USFDA 483 / Cipla,  Pithampur, India / FEI 3008581988/ Inspection Feb 6 – Feb 17, 2023 / FDA Inspectors – Saleem A Akhtar, Jose E Melendez / Observation 5

Procedures for handling, investigation of written and oral complaints related to drug products are deficiently written or followed.

A.       

Number of patient complaints received each year since 2020:

In addition, as of 2/4/2023, the Firm received about 266 complaints in 2023 that are under investigation. The site did not perform any Health Hazard Evaluation (HHE) about these complaints to evaluate if any market action is warranted.

In 01/2021, the firm performed a risk assessment for complaints received in the year 2020 as patients complained about many issues including, medication not working. On 1/18/2021 site concluded that adequate measures are available and there is no risk to the product quality and patient safety.

As per the Executive summary, (effective date 1/31/2023) of complaints, over 91% (2747 / 3008 ) of the complaints are related to performance of the product. Even with the increasing number of complaints received in subsequent years (2021 and 2022), the QA Site Head stated on 2/16/2023 that the firm has adequate controls in place. There is no risk to product quality and patient safety and the firms risk assessment performed in 01/2021 is still valid. The firm’s quality unit failed to implement effective corrective actions to reduce the number of complaints related to the performance of the product.

B.

Firm received two confirmed complaints # COM-1035-2021-01785 & 02088 on 6/29/2021 and 7/30/2021 respectively. During investigation of both the complaints Firm confirmed an issue with an vendor supplied (input) material. The vendor that supplies the material examined the impacted samples and confirmed the same. The vendor reported maintenance work was done when specific batches of supplied material were manufactured and also identified other batches supplied almost at the same time when maintenance work was done during manufacturing. These potentially compromised batches of vendor supplied material was used for manufacturing of several batches of drug product. Review of complaint records indicated the customer reported similar complaints pertaining to all above batches (about 14 similar nature complaints were received).

C.

The Firm’s complaint SOP (# 1035-G-011, Version: 14), “Handling of Product Complaints” requires all complaints to be investigated, reviewed and closed within specified number of days. In addition, the complaint SOP does not require any formal request for extension and approval in case the complaint investigation is overdue. Some complaints were kept open for extended period of time such as 314 days, 278 days and 210 days without a written justification.

During investigation of complaints whether the Complaint require a Health Hazard Evaluation (HHE) to be evaluated and if not required, it should be sufficiently justified documented. Similarly the investigation procedure and checklist should also evaluate any market actions (Recall, Stop Distribution etc.) or regulatory actions (Field alerts) required, and if it is concluded as not required, it should be sufficiently justified. The investigation procedure and checklist should also review previous complaints of similar nature and effectiveness of corrective actions taken.

Health Hazard Evaluation (HHE) will typically consider Probability of Occurrence of defective product in a Lot, Chance that the Defective Product is undetected (Detectability) and Severity of exposure to the defective product and based on this calculation of a Health Hazard Index. Based on the Health Hazard Index different actions will be defined (No Action / Low level of Action such as a Response or a Technical Note with explanation or recommendations to customer(s) /Moderate level of action such as withdrawal from point of use, modified instructions for usage of product / High level of action such as Recall).

When the complaints are increasing and repeating, (though the Risk Assessment shows there is no risk to product quality and patient safety) further actions are necessary. This is why during investigations of Complaints (as well as any other Quality events), there should be a check for previous history of similar events and effectiveness of actions taken. If there is a Product issue, definitely market actions like recall / stop distribution should be considered; or else actions such as Recommendations / Advice to users, modification of usage instructions may be required. The objective should be to see that the complaints are progressively reduced / stopped. Merely a Risk assessment showing there is no product quality or safety issues alone is not sufficient.

When an investigation to a complaint identifies a root cause (such as issue with Vendor supplied material), the investigation should also extend to evaluate the potential impact – Eg: How many batches of the vendor supplied material are potentially impacted; in how many drug product batches this material is used. The list of impacted drug product batches should be identified, HHE performed and based on this actions including recall should be evaluated. The whole investigation, evaluation should be well documented and justified. If the evaluation concludes that no market actions are required, it should be well documented with sufficient justification.

There should be positive effort to complete the complaint investigation, response and closure within the defined timelines in SOP; But in spite of best efforts and due to nature of complaints, it is some times possible that the Complaints are not closed within these timelines. It could be due to several reasons – lack of further information from market / customer, identification of exact root cause, closure of corrective actions or mitigation actions (such as Recall, Changing Usage instructions of product etc.). But there should be a system and procedure to track such overdue Complaints, review the status of investigation and actions and redefine the time lines for closure with sufficient justification. Typically such extensions should go for a higher level of review and authorization, which will help ensuring that sufficient resources and support is provided for investigation and closure of complaint. At times the closure of Complaint is pending for lack of Customer / User response, even after a Firm has taken all actions as identified in the investigation and CAPA. In such cases there should be a procedure defined to close the complaint after affirmative communication to complainant / user on status of complaint and the Firms conclusion to close the complaint.

Effective Management review with defined agenda items which include – Review of Complaints and other Quality events, Trends, Closure status. The Management Review should identify additional actions for remediation and closure of open issues, where required and follow up the same through subsequent reviews.

A comprehensive review of Complaint Handling and Investigation procedure addressing HHE, requirement of regulatory actions, review of previous history and effectiveness of actions taken, authorization for Complaint investigation and closure extensions, Impact evaluations. Elaboration of procedure with typical examples, training and coaching the team on the revised and enhanced procedure. The training coaching should go beyond SOP training and use more effective methods like live case studies, workshops.

Management Review procedure with defined agenda and frequency of review. Documentation of Management review meetings

A comprehensive reevaluation of all Complaints with impact evaluation of all batches within valid expiry. Make a priority list for the review with products and batches having maximum impact getting a higher priority for review, identification of additional remediation actions. Time bound closure of identified actions which may include – Recall / Stop distribution of products / batches; Recommendation to users; Modification of usage instructions; Other actions for improving the Quality, Integrity and consistency of batches where warranted.