Warning letter / Mylan / MARCS-CMS 607508 / 320-20-44 / August 20,2020 / Observation 1

Failure to have adequate cleaning procedures to prevent contamination or carry-over of a material that would alter the quality of the API.

Inadequate controls and documentation of cleaning, storage, usage of bulk solvent storage tanks used for recovered solvents and mother liquors in various products in a multiproduct facility. Impurity profile of the recovered solvents were not performed. CMO (Contract Manufacturing Organisation of facility) for solvent recovery is not evaluated adequately, impurity profile of recovered solvents was not evaluated. The Firm received from a CMO recovered solvents, stored the solvents in non dedicated tanks and used the same in multiple lots of API; This CMO was on an Import Alert (66-40) for inadequate impurity profile in recovered solvents. Unknown peaks in recovered solvents were not investigated, but used in manufacture of APIs. Assurances that the non-dedicated equipment would not contribute to cross-contamination or carry-over of residual impurities is limited

Cleaning validation and verification program for non-dedicated manufacturing and storage equipment of the Firm are inadequate. Methods were not adequately validated for detecting and quantifying impurities.  An inadequate scope of impurity analysis, in combination of non-dedicated equipment, lack of cleaning records, and introduction of elevated unknown impurities, increase the risk potential for API and API intermediate cross-contamination.

Firms response to agency that cleaning validation and verification program was adequate based upon the absence of out-of-specification investigations, lack of complaints, and undetected impurity testing is inadequate. Cross-contamination cannot be assumed to be uniformly distributed. Testing alone is insufficient to mitigate the observed contamination hazards. Also the Firm did not discontinue the CMO cited for recovered solvents.

In response to Warning letter, Firm to :

• Provide Written confirmation that the cited CMO is no longer used to supply materials for drug manufacturing operations
• Comprehensive third-party retrospective assessment of cleaning effectiveness to evaluate scope of cross contamination hazards, identify residues, other manufacturing equipment and risk of release of cross contaminated products for distribution covering each piece of non dedicated equipment used to manufacture products.
• Risk assessment and plan to test all API manufactured on non dedicated equipment for impurities such as Nitrosamines
• Provide improvements in cleaning validation program addressing all worst cases (such as drugs with higher toxicities, potencies, lower solubility, difficult to clean drugs, difficult to clean and sample areas, maximum hold times after cleaning), improvements in change management system for introduction of new equipment and products, CAPA plans to implement vigilant operation management oversight of facilities and equipment and improved systems for management review.

Firms should have procedure to evaluate and assess what are possible impurities that can be present in recovered solvents and mother liquors (including nitrosamine impurities), qualify recovered solvents, control over usage of bulk storage tanks for recovered solvents (usage, cleaning, cleaning verification, documentation). Firms should establish:

• Procedures for control of usage of bulk storage tanks and documentation, cleaning procedures with frequency of cleaning, justification of frequency of cleaning (through profile analysis).
• Procedure for qualification of recovered solvents before using the solvents first time (based on process of recovery, matrix of impurities /contaminants including solvents/reagents / organic impurities of the process) and meaningful specifications.
• Procedure for Qualification of CMOs used for solvent recovery as well as own solvent recovery unit and establish controls with respect to usage of solvent recovery facility, change over cleaning of the recovery facility and storage tanks (input and output), periodic audit of the CMO specifically with respect to controls on usage of recovery unit and cleaning. Firms should asses and know what all other products and intermediates a CMO is handling and potential of contamination of the Firms product from the CMO activities.
• Systems and procedures to ensure that unknown peaks in recovered solvents (and products) during analysis are reported, evaluated, resolved before the material is released for usage. Quality unit personnel (analysts) should be adequately informed and trained about reporting abnormal observations like unknown peaks in chromatograms – not enough to see whether material meets specifications.
• Methods for analysis of cleaning samples should be adequately validated for detecting and quantifying impurities at the required levels.

• Engage a respected third-party consultant for a comprehensive assessment of Firms cleaning procedures and effectiveness, potential for cross contamination due to Non dedicated equipment, identify residues, impact of cross contamination on distributed batches
  • Map the list of products which is manufactured in multipurpose facility and within valid expiry. Classify batches where recovered solvent is used (higher risk) and batches where recovered solvent is not used (lower risk or nil risk). For each product, map out the recovered solvents that  was used (there could be more than one) and the product-process matrix from which the recovery was performed. From this project a list of potential impurities (reagents / degradants / impurities including nitrosamines).
  • Do a risk evaluation of nitrosamine impurities (most probable impurities based on who all use the CMO facility for recovery and their product matrix). Select a certain number of batches for evaluation of the possible impurities using a risk rationale (Batches where full recovered solvent were used, higher proportion of recovered solvent were used etc). Analyse these batches using a validated method for (nitrosamine) impurities. If these batches don’t show impurities, can conclude that as the most risky batches did not show impurities. Other batches can be considered safe. If impurities are observed in batches tested, expand the number of batches to be analysed and based on results take further actions (Like recall / risk evaluation of impurities).
• Stop the services of the specific CMO for recovery of solvents / other activities. Establish a procedure for qualification and monitoring of CMOs which will cover evaluation of the product / activity matrix at CMO and analysing the risks and accordingly define controls (periodic monitoring).
• Establish procedures for Qualification of CMOs, control of CMOs and CMO supplied materials
• Establish procedures for Qualification of Recovered solvents for use in products, appropriate specifications for recovered solvents including impurity profile, validation of methods for recovered solvents, methods for analysis of cleaning samples. Cover risk of carry over impurities in the specifications.
• Establish procedures for cleaning and cleaning verification, documentation of usage of bulk storage tanks for recovered solvents and mother liquors, solvent recovery units.
• Educate the Quality unit (QA/QC) to be alert to abnormal observations like unknown peaks in the chromatograms and escalation of the same. Establish procedures to ensure such events will be investigated and concluded before the materials are released for use. Establish usage and cleaning records and procedure for all bulk storage tanks
• Enhance cleaning validation program addressing all worst cases (such as drugs with higher toxicities, potencies, lower solubility, difficult to clean drugs, difficult to clean and sample areas, maximum hold times after cleaning)
• Enhance change management system for introduction of new equipment and products, specifically addressing cleaning methods, sampling locations, residue limits for change over cleaning for non dedicated equipments.
• Enhance procedures for Management oversight of facilities – Internal Audits, In process Quality checks (IPQA), periodic Management review with defined agenda (which include review of Quality events, status of CAPA and effectiveness.