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Cleaning validation

Manufacturers of medicinal products must ensure that they are fit for their intended use, and do not place patients at risk due to inadequate safety, quality or efficacy. To achieve the quality objective, a significant GMP requirement is that manufacturers pay appropriate attention to those factors that present risks of cross-contamination of the products being manufactured with other materials handled on the site or facility. It is expected that the risk control measures should be identified, designed on the basis of the hazard presented by the materials being handled. The controls should be fully documented and their effectiveness monitored and periodically reviewed taking account of technological and technical progress. The cross-contamination risk management system must clearly link to the protection of the patient.

It is important that possible mechanisms for cross-contamination are considered. The primary mechanisms for cross-contamination include but are not limited to:
– Surface to Surface

  • Originating from inadequately cleaned shared equipment/tool surfaces through failures or inadequate design of cleaning/equipment
  • Originating from contact with contaminated cleaning equipment
  • Originating from personnel gowning

– Airborne to air/surface

  • Originating from poorly controlled and unintended release into the environment due to inadequate control of dust, gases, vapours, sprays or organisms after which the contamination settles on product contact surfaces
  • As above but resulting from loss of primary containment
  • From recirculation in air handling systems between areas where filtration is inadequate
  • From inadequately controlled exhausts
  • Micronized powders and materials that have been aerosolized present higher risk due to their extended dwell time in the air

– Direct or indirect contamination from process or equipment failure

  • Backflow from waste or vacuum systems
  • Technical failure of equipment
  • Spillage and leaks

– Originating from movement and mix up of personnel, materials or equipment or parts.

 

Regulatory agencies have placed great emphasis on demonstrating that a cleaning process prevents cross-contamination.

Cleaning validation is documented evidence that an approved cleaning procedure will reproducibly remove the previous product or cleaning agents used in the equipment below the scientifically set maximum allowable carryover level.

We can assist you at all steps of cleaning validation:

  • cleaning validation training
  • cleaning validation SOP development
  • toxicological assessment of APIs
  • calculation of MACO
  • product bracketing and choose the worst-case product(s)
  • calculation of acceptable residue limit (ARL) for Swab and Rinse sampling
  • calculate acceptance criteria for cleaning verification
  • development and validation of analytical methods for cleaning validation samples
  • perform recovery study
  • design of cleaning validation protocols
  • design of cleaning validation report
  • analysis of validation samples (direct surface samples and rinse samples)
  • filling in cleaning validation report
  • cleaning verification SOP development

 

The toxicological assessment of APIs is the most challenging step. Toxicological assessment can be based on the No Observable Adverse Effect Level (NOAEL), Lowest Observed Adverse Effect Level (LOAEL).

NOAEL is defined as follows:

  • NOAEL must be established for all critical effects identified
  • the NOAEL is the highest tested dose at which no adverse effect is observed
  • if NOAEL is not calculable, the lowest-observed-effect level (LOEL) may be used
  • determined by toxicological expert

PDE is calculated based on NOAEL/LOAEL. After calculation of PDE Maximum Allowable Carryover (MACO) can be calculated. MACO is the mathematically calculated quantity of residue from a previous product when carried over into a different product that can represent potential harm to the patient.

To minimize sampling the bracketing approach can be applied. Bracketing groups typically based on:

  • equipment
  • cleaning procedure
  • dosage Form
  • cleaning SOP

Any product that does not conform to ‘bracket’ must be validated individually.

 

Worst-case product determination is based on:

  • product toxicity
  • product solubility
  • cleanability
  • product contact area
  • batch size
  • product potency
  • release mechanism