Warning letter / Lupin / MARCS-CMS 633703 / 320-22-25 / SEPTEMBER 27, 2022 / Observation 1

Failure to establish adequate written procedures for equipment cleaning and its release for use in manufacture of intermediates and API. Assessment performed by Lupin to verify whether the existing cleaning procedures reduce cross contamination of intermediates and API – by evaluating residues on non-dedicated production equipment and within recovered solvents – are deficient. The risk assessments lacked data to support existing equipment cleaning procedures are effective in removing or reducing genotoxic impurities (possibly nitrosamine impurities?) generated through manufacturing process of API (call it Products A) along with residual API from each equipment to acceptable levels.

Quantifiable levels (nearer to specified limits) of impurities were observed in four of the API batches (call it Products B) manufactured on non-dedicated equipment following manufacture (and product-to-product change over cleaning) of Products A from 2019-2021; no further investigations were performed. In the hypothesis testing protocol, identification of the first batches of API (Product B) for evaluation of genotoxic impurities lacked documentation support; specific pieces of equipment used for manufacture of these products are not identified in the protocol. The protocol does not address cross-contamination from indirect sources including non-dedicated equipment used to recover solvents.

Conflicting data is provided with respect to the detection and quantitation of genotoxic impurities in API (call it Products B) after change over from previous API (call it Products A). The assessments reported quantifiable levels of impurities in all batches of API tested (and near the specified limits in at least 4 of the batches) suggesting excursions are possible, however, quality risk assessment stated the same impurities were not detected in the same product and batches. The firm disregarded the unfavourable analytical results without appropriate scientific justification and concluded there was no risk of carryover of these genotoxic impurities to other intermediates and API manufactured with non-dedicated equipment. All intermediates and API manufactured on non-dedicated equipment used to manufacture drugs (Products A which has potential to generate genotoxic impurities in the manufacturing process) should be subject to validated sampling and analytical testing to ensure they are not contaminated with unacceptable levels of genotoxic impurities.

The firm committed to only dedicate solvent recovery tanks during the manufacturing campaigns of specific products; but as solvent recovery tanks are not dedicated to specific products only, the cross-contamination risks remain and firm should appropriately assess the risk and validate procedures to ensure cross-contamination does not occur from non-dedicated solvent recovery equipment.

Lupin to provide a comprehensive, independent retrospective assessment of cleaning effectiveness to evaluate the scope of cross-contamination hazards. This assessment should include identity of residues, other manufacturing equipment that may have been improperly cleaned; an assessment whether cross-contaminated products may have been released for distribution, any inadequacies of cleaning procedures and practices, encompass each piece of manufacturing equipment used to manufacture more than one product, including both API and finished products. A corrective action and preventive action plan which include 1) detailed summary of vulnerabilities in process for lifecycle management of equipment cleaning, 2) appropriate remediations to cleaning processes and practices, 3) improvements to cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations. Improvements to the cleaning validation programme, with special emplasis on all possible worst cases (drugs with higher toxicities, higher potencies, lower solubility, difficult to clean, locations difficult to clean and sample), change management programme for introduction of new equipment / product. The Firm should also provide updated SOPs to ensure appropriate verification and validation of cleaning procedures in in place.

Warning letter

When genotoxic impurities are observed in batches of API (say Products A whose manufacturing process can generate genotoxic impurities) and assessment of effectiveness of cleaning procedures show quantifiable levels of impurities in batches, this indicates there is possibility of excursion of carry over impurities in other products, the investigation should also look at why these impurities are carried over to other Products (even after a product change over cleaning), why observed levels of impurities are varying. The number of batches to be tested for genotoxic impurities carry over, how the (cut off for) first batches and the pieces of equipment used in the manufacture of the batches to be investigated were arrived at should be adequately documented with scientific rationale. The assessment should consider all possible sources of contamination / carry over. All non dedicated piece of equipment shared between two products (A & B) are potential sources of residue carry over contamination including Non dedicated equipment used in solvent recovery and solvent recovery tanks and there should be procedures for cleaning and cleaning verification of the solvent recovery tanks during changeover of products and campaigns. Assessment to evaluate whether cross-contaminated products may have been released for distribution should be comprehensive and should identify the follow up actions. If there are intermediates and/or APIs whose manufacturing process can lead to generation of genotoxic impurities, all or several of the following controls should be in place to ensure there is no potential of carry over of the genotoxic impurities (including Nitrosamine impurities) to other products:

·        Specification limits established for the genotoxic impurities for the APIs whose manufacturing process has potential to generate the genotoxic impurities. Testing of all batches with validated sampling and analytical procedures.

·        Identify all manufacturing equipment which are shared between the API (Product A) which has scope for generation of genotoxic impurities and other intermediates and APIs. Evaluate the effectiveness of the equipment cleaning procedures for reducing / removing previous product residues as well as genotoxic impurities for each equipment. Establish a cleaning verification for evaluating the cleaning effectiveness after each product change over cleaning with appropriate sampling and testing methods and acceptable residue limits and validate the same. Continue the cleaning verification after each product change over cleaning even after the validation.

·     Establish the level of residues in cleaned equipment are less than the specified limits (ideally less than 10% of the specified levels) through appropriate cleaning followed by sampling and testing. Also test the next immediate product manufactured through the equipment for the genotoxic impurities at least for 3 batches manufactured after a product change over cleaning. If the levels of genotoxic impurities are less than 10% of the acceptable limits for the residues, it can be justified that no routine testing of other products manufactured is necessary for carry over genotoxic impurities.

·        Target to achieve residual impurity levels at less than 10% of the specified limits for genotoxic impurities in cleaned equipment. This can justify why no further testing required in the API batches manufactured in this equipment. This can also justify periodic testing of residue levels in cleaned equipment after accumulating sufficient data (rather than testing after each change over cleaning).

·      While performing a risk assessment of carry over impurities by testing API batches, establish a justified criteria for selection of batches and document the same with proper rationale. For example, all batches of APIs within expiry can be considered as a cut off.

·      When in the manufacture of intermediates/ API, genotoxic impurities (nitrosamines) cannot be avoided, consider possibility for dedicating the equipment for specific products; especially for those steps which generate genotoxic impurities.

·    Where dedication is not easy, run the products which has genotoxic impurities generation potential in campaigns. Establish comprehensive cleaning procedure and cleaning verification for equipment after a product change over. Firms can also have a procedure to evaluate the first batch of subsequent product manufactured for carry over impurities against a specified limit. Such procedures should be applicable for solvent recovery unit as well as tanks used for storage of recovered solvents and mother liquors.

·    Pipelines and transfer lines will be vulnerable and most difficult to clean piece of equipment. Have dedicated pipelines / transfer lines for products which has potential to generate genotoxic impurities. 

·     While performing Quality risk assessment, consider all sources of information. The risk assessment should be performed by a knowledgeable cross functional team. If new information is generated / made available after initial risk assessment, repeat the Quality risk assessment and identify additional remediation measures. The assessment should also consider whether the cleaning processes will adequately remove impurities with high toxicity, low allowable limits – their solubilities in the cleaning agents.

Comprehensive assessment remediation plan covering:

·   Assessment of whether cross-contaminated products may have been released for distribution & remediation plan :- Matrix all equipment and identify which of the equipment are involved in manufacture of intermediates / APIs with potential for generation of genotoxic impurities. Identify all other intermediates and APIs manufactured where these equipment are shared and identify the batches of other API / intermediates which are most vulnerable for carry over impurity contamination – eg: batches manufactured immediately after a product change over cleaning. All vulnerable batches of other APIs / intermediates within expiry (or a cut of off for example previous 5 years, considering the retest /expiry assigned to APIs) to be tested for carry over impurities. Develop a rationale for prioritising the testing (latest batches, difficult to clean residues, potential for formation and carry over of impurities etc). Based on the testing, initiate further actions (like recall of the products where the level of impurities is higher than limit) incoordination with drug product manufacturer. Include equipment and storage tank of solvent recovery unit also in the assessment.

·     Investigate all instances of observation of higher carry over residues in the API – FDA cited instances, other such observations and results from new evaluations. Develop scientific rationale for observation of varying results of carry over impurities with some batches closer to threshold or outside the limits. Review various factors for example – difficult to clean residues, cleaning process followed and cleaning agents, API manufacturing process and potential for formation of genotoxic impurities as well as purging of impurities during workup, stability of the impurities – easily degradable/ less degradable, time lapse between batch completion and cleaning and so on. Based on the assessment identify all possible actions that can be taken to improve effectiveness of cleaning and cleaning verification – alternate cleaning procedures, changing cleaning reagents, number of cleaning cycles and so on.

·    Identify other vulnerabilities in cleaning processes through a protocol based evaluation – difficult to clean areas, eg – transfer lines, pipelines, specific pieces of equipment, facilitating conditions for formation of impurities and so on. Identify corrective and preventive actions – eg: dedication of transfer lines, dedication of specific pieces of equipment, modification of processes, work up procedures.

·      Assess current cleaning procedure and practices. Manual cleaning procedures are generally difficult to reproduce and validate. Consider automation of cleaning – clean in place systems (CIPs).

·      List out all vulnerabilities of the cleaning program. Comprehensively assess and enhance the cleaning procedures, verification of execution of cleaning procedures, cleaning verification and analysis.

·     Do an independent and comprehensive assessment of all actions and assessments performed by the firm, the corrective and preventive actions taken as well as a complete review of the manufacturing process flow and cleaning procedures and practices. Based on the assessment identify additional measures and implement. 

·     Develop a procedure for verification of execution of cleaning processes – how cleaning steps are followed consistently whether automated or manual. Online verifications as well as periodic audits and surprise checks. These are in addition to cleaning verification by sampling and analysis.

·      Review the procedures and checklists for new equipment introduction – Identification of difficult to clean areas, sampling procedures, assessment of cleanliness after product change over cleaning, testing of first batches of other products manufactured for carry over impurities.

·     Review the procedures and checkpoints for new product introduction – cleaning procedures should be able to remove previous product residues including impurities. Cleaning verification should cover previous product residues, genotoxic impurities.

·     Implement improvements and enhancements to Cleaning program – cleaning verification and cleaning effectiveness. For all non-dedicated equipment and systems implement cleaning verification by sampling and analysis of equipment after each product change over cleaning. Review trends and work on continuous improvements. Validate the cleaning programs over cleaning cycles and continue cleaning verification. This will help in addressing all worst cases in cleaning validation and verification program – higher toxicities, lower solubility, difficult to clean residues, equipment areas, maximum dirty hold times.

· Perform a comprehensive Quality risk assessment covering all assessments and additional measures implemented.