
• feeding of distillation units or ultra-filtration
  units
• Water for Final Rinse
• Water for Injections (if permissible)

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• Ultra-filtration
• Can be used for WFI or for Water For Final
  Rinsing for parenteral manufacturing (if
  permitted)
• Removes organic contaminants, such as
  endotoxins
• Operation at 80C, and sterilization at 121 C

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• Single-effect distillation
• simple distillation, single effect
• vapour compression, thermo compression
• Multi effect distillation
• multiple effect stills
• Clean steam generators
• used where steam can come into contact with
  product contact surfaces, e.g.
  sterilization-in-place (SIP)

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• Disinfection (1)
• Heat
• One of the most reliable methods of disinfection
  of water systems
• Ozone
• Produced easily
• Leaves no residue

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• Disinfection (2)
• UV
• UV does not sterilize
• Flow rate critical
• Post-irradiation recontamination may be an issue
• Lamps have finite life
• Other chemicals
• XO2
• Halogen
• Formaldehyde

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• Sampling (1)
• There must be a sampling procedure
• Sample integrity must be assured
• Sampler training
• Sample point
• Sample size

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• Sampling (2)
• Sample container
• Sample label
• Sample storage and transport
• Arrival at the laboratory
• Start of test

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Testing - setting specifications for purified
water or WFI - (1)

• Ph. Eur. JP USP Int. Ph.
• pH 5.0-7.0 5.0-7.0 5.0-7.0 pass
  test
• Cl lt 0.5 pass test -
  pass test
• SO4 pass test pass test -
  pass test
• NH4 lt 0.2 lt 0.05 -
  pass test
• Ca/Mg pass test - - pass
  test
• Nitrates lt 0,2 pass test -
  pass test
• Nitrites - pass test -
  -

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Testing - setting specifications for purified
water or WFI (2)

• Ph. Eur. JP USP Int. Ph
• Conductivity (µS/cm) - - lt 1.3
  -
• Oxidizable subs. pass test pass test
  - pass test
• Solids (ppm) lt 10 lt 10 - nmt() 10
• TOC (ppm) - lt 0.5
  lt 0.5 -
• Heavy metals - - - pass
  test
• CO2 - - - pass test

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• Testing
• Method verification
• Chemical testing
• Microbiological testing
• test method
• types of media used
• incubation time and temperature
• objectionable and indicator organisms
• manufacturer must set specifications

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• Water for Injections
• International pharmacopoeia requirements for WFI
  are those for purified water plus it must be free
  from pyrogens
• Usually prepared by distillation
• Storage time should be less than 24 hours
• Microbial limits must be specified

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• Water for Final Rinse
• Water for final rinse must be of the same
  quality as the water required for pharmaceutical
  preparation

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• Pyrogens and endotoxins
• Any compound injected into mammals which gives
  rise to fever is a Pyrogen
• Endotoxins are pyrogenic, come from Gram negative
  bacterial cell wall fragments
• Detect endotoxins using a test for
  lipopolysaccharides (LPS)
• rabbit test detects pyrogens
• LAL test detects endotoxins
• Ultrafiltration, distillation, RO may remove
  pyrogens

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Suggested bacterial limits (CFU /mL)