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Warning letters, 483s, Recalls, Import Alerts, Audit observations

Updated on April 28, 2023

USFDA 483 to Lupin Pithampur in Mar 2023 (Inspectors Eileen A Liu, Yvins Dezan) cites deficiencies in Training Management, Defining responsibilities of Quality unit, Change Management, Quality Agreement with suppliers 

USFDA 483

Observation 4

Employees engaged in the manufacture processing, packing and holding of a drug product lack the training required to perform their assigned functions.

Firm failed to monitor and ensure that personnel complete their assigned training by the due date. Training is assigned in SABA software (which was validated in 2011) and Firm do not assign the due dates in SABA. Firm failed to provide an ongoing CGMP training to contracted personnel.

Observation 5

The responsibilities and procedures applicable to the quality control unit are not [in writing], [fully followed]. Specifically,

A. Firm failed to adequately classify and assess Change Control #CCP-MM-941-21-00030003 initiated on January 14, 2023 for upgrading the Windows operating system from 2008 to 2016. Firm classified the change as “Minor” where revalidation is required and did not perform an assessment of the change.

B. Firm has not established quality agreements with specific suppliers for excipients.

Training:

  • Companies should have systems, procedures and processes to ensure personnel complete the assigned trainings within a defined timeframe. It is usual procedure and practice that training requirements for personnel are identified at the time of employee joining, during periodic performance appraisals, after incidence of Quality events etc. However without sufficient processes it is easy to miss out on personnel completing the assigned training, even more so in larger organisations. It will be difficult to track and ensure personnel complete the assigned trainings only through manual systems; Electronic Training Management systems / Learning Management systems will help in this. Companies should establish a comprehensive system which address:
  • Well defined Job roles or Job descriptions (JDs) which reflect direct responsibilities handled by each position/person, Skills required to perform the job roles, Trainings required to impart the skills and knowledge (SOP trainings as well as general trainings like cGMP, Data Integrity, Hygiene, Safety), date by which these trainings to be completed. A matrix of

JD – > Skills required – >Trainings required (SOPs, other Technical trainings)

  • documented in manual or electronic training cards for each employee.
  • Before the employees are assigned to specific jobs, there should be documented system to ensure the employees have completed the identified, mandatory trainings (like a Training certificate) for the job / assigned tasks.
  • There could be some trainings which the employees can complete even after the person has been assigned to specific tasks (for imparting additional knowledge, general trainings etc.). There should be system / process to track completion of such trainings by employees, inform employees in advance to complete the trainings before due date. In an electronic system this can be achieved through email alerts, messages. Adequate checks and balances and controls should be part of the system  – like an employee will be allowed to attend to the job / tasks only when the trainings which are due are completed.
  • There should be a well defined procedure to address training of Contract Employees just as for regular employees. The extent of training will  be decided by the tasks to be performed. Where Contract Employee are handling GxP tasks, they need to be trained in the tasks and skills before they are assigned to specific jobs. One challenge with contract employees will be frequent churn out; however there should be systems and checks to verify the  contract personnel is sufficiently trained to perform the assigned tasks. This can be achieved either through electronic Training Management system or manual Employee Training cards for each contract employee. The training cards shall identify the trainings the contract employee should undergo and due dates. Contract employee may be allowed into work area after checking the training status, ensuring the person has completed assigned trainings. The contract employee should also be provided general trainings like applicable cGMP trainings, safety, personal hygiene etc.in defined frequency (typically once in a year).

Change control systems:

Change Management procedure and process should consider the potential impact due to changes and accordingly consider level of change actions. The Change control documentation (form) should identify:1)  Change (existing system and proposed system), 2)    Rationale for Change (why change is required).

Many a time rationale for change only document that change will not have an impact on the system /procedure/ product; but fail to recognize why the change itself is required – is it going to simply the process / operation; improve the quality of product – process, improve efficiency. This should be adequately documented

The classification of the change (Major/Minor) should be commensurate with the impact / risk on the system, procedure, product. The Change categorization as Major / Minor guides the extent of actions for implementing the change (Validation, Qualification, Updating Regulatory agencies, customers etc). Obviously, the extent of actions to implement the change will be less when the change classification is minor. But the rationale for classifying a change as Major / Minor should be sound – avoid the temptation to classify the change as minor, so that the change implementation actions are minimal. The Change control documentation should also document the rationale for classification as Major/Minor; this will help in avoiding the pitfall of classifying a Major change as Minor.

Changes such as change to Computer systems, Operating systems should evaluate the impact in detail – Is the change impacting any GxP system, with a comprehensive list of systems that will be impacted by the change identifying whether the system is GxP or not. This will help in concluding the impact of change and extent of change implementation actions to be performed. For example, if a change like upgradation of Windows operating system is limited to computer systems used for documentation and communication, it may not have a GxP impact and no validation is necessary; a verification of systems to check whether each system is upgraded is sufficient and the change could be classified Minor. But if this change is also going to have an impact on GxP systems / computers connected to GxP systems (for example – Computer systems connected to analytical instruments or a QMS system), change category become Major,   Validation / Qualification will be necessary to implement the change. The rationale should be well documented.

Companies should have Quality agreements with suppliers of all key input materials, including excipient. This should be part of the Vendor Qualification and approval process. As per Pharma GMP requirements excipients also should comply to applicable GMP; the Quality agreement shall elaborate the commitments, controls and procedures from the excipient vendors. Addition of new excipients / excipient vendors shall be handled through the Change control procedure, and Establishing Quality agreement should be one of the change actions to be completed while introducing a new vendor / new excipient.

  • Upgrade the Training system / procedure to update the Training due dates and completion of training by employees by due dates. The system should also alert the employees well in advance of the due dates, so that employees are able to complete the identified Trainings before due date.
  • Review the Trainings Completion status of all the employees. Have a comprehensive list of all pending trainings for each employee and assign fresh training due dates. The fresh dates should be logical to ensure critical / job impacting trainings get priority and are completed as soon as possible.
  • Review the training status of all Contract employees and provide the necessary training, where not provided. Implement procedures for training and tracking of training for Contract employees (Refer What companies should do..). 
  • Re open and review the Change control related to Windows operating system – Whether it is impacting any GxP system. If not document the same with sound rationale, listing the computer systems which were upgraded. If there are GxP systems involved, identify the requirement and extent of Qualification / Validation and perform the same against a defined timeline. Review the Change control procedure / system for enhancing the procedure addressing classification of Change and other aspects (refer discussion under What companies should have in place..).
  • Review the status of Quality agreements with all input material suppliers. Initiate and establish Quality agreements where missing.

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