Warning letter / Glenmark, Goa, India /FEI 3004672766 / MARCS-CMS 637314/ 320-23-04/ NOVEMBER 22, 2022/ Observation 1

Failure to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications. Investigations into rejected batches failed to extend to other batches, dosage strengths, and drug products for tablet compression machine settings.

From 2018 to 2021, firm rejected 14 batches of 0.1mg and 0.2mg strength desmopressin acetate tablets for out-of-specification (OOS) results for (masked) and content uniformity results. Firm implemented additional stratified sampling and conducted engineering batches to simulate the root cause for the failures for both dosage strengths. Although attributed the content uniformity failure to the lack of defined compression parameters for desmopressin acetate 0.1mg batch 20210776, firm failed to test other batches or drug products that used the same process and compression equipment.

In firms’ response, it was acknowledged batches were rejected for the 0.1mg and 0.2mg desmopressin acetate tablets and that firm did not apply the corrective actions for the compression parameters for 0.2mg strength tablets. As a result of this inspection, firm conducted a retrospective review and discovered a failing stratified sample assay result for desmopressin acetate 0.2mg tablets batch 20220121 and initiated a voluntary recall of this batch on June 10, 2022. However, firms’ response did not adequately address its failure to investigate the assay failure and market impact at the time of its occurrence and it did not include an overall management strategy for improving all phases of firm’s investigations.

In response to the Warning letter, Firm to provide:

• A comprehensive independent assessment of the overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system to include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, corrective action and preventive action (CAPA) effectiveness, quality oversight, and written procedures. Address how Firm will ensure that all phases of investigations are appropriately conducted.
• An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates whether the program includes effective root cause analysis, ensures CAPA effectiveness, analyzes investigations trends, improves the CAPA program when needed, implements final quality assurance decisions, and is fully supported by executive management.

When failure investigations show root cause of a general nature (for e.g, failure of content uniformity attributed to lack of defining compression machine settings), obviously an impact assessment on other batches and products should be considered; the corrective and preventive actions (CAPA) should be applied to all similar situations – The CAPA should be global. This should be part of investigation procedure and should be captured in a well-structured manner with checks and balances (like a checklist).

• When performing failure investigations perform each phase of the investigation comprehensively. 
• For example in the case of out of specification results, follow a structured approach (refer USFDA & MHRA guidance for OOS investigations):

o   Phase 1A (Obvious error)

o Phase 1B (Laboratory error)

o Phase 2 – Detailed investigation (including manufacturing investigation)

• Investigation into failure of parameters such as content uniformity should look at possible laboratory errors thoroughly. Sampling, Sample handling, glassware, contamination during analysis. Performance of content uniformity test of low strength dosage forms in a QC laboratory (which handles several samples from products of different strengths, raw materials, active ingredients) is a task which require extreme precautions and discipline. All possibilities of a laboratory error should be thoroughly evaluated when concluding the product failure. Also implement all possible preventive measures for laboratory failure – where possible consider dedicating the glassware for the content uniformity test of products, keep the area well protected. 
• Perform manufacturing investigations thoroughly. Identifying possible root cause and CAPAs for the root cause is only half the job. When a root cause or probable root cause is identified, an impact and risk assessment considering other batches of the same product, different products have to be performed. Scientifically develop the scope of the investigation with respect to number of batches and products – same / similar manufacturing equipment, process and product. Review how the scope of the impact assessment can be narrowed down by reviewing all available data. For example, look at the machine operating data (if available) such as the compression machine speed, feeder ratio, type of feeder used, characteristics of the bulk intermediate. This will help in narrowing down the scope to most relevant batches and products and limit the number of batches to be investigated / tested for impact. (Note that in a test like content uniformity complying results in other batches and products is not a sufficient justification for not performing an investigation and impact assessment. Content uniformity is a test for evaluating variability in a batch; the existence of a condition which can cause failure -such as not defining compression machine parameters adequately – could have impacted other batches, but revealed in the test. A passing test result can be a strong supporting factor for a detailed investigation and conclusion that other batches / products are not impacted, but this alone do not rule out the possibility).
  • The investigation and impact assessment on other batches can take support of other complementing factors – complying content uniformity results along with other complementing parameters (such as dissolution test, assay, in process results of blend uniformity) for rationalizing how other batches / products would not have impacted. The key point is that all the evaluations and assessment should be documented elaborately with adequate scientific rationale, rather than skip it altogether.
• Based on the investigation and impact assessment if there are batches / products identified with a potential failure further action such as product recall should be initiated. 
• When probable root cause(s) identified, establish the corrective and preventive actions (CAPA) that addresses the root cause. The CAPA should be implemented in all applicable products, processes, equipment (global CAPA). 
• Evaluate the effectiveness of the CAPA – has it addressed the issue (the quality event) and achieved the stated objective. If even after the implementation of the CAPA, the quality event is repeating, CAPA is not effective and probably the root cause identified may not be the real root cause or not the only root cause. If so investigations should be reinitiated.

• Reporting of Out of specification
  
  • This should address prompt reporting, and initiating investigations and escalation matrices.
• Preliminary investigation:
  
  • Laboratory investigation – Phase 1A
  • Laboratory investigation – Phase 1B
• Detailed investigation (Full scale investigation) including manufacturing investigation – Phase II
• Investigation process:
  
  • Investigation team
  • Investigation tools
  • Investigation capabilities of team (training in appropriate tools such as Fish Bone analysis, Why-Why, Pareto diagram, Process flow analysis, FMEA…)
• Identification of root cause(s) or probable root cause(s). 
• Process for impact assessment – defining the scope of impact assessment scientifically (considering similar processes, products, equipment, area / facility, operational parameters, people), rationalizing the impact assessment and conclusion on batches impacted. 
• Comprehensive corrective and preventive actions which will address: The CAPA(s) should directly address the identified root cause(s):
  
  • CAPA addressing the specific instance of failure; actions to remediate the impact of specific instance /batch (such as batch rejection, recall); actions to address the similar situation across other processes, products, areas (global CAPA); actions to remediate any failures of other batches, products which is identified through impact assessment (actions such as recall).
  • Actions to ensure in all future products and processes how such gaps will be prevented (e.g – system to ensure defining compression machine parameters adequately for all new products and processes)
• Process for verification of effectiveness of corrective actions
  
  • This should address reviewing similar products, processes which were taken further to the CAPA implementation over a reasonable timeframe (for statistical significance). The effectiveness verification should look at any similar occurrence as well as any indicators which show now the process / product has improved (eg: trend analysis, improvement in variability of the test parameters etc).
• Training and education of the personnel. Improving competency for investigations.
  
  • This should not be limited to training the people in a revised standard operating procedure (SOP) or format. But work out a continuous learning program which will involve workshops, case studies and periodic assessment of the failure investigations, management reviews at different levels.
• Quality oversight
  
  • The quality oversight improvement should consider several elements at different levels – Site QA review, Corporate quality reviews, Periodic independent assessment (3rd party auditors), Periodic Review by senior management and leadership.