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 regulatory authority inspects the manufacturing site of pharmaceutical company before giving manufacturing license or approving the site for manufacturing product for relevant country. Also, they inspect manufacturing site 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 satisfactory inspection outcome. In this article, strategy for inspection management has been described step by step. This article is based on regulatory expectations, experience of the author and based on pharmaceutical industry practice.
Strategy for Inspection Management
It is considered that necessary manufacturing facilities (building, machines, utilities, laboratory facilities etc.) are already ensured when the company is preparing for regulatory inspection. For highly regulated authority (e.g. US FDA, MHRA, ANVISA), company should start inspection preparation before 6-12 months of inspection. For other or local authority, 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
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 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 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 example:
a) Failure to thoroughly investigate discrepancy (OOS/Deviation).
b) Investigation was not extended to other batches.
c) Inadequate cleaning validation/ cleaning procedure
d) Inadequate computerized system management (user access, audit trail review, data back-up, validation, data security issue)
e) Process validation is deficient since all applicable process parameters were not considered for validation. Process validated without appropriate understanding of process.
f) In-process sampling plan is not defined/ not based on statistics.
g) Additional batch record/ pages were issued. In these cases, procedure was not defined and documented justification was not found.
h) Sample quantity for hold time study is not representative of bulk batch.
i) Independent verification was not performed in real time.
j) 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:
a) Quality Exceptions (Deviations, OOS, OOT, recalls, complaints, etc.)
b) Previous Health Authority Commitments
c) Self-Inspection / Internal Audit Observations
d) Repeat findings which have identified systemic issues
e) Site Quality Plan/ Site Quality Risk Mitigation Implementation deficiency
f) 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 upon the level of risk and impact to 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
Compliance check must be performed against the dossier or documents submitted to regulatory authority. Product formula, manufacturing process, specification, testing method etc. must comply with the dossier or documents submitted to regulatory authority. If any gap is identified, appropriate action should be defined through 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 regulatory inspection to assess the readiness. Necessary remediation should be performed addressing 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 Head of Quality Assurance or Manager of Quality Assurance/ Quality Compliance. Also, any qualified person capable to lead and who have knowledge & experience on inspection management can be Inspection Lead. Then Inspection Lead should form an ‘Inspection Preparation Team’ including representative of all applicable departments/ functions.
Minimum two representative should be the member from each department- preferably first representative is manager or lead of relevant department and second representative is as back-up representative from relevant department who can take care of activities on behalf of manager when required. Inspection Preparation Team will be responsible to execute/follow-up preparation activities and communicate & coordinate with intra/inter department as applicable.
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 & back room
- Necessary training on inspection management including inspection behavior
- Mock inspection
Phase 3: Host Inspection
- Opening meeting
- Site tour
- Document review
- Inspection interview
- Daily wrap-up
- Final wrap-up/Exit meeting
