Pharmaceutical companies are governed by regulations and thus regulatory inspection management is very important for pharmaceutical companies. They must follow the regulations and/or regulatory guidelines of the country where they are authorized to sell their products. Generally, the regulatory authority inspects the manufacturing site of the pharmaceutical company before giving a manufacturing license or approving the site for manufacturing products for the relevant country. Also, they inspect the manufacturing sites for license renewal and/or due to any cause (for example: as part of regulatory monitoring).

Manufacturing license or approval of manufacturing site depends on satisfactory inspection outcome. Appropriate inspection management is necessary to get a satisfactory inspection outcome. In this article, the strategy for inspection management has been described step by step. This article is based on regulatory expectations, the experience of the author, and based on pharmaceutical industry practice.

Strategy for Inspection Management

It is considered that necessary manufacturing facilities (buildings, machines, utilities, laboratory facilities, etc.) are already ensured when the company is preparing for regulatory inspection. For highly regulated authorities (e.g. US FDA, MHRA, ANVISA), the company should start inspection preparation before 6-12 months of inspection. For other or local authorities, the company should start inspection preparation as per their convenience (e.g. before 1-3 months).

Regulatory Inspection Management can be performed in four phases:

Phase 1: Continuous Compliance

Phase 2: Pre-Inspection Preparation

Phase 3: Host Inspection

Phase 4: Post-Inspection Activities

Phase 1: Continuous Compliance	Proactive identification, assessment, and mitigation of any potential quality or compliance-related issues and secure compliance. Such as: ‘Hot Topics’ or Regulatory Trends assessment, Gap assessment against guidelines, Regulatory Filing Compliance, Monitoring & Evaluation of Quality Metrics, Readiness assessment through self-inspection/ Quality Oversight, etc.
Phase 2: Pre-Inspection Preparation	This phase will start when the company will be aware of the Inspection date or tentative date. The Inspection Team will ensure: the closing of open actions from phase 1, focused preparation considering inspection scope, logistics, SME selection, opening presentation, infrastructure, and processes to support the inspection including front room & back room, mock inspection, etc. Necessary training on inspection management including inspection behavior is to conduct in this phase.
Phase 3: Host Inspection	This phase of the process begins upon the arrival of the inspector. The opening meeting, plant tour, document review, interview by Inspector, system inspection, daily wrap-up, and closing meeting- all of these will be managed by Inspection Team.
Phase 4: Post-Inspection Activities	Response or CAPA to the observations. CAPA Implementation and Follow-up. CAPA Implementation report to HA.

Phase 1: Continuous Compliance

In this phase, it is the responsibility of relevant stakeholders to proactively identify, assess and mitigate any potential quality or compliance-related issues and secure compliance. This is a continuous process to ensure inspection readiness. However, formal preparation targeting any specific regulatory inspection can be started at any suitable time as per the need of the site. The approach taken to assure continuous compliance involves various aspects utilized to identify risks or potential issues, which may impact the compliant operations within the site.  These continuous compliance aspects may include (as applicable) but are not limited to:

I. ‘Hot Topics’ or Regulatory Trend Assessment

Hot topics are any current areas of focus or intensified scrutiny for inspectorates within a system or process.  Regulatory trends can be identified from available recent inspection observations (e.g., 483 reports from the FDA website). Proactively assessing these areas for the level of compliance and addressing any gaps within the system or process will help to ensure a positive presentation to regulatory authorities when required.

The QA function should continuously review regulatory trends and distribute updates to internal stakeholders to assess and mitigate the risk.

Following are the ‘Hot Topic’ or ‘Regulatory Trend’ as examples:

1. Failure to thoroughly investigate discrepancy (OOS/Deviation).
2. The investigation was not extended to other batches.
3. Inadequate cleaning validation/ cleaning procedure
4. Inadequate computerized system management (user access, audit trail review, data back-up, validation, data security issue)
5. Process validation is deficient since all applicable process parameters were not considered for validation. Process validated without an appropriate understanding of the process.
6. The in-process sampling plan is not defined/ not based on statistics.
7. Additional batch records/ pages were issued. In these cases, the procedure was not defined, and documented justification was not found.
8. The sample quantity for the hold time study is not representative of the bulk batch.
9. Independent verification was not performed in real-time.
10. Data Integrity concern: deficiency in data review/ Incomplete record in batch manufacturing records.

For any ‘Hot Topic’ or Inspection Trend, storyboards or presentations and/or risk assessment/ QMS report may be required to support the inspection and/or defend a compliance issue.  These should be prepared and maintained to ensure availability in the event of an inspection with that area in scope.

II. Gap Assessment

Gaps within systems and processes must be proactively managed in accordance with relevant procedures.  Gaps may be identified from a number of different sources, all of which must be considered as part of the assessment (where applicable).  These sources include:

• Quality Exceptions (Deviations, OOS, OOT, recalls, complaints, etc.)
• Previous Health Authority Commitments
• Self-Inspection / Internal Audit Observations
• Repeat findings which have identified systemic issues
• Site Quality Plan/ Site Quality Risk Mitigation Implementation deficiency
• Gap assessment against regulatory guidelines (e.g. checklist based gap assessment)

Addressing compliance gaps ensures that the site has a key awareness of potential vulnerabilities.  This enables the relevant stakeholders to dedicate resources to address any gaps in advance of the inspection.

Identified gaps should be addressed, based on the level of risk and impact on the product, patient, company, and success of the inspection. In cases where full mitigation is not possible prior to the inspection, a plan must be developed to address how the topic will be presented during the inspection.

III. Regulatory Filing Compliance

A compliance check must be performed against the dossier or documents submitted to the regulatory authority. Product formula, manufacturing process, specification, testing method, etc. must comply with the dossier or documents submitted to the regulatory authority. If any gap is identified, appropriate action should be defined through the applicable QMS tool (e.g. deviation, risk assessment).

IV. Monitoring and evaluation of Quality Metrics

The aim of Quality Metrics oversight is to have continuous awareness of potential quality or compliance deficiencies.  Quality Metrics should be established and monitored regularly to ensure that potential issues are identified, addressed, and escalated, as necessary.

V. Readiness assessment through self-inspection/ Quality Oversight

Self-inspection and/or Quality oversight should be performed before the regulatory inspection to assess the readiness. Necessary remediation should be performed to address the findings.

Phase 2: Pre-Inspection Preparation

This phase begins upon realization (previously announced or unannounced) of an inspection.

First, site management should nominate the ‘Inspection Lead’ to lead the inspection management. Usually, Inspection Lead is the Head of Quality Assurance or the Manager of Quality Assurance/ Quality Compliance. Also, any qualified person capable to lead and who has knowledge & experience in inspection management can be an Inspection Lead. Then Inspection Lead should form an ‘Inspection Preparation Team’ including representatives of all applicable departments/ functions. A minimum of two representatives should be members from each department- preferably the first representative is the manager or lead of the relevant department and the second representative is as the backup representative from the relevant department who can take care of activities on behalf of the manager when required. The inspection Preparation Team will be responsible to execute/follow-up preparation activities and communicate & coordinate with Intra/inter-department as applicable.

The Inspection Team should select the personnel for the front and back room. If possible, as per site resources, the following role should be assigned:

Front Room Role	Responsibility
Lead Host	Acts as the lead host and sits beside the lead inspector
Second Host	Acts as the second host and sits beside the second inspector (More hosts should be assigned if there are more inspectors)
Scribe	Documents the proceedings of the inspection

Back Room Role	Responsibility
Back Room Lead	Manages the Back Room, Contacts Subject Matter Experts
Document Quality Control (QC) Reviewers	Responsible for the review of documentation prior to it being released to the Inspectors
Document Tracker	Manages Document Request Log
Advisor/ Mock Interviewer	Releases documents as inspection ready. Prepare/ De-brief Inspection Interviewees for their interviews with the inspectors
Runners	Transfer documents/requests between the Front and Back Rooms (May not be required if online communication such as Microsoft Teams/ Skype/WhatsApp is used.)
Subject Matter Experts	To provide in-depth knowledge on inspection topics to the inspector.
Touring team	Assembled personnel to tour with the inspector(s) during the site visit

Personnel may assume more than one role, as needed during an inspection.

The inspection Preparation Team should finalize the following:

• Closing of open actions from phase 1
• Opening presentation
• SME selection
• Focused preparation considering inspection scope (products/production lines to be inspected)
• Infrastructure and processes to support the inspection including front room & backroom
• Necessary training on inspection management including inspection behavior
• Mock inspection 

Phase 3: Host Inspection

This phase of the process begins upon the arrival of the inspector.

When an inspector announces themselves, the reception/security staff must notify the designated single point of contact/contact list of the inspector’s arrival.

The inspector must be registered as a visitor and provided with the relevant identification in accordance with the procedure.

For unannounced inspections, the single point of contact will liaise with the inspector to determine the focus and scope of the intended inspection, and gather the relevant QA and business functions to host the inspection.

For announced inspections, the assigned escort from the Inspection Team is dispatched to escort the inspectors to the designated front room for the inspection. Then following inspection activities should be performed as agreed with the inspectors:

• Opening meeting
• Site tour
• Document review
• Inspection interview
• Daily wrap-up
• Final wrap-up/Exit Meeting

Phase 4: Post-Inspection Activities

Before the receipt of the final inspection report, potential responses to the provisional observations received during the inspection Exit Meeting should be discussed, including possible CAPA plans. 

QA and the involved functions jointly determine a strategy for responding to any inspection observations. 

Once the proposal for the response to Health Authority is agreed upon by all required parties, the response is sent to the Health Authority by the Inspection Lead, or other designees (i.e., QA representative, Regulatory Affairs, etc.).

If the Health Authority provides a response or inquiry around proposed CAPAs, this must be carefully reviewed and all concerns from the Health Authority addressed in a follow-up response.

If the Health Authority accepts the response/ proposed CAPA, the CAPA must be tracked through the QMS system. As actions are implemented, the CAPA and evidence must undergo a quality review to ensure the implementation of the CAPA is adequate and effective.

Author: Mohammed Raihan Chowdhury

Quality Assurance and Data Integrity Expert

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