The integration of Cleaning Validation within an effective Quality System supported by Quality Risk Management Processes should give assurance that API Manufacturing Operations are performed in such a way that risks to patients related to cleaning validation are understood, assessed for impact and are mitigated as necessary.


It is important that the requirements for the finished manufacturing companies are not transferred back in the process to active pharmaceutical ingredient manufacturers without consideration for the different processes that take place at this stage.


The document reflects the outcome of discussions between APIC member companies on how cleaning validation requirements could be fulfilled and implemented as part of routine operations.

In addition, APIC has aligned this guidance with the ISPE Risk MaPP Guide3 that follows the Quality Risk Management Processes as described in the ICHQ9 Guidance on Quality Risk Management.


The criteria of Acceptable Daily Exposure (ADE) or Permitted Daily Exposure (PDE) are recommended to be used by companies to decide if Dedicated Facilities are required or not and to define the Maximum Acceptable Carry Over (MACO) of API’s in particular, in Multi- Purpose Equipment.


Chapter 6 defines factors that should be considered in controls of the cleaning processes to manage the risks related to potential chemical or microbiological contamination.


The PDA Technical Report No. 29 – Points to Consider for Cleaning Validation is also recommended as a valuable guidance document from industry.


The following topics are discussed in the PDA document:

  • Cleaning process (CIP/ COP): design and qualification
  • Types of residues, setting acceptance criteria, sampling and analytical methods
  • Maintenance of the validated state: critical parameters measurements, process alarms, change control, trending & monitoring, training and periodic review


Documentation

The  document has been prepared to assist companies in the formulation of cleaning validation programs and should not be considered as a technical standard but a starting point for internal discussions. 


The document includes examples on how member companies have dealt with specific areas and issues that arise when performing cleaning validation.


Six specific areas are addressed in this Guidance document:

  • Acceptance Criteria
  • Levels of Cleaning
  • Control of the cleaning process
  • Bracketing and Worst Case Rating
  • Determination of the amount of residue
  • Cleaning Validation Protocol


Finally, the most frequently asked questions are answered to give further guidance on specific points related to cleaning validation.