#TIPS to effectively respond to FDA 483 observations:

Now a days regulatory bodies have increased the frequency of inspection of the pharmaceutical industry to ensure that the drug substances or drug products are being manufactured as per the current cGMP regulation.

Any non-conformity to these regulations led to issuance of 483 form to the organization.

So, in this topic I've tried to touch upon the ways to effectively respond to the FDA's 483.

Dring regulatory inspection if, FDA investigator notice any of the observation or any non-conformity which indicates the potential regulatory violations?w.r.t patient safety, quality of the product, facility, equipment, processes, controls, products, employee practices, or records. Such observations are being documented, read and discussed with a company’s senior management team at the time of close out to ensure that there is a full understanding of what the observations are and what they mean.

After discussion with the management team investigator shares this observation with organization through a regulatory body form which is called “483”.

After receipt of the 483 companies are encouraged to respond to the observations in writing with their corrective action plan and its implementation.

Remember: after receipt of 483, organization need to respond to it within 15 business days.

Below are the key points that shall be considered while responding to the 483,

1.?Understand each observation clearly:

This is the most important point that shall be considered before responding to the 483. Make sure that all observations are discussed and clearly understood. Before inspection is concluded and it is closed, ask as many questions as you can to get more clarity on the observation shared by the investigator. This is the best time for the discussion to ensure that you have understood the identified compliance gap from the investigator point of view.

It is also considered to be important to involve the subject matter experts during the discussion so that it will be beneficial while drafting the response. ?

2.?Investigate the identified gap:

It is always preferred to do some re-search work to fully understand the background of the observation. This will help in accurately defining the compliance gap and framing a precise problem statement. Write down the problem statement i.e. Detailed descriptions of the conditions or practices that are considered objectionable.

After defining the problem statement start the investigation, perform the initial assessment to understand the scope and impact of the observations. Identify the root cause for the compliance gap and determine the appropriate corrective actions that address that specific problem.

Following points shall be considered in investigation,

Scope of the investigation

Mention the investigation tool used to identify the root cause i.e. Fishbone, Why Why analysis, Process flow diagram, brainstorming etc.

Outcome of the investigation

Corrective and preventive actions

Perform the impact assessment of identified compliance gap on the product, patient impact, including evaluation of the safety, identification, strength, purity, and quality of the product, same must be addressed in response.

Example:

Problem statement:

The observation pertains to the inadequate documentation of cleaning procedures in the manufacturing area.

?Root cause:

Review of SOP revealed that the cleaning SOPs were outdated and not aligned with current regulatory requirement.

Corrective Actions:?

·?Revised the cleaning SOPs to reflect current requirement.

·?Conducted training sessions for all relevant staff on the updated SOPs.

·?Implemented a new documentation system to ensure accurate record-keeping.

Preventive actions:

· Scheduled regular reviews and updates of all SOPs.

·?Established a cross-functional team to monitor compliance with cleaning procedures.

Extrapolate investigation to find the impact of identified compliance gap on other lots of products that could potentially be affected, evaluate impact on safety concerns that may raise due to the previously marketed batches on the patient.

With this preventive action mindset, review for similar gaps in other systems — look at a longer time span, other products using the same systems, and any similar processes in other quality systems.

Mention the strategy how the preventive action taken for the identified compliance gap will be monitored and evaluated to avoid such recurrence in the future.

Mention the target date for the implementation of the CAPA.

3.?Define the robust CAPA plan:

Document all planned corrective and preventive actions in CAPA plan. This section is used to document your intended actions and demonstrate progress along the way, as well as report individual actions have been completed.?

This section will describe the timeline for the CAPA, implementation of the corrective action taken and solution that is achievable in defined timeline.

If during the investigation any similar discrepancies identified w.r.t same compliance gap, then this section will also address the correction of both specific and systemic issues.

Sometime some CAPAs that are related to change in the process, system or procedure which require more time to implement in such case, additional time can be granted by provide a detailed explanation with time frame for completion. However, identification of mitigation plan shall be defined through which compliance shall be monitored till the permanent solution is identified and implemented.

The CAPA plan should also include focused and measurable effectiveness checks to verify that the actions taken have had the intended impact to resolve the identified issues.

4. Respond to FDA regulatory body:

After receipt of 483, organization need to respond to it within 15 business days. If the form 483 has many observations, it's permitted to request an extension during these 15 days to prepare a more detailed response.

Response letter should include each observation apart from this, during investigation if any similar compliance gap additionally identified, its root cause analysis, investigation outcome, a complete description of the actions taken to immediately correct the issues, along with evidence of completion.

If additional time is required for further investigation, or for implementation of CAPAs, provide target dates for completion.

Before submitting the response do not forget to make sure that response letter should be,

Very much clear: It involves all cited observations with response in simplified and easily understandable language. First state the observation and then respond it in a clear, sequential format.

Convincing: Response is in story form which narrate detailed response with supporting evidence to support your claims.

Evidence based: Support all claims with objective evidence i.e. hard data, test results, and other evidence. ?Ensure that you have the necessary evidence to support your claims, consider thorough review of your processes and procedures.

Properly reviewed and evaluated: Take enough time to review your response letter. If require, edit and re-work your response before submission to ensure it is complete and convincing. Ensure there should not be any inaccurate statement which may raise concern to the FDA and led to the warning letter.

Commitments toward the compliance: It’s important to convey a commitment to compliance by including and implementing new procedures, policies, and training programs to prevent similar issues from occurring in the future.

Make sure that response letter should include the detailed remedies for the compliance gap, any additional gap identified during the compliance, risk identification, risk analysis, risk evaluation and risk mitigation and risk review plans. ?

Response letter can be made more effective with the aid of more experienced personnel, subject matter experts from the cross-function team.

I hope you must have liked this article. Stay tuned to keep reading and keep learning.

Thanks & regards,

Shailesh Mewada.