Cleaning Validations Criteria

Is there any specific guideline on how to perform cleaning method validations for Nitrosamine after product change over. Most of the Nitrosamine are volatile.

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basis the RECENT FDA warning letters, the highligted gaps/focus-areas are
1.(a) assess the potential cross-contamination derived from non-dedicated equipment ( product to product change over , sampling protocol to address the uniformity, sampling quantities, number of samples etc)
2. assessment of in-direct sources viz., equipment used to recover solvents, storage tanks, transfer lines )
3. assessment of results .( viz., exdursions/ trends, scientific rationale for differences in batch results - change_over results,
4. use of dedicated equipment ( not just for campaigns)

from QMS POINT OF VIEW, Hereā€™s few thoughts around it, assessment would touch each of the QMS elements from the beginning (b), i.e., material handling, cleaning procedure/matrix, etc and specific to cleaning validation all the key processes to be revisited for updating the control strategy

  1. selection of cleaning procedures to include the assessment & consideration of nitrosamine-impurities.( this should address the particular to solubilities/interactions ), usage of warm/hot cleaning agents/conditions to suit the relevant contaminants through degradation,
    +(a) at least for simulation purposes, usage of cold/chilled diluents of collecting samples for analysis
    +(a) simulate the results in/during the lab-development to address the differences in the ā€˜specific vs routineā€™ cleaning procedures.

  2. analytical method. additionally address the ā€˜SPECIFIC & particularā€™ to the nitrosamine/volatile impurities,
    +(a) suitability of method for detecting the concerned impurities ( viz., characterizing LC/MS ETC
    +(a) using 2-8 degrees condition at sample collection
    +(a) selection of PDA detector for analysis; and
    +(a) inclusion of solvent-flush at the end of method to ensure elution of any / remaining peaks and evaluation of same during analysis viz., no peaks eluting after the standard run time.
    +(a) solution stability
    +(a) simulate the impact/benefit of with & without-out controls to be established during development

  3. effectiveness of the cleaning procedures .( eliminate the obvious situations/instances which are identified by external auditors; and evaluate the consistency of results which could come up with assessment )
    +(a)evaluation of the PDA spectra, investigation of unknown peaks.

(b) these processes are related to overall development processes and control strategy of the product.
i. handling of raw material containers; ( solvent drums / containers )
ii. solvent recovery process.
iii. cleaning procedure ( cleaning agents selection, in the context of NDSRI)
iv. development data ( method development, drug-excipient compatibility etc )
v. specification - JoS
vi.stability data and beyond.

  • vendor qualification ( specific & similar controls relevant to nitrosamines )
  • periodic / routine review & verifidation