Is there any specific guideline on how to perform cleaning method validations for Nitrosamine after product change over. Most of the Nitrosamine are volatile.
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)
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/american-cleaning-solutions-632881-09062022
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/kvk-tech-inc-608236-10082020
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/mylan-laboratories-limited-unit-7-607508-08202020
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/mylan-laboratories-limited-unit-8-589297-11052019
from QMS POINT OF VIEW, Hereās 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
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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 āspecific vs routineā cleaning procedures. -
analytical method. additionally address the āSPECIFIC & 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 -
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
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