How to host GMP and Regulatory Inspections
Practical advice for preparation and readiness
What is Regulatory inspection in healthcare industries?
Regulatory inspections are the inspection carried out by the healthcare regulatory bodies and government bodies of the respective countries to ensure the compliance level of operations carried out by the organizations such as pharmaceutical, biopharmaceutical, or medical device manufacturers.
The organizations that are involved in pharmaceutical or biological products’ manufacturing or supply for regulated markets such as United Kingdome (U.K.), European Union (E.U.), or United States (U.S.) must be all time ready for a potential inspection by MHRA (Medicines and Healthcare products Regulatory Agency), E.U. Agency, US FDA (United States Food and Drug Administration) or local drug authority of the country of origin.
These regulatory inspections are very different from the customer or ISO certification or surveillance audits. The pharmaceutical, biopharmaceutical, and medical device industries are highly regulated. The key to success is to stay abreast of what regulatory authorities expect and to be compliant all the time.
For all time readiness for an inspection, the organization should have a procedure or policy. The organization should identify various teams to manage essential elements of an inspection. Considering the current scenario and trend of unannounced inspections by regulatory agencies, management should consider having the following lists of the team and resources all the time.
- List of Most responsible persons for the site
- List of the site leadership team and escort
- The management team of an organization
- List of Subject Matter Expert (SMEs) for various areas and functions
- List of functions associated with the manufacturing facility, organizational structure, and the relationship between manufacturing facility, and corporate functions
- List of supporting staff – Scribes, Runners, Document controllers
- A typical list of resources required during the inspection
- Site presentation for an opening meeting
- Document preparation plan
- Inspection flow and plan
- Virtual regulatory inspections plan (Considering ‘new normal’)
Why regulatory inspections?
The main goal of the health authority inspection is to ensure patient safety by verifying the adequacy of the firm’s quality systems to produce safe and efficacious health care products such as pharmaceutical formulations, medical devices, etc.
What are the types of inspection and its objective?
Site pre-approval inspections: Inspections carried out to approve the manufacturing, packaging, testing, or warehouse facilities.
Periodic routine inspections: Periodic risk-based facility inspection to reassess the compliance status of the facility.
Product approval inspections: If the firm has submitted a new formulation or authority wants to bring the product into the market on the fast track, agencies carry out product-specific inspections.
Compliance verification inspections: When the regulatory agency cites major and critical deficiencies, actions implemented by the firm are verified by the agency to ensure the state of compliance.
For-cause inspections: Authorities trigger for-cause inspections for various reasons to ensure the compliance status of the firm. The reasons could be whistleblower by employees or customers or the events that may have caused significant harm, death, or a product recall.
Inspection process and flow
The firm decides the most responsible personnel for the manufacturing location and organization. The responsibility is based on the hierarchy and area of responsibility. For the manufacturing site, the Factory Manager or Plant Head is considered as the most responsible person. In the case of announced inspection, if responsible management person such as COO (Chief Operating Officer), CEO (Chief Executive Officer), or Managing Director (MD) of an organization present at the manufacturing site, the senior-most person would be considered as a most responsible person for the site. It is decided by the organization in the policy document or defined in a Site Master File (SMF).
Once the inspector arrives at the facility entrance, the information from the main gate should reach the most responsible person at the site. The most responsible person should receive the inspector and first introduce him/ herself as the most responsible person at the site and request the inspector’s credential, a notice of inspection, or the relevant document. As per US FDA regulation, Form 482 is an official notice of FDA for inspection, signed by the FDA officials.
Once the above formality is completed, as per organization policy, the entry log should be maintained in the register and produce an appropriate badge for the inspector to wear during the inspection at the inspection facility.
After completing the above process, guide the inspector to the designated room to start the opening meeting. Inspections generally start with an introduction session between the inspector and the firm’s key personnel present at the site. A site presentation should generally follow the introduction to a brief about inspection facility, organogram, product profile, site layout, and quality system. Offer a comfortable environment to the investigator to perform his/ her duty.
Suppose any policy implemented for visitors such as safety awareness process, restrictions, or any similar process should be informed to the inspector. Inspector may decide to go through the same or not. The firm’s responsibility is to provide information to the inspector but should not force it. Inspectors should also be informed about the policy for ornaments, photography, and mobile usage at the site. The firm should maintain a professional atmosphere and offer congenial cooperation.
Management, site leadership team and escorts
The site leadership team consists of the plant head, quality assurance head, manufacturing head, engineering head, warehouse head, human resource head, quality control head, and other functional heads. The escort team should consist of department heads, key personnel from the quality assurance department, and SMEs for respective areas.
The responsibilities of escorts are to facilitate and execute the inspection plan, accompany the inspector during a site tour of various functions, familiarize with the department functions, and facilitate the information requested by inspectors.
Subject Matter Expert (SMEs)
A subject matter expert is an individual with a thorough understanding of a particular subject, process, function, technology, machine, material, or specific equipment.
The responsibility of the SME is to explain the information concerning the respective subject and ensure that the information requested by the inspector is provided accurately. If any concern noted or potential for any observation, it should be immediately escalated to the site leadership team and management for resolution.
Scribes, Runners, Document controller
The scribe’s responsibility is to record the details of the discussion that happens during the inspection, in the inspection room, during the site tour, questions asked by the investigator, and answers given by SMEs or anyone who had interacted with the investigator. Scribe shall also support coordination with the war room for document requests and SMEs. Scribe is also responsible for maintaining the list of personnel who interacted with inspectors and topics discussed. Generally, inspectors used to ask the firm to provide the list at the end of the inspection, which they can use for their record.
Runners are an important part of the inspection team. They are the one who supports to communicate request from inspection room and to bring documents from the war room to the inspection room, communicate to the SMEs time to time during the inspection. Personnel who would be selected as runners must have an excellent understanding of the inspection process.
Document controllers are the team members who manage the document movement and flow during the inspection process. The key tasks of document controllers are as follows:
- Records the name and reference number of documents going to the auditors and the name of the corresponding inspector
- Maintaining additional copies of the document which the auditor takes
- Reconciling the document once the document is returned from the audit room
- Identify and communicate to SMEs based on the inspector’s request
Resources required during the inspection
Commonly required resources during the inspection are as follows:
Inspection room: An inspection room is a room required for hosting the inspection. The location and size of the room should have easy access to all the areas of the facility and accommodate inspectors, inspection leads, scribes, SMEs, and management team as per need. It should be sufficient enough to conduct the opening meeting. It should able to accommodate multiple inspection conversations as per the number of inspectors. It should have a locker arrangement for storing belongings of inspectors, i.e., mobile phones, laptops, etc., while they go for plant tours or during breaks.
War room or inspection preparation room: The war room should be available near the inspection room but not adjacent to the inspection room. It should be big enough to manage the following activities:
- It should accommodate the document controller and supporting staff to process the document requests
- It should have good connectivity with the document storage room
- It should have facilities such as laptops, P.C.s, printers, photocopy machines, scanners, temporary document storage facility, stationary, Local Area Network (LAN) connections, and sufficient phones/ communication devices
A list of SMEs, leads, escorts, scribes, runners, and key personnel with contact numbers must be available in the war room, reception, and the security gate for accessible communication.
Site presentation for opening meeting
The key objective of the opening meeting is to introduce the site team members and provide brief details about the site. The meeting should be conducted in a welcoming manner to build trust in the organization. The opening meeting allows an opportunity to show the management commitment and support.
Opening meeting presentation should consist of the following information to brief about facility and organization.
- Welcome slide
- Foundation and objective of organization
- Market presence
- Strength of an organization
- Site and corporate location
- Other facilities
- Plan layout and design
- Organogram, key personnel and site strength
- Working hours
- Site inspection history and approvals
- Product profile
- Brief about quality system
- Major equipment, instrument and facility
- Major utility systems
- Major changes since last inspection
Document preparation plan
The document controller should ensure the availability of required documents in the preparation room. Following are the documents that should be available in advance for inspection.
- Master list of SOPs
- Key SOPs
- Complaint Logs
- Recalls logs
- Deviation Logs
- OOS Logs
- Change Control Logs
- CAPA Logs
- CAPA logs
- Process Validation Documents
- Cleaning Validation Documents
- Analytical Method Validation, Verification and technology transfer documents
- Annual Product Quality Review
- Trends of water systems, environmental monitoring, personnel monitoring
- Equipment and Instrument Qualification
- Calibration records
- Preventive maintenance records
- Batch Manufacturing Records (examples)
- Self-Inspection records
Selection of key personnel, SMEs and requirement of training
Completing successful inspection is all about presenting all the hard work you have done in past years to improve your organization. In this process, understanding your weak area is essential and how to deal with it. The human factor can make or break an inspection depending on the preparedness for the inspection. This factor cannot be completely controlled but can carefully manage by preparing staff well in advance.
Following elements can be considered as part of the preparation for inspection:
Identify SMEs: Competent, able to manage stress, quick decision-maker, confident, and able to manage unexpected situations efficiently.
Prepare for difficult topics in advance: Identify difficult topics you think are challenging to manage, such as complex investigations, emerging topics in the industry, or complex systems. Prepare storyboards/ white papers for the topics and practice them.
Training to SMEs: The training topic should cover inspection etiquette, presentation skills, types of questions investigator may ask, how to respond to it, etc.
- Close-ended questions
- Open-ended questions
- Probing questions
- Leading questions
- Loaded questions
- Hypothetical questions
- Comparative questions
- Indirect Questions
Simulating inspections and interviews: One of the most effective methods to prepare the team for an inspection is to conduct simulated inspections. Get a mock inspection is done by a third person, such as the quality head of another site, corporate functions, or third-party auditors.
Dos and Don’ts during regulatory inspections
- Provide true answer with honesty
- If you do not know, Say “I don’t know” or “I’ll get the answer for you” or “Let me call the right person to give you an answer”
- Avoid phrases such as “I think”, “Sometimes/ usually” etc.
- Avoid words, such as “typically”, “generally” and “usually”
- Provide only required information
- Ask if you have not understood the question
- Control your temper
- Only answer questions related to your role
- Restrict conversations in common areas
- Ensure you understand the question before answering it
- Volunteer additional information
- Promise things you are not sure you can deliver
- Provide direct access to any electronic systems
- Walkthrough the facility unescorted
- Comment on quality or admit non-compliance
- Argue with the investigators or your peers
- Forge someone else’s signature
- Fabricate documents
- Be sarcastic
- Guess answers
- Apologize for problems or comments made by an investigator
- Become defensive or evasive
- Make statements about your personal opinion
- Make investigator ask for the same document again and keep them waiting for the document
- Interrupt while the investigator is speaking
Virtual regulatory inspections plan (Considering ‘new normal’)
Being a regulated and healthcare industry, periodic inspections of the firms for Good Manufacturing practices (GMP) and Good Distribution Practices (GDP) are mandatory requirements by regulatory agencies. This can be a challenge in crises such as the COVID‐19 pandemic.
If the situation does not improve, regulatory agencies may decide to carry out virtual inspections to ensure the firms’ compliance status and supply pharmaceutical and biopharmaceutical goods. The most critical factors for prioritizing the inspection would be based on the inspection history of the site. The sites categorized as low risk during previous inspections would be considered the lowest priority for virtual inspection.
In March 2020, there was an announcement regarding foreign and domestic surveillance facility inspections and reviewing records remotely considering the COVID-19 pandemic situation.
“During COVID-19, the U.S. Food and Drug Administration will continue to utilize and implement additional alternative inspection tools and approaches while postponing domestic and foreign routine surveillance inspections. This will continue as local, national and international conditions warrant, with the exception of certain mission critical inspections. Mission critical inspections are identified on a case-by-case basis and conducted with appropriate safety measures in place”
Reference: Coronavirus (COVID-19) Update: FDA updates on surveillance inspections during COVID-19, 11 May 2020 [Source of information]
On August 19, 2020, FDA announced the availability of a temporary guidance for industry, “Manufacturing, Supply Chain and Drug and Biological Product Inspections during COVID-19”. As per this guidance:
“With respect to pre-approval inspections, FDA intends to continue using other tools and approaches where possible, including requesting existing inspection reports from other trusted foreign regulatory partners through mutual recognition and confidentiality agreements, requesting information from applicants, and requesting records and other information directly from facilities and other inspected entities”.
MHRA had announced in the month of March 2020 about strategy regarding the inspection during the COVID-19 pandemic situation.
“We are expecting organisations to maintain GxP compliance, and will support the industry and NHS to focus on service continuity by using alternative approaches for routine regulatory oversight, such as office-based assessment and the sharing of information within the international regulatory network.
We will prioritise essential on-site inspections linked to the UK Government’s COVID-19 response or any other potential serious public health risk, where these sites cannot be assessed remotely. Essential clinical trial authorisation applications will not be affected by this change and will remain prioritised.”
The term ‘virtual inspection’ is the off-site inspection done using communication and information technology to comply with the legal requirement of an on-site inspection. This can also be called remote inspection.
Since virtual inspections are completely dependent on Informational Technology (I.T.), it is very important to carefully set up the technological aspect for flawless inspection. The key concern during such inspection is data security and confidentiality of connections.
Points to get clarified before virtual inspection: Virtual inspection is not a traditional inspection method and a new experience for regulators and firms. To avoid any surprises and misunderstandings during the inspection, few basic things need to get clarified between the auditing agency and the firm. Following are a few key aspects, which are very important in my opinion.
- The virtual platform suggested by the agency to carry out an inspection. Popular used platforms for video conference, and screen sharing are Skype, GoToMeeting, Google Meet, Microsoft Teams, and WebEx. When choosing the platform, look for ease of usability. Also, ensure that the platform meets auditing requirements and should work with the basic configuration of equipment requirements, and does not demand very high internet speed.
- Document sharing platforms
- Virtual tour/ video recording requirement within the facility and discussion on restricted areas
- Recording requirements
- Number of investigators and number of days
- Access control on connections, visibility of connected participants, document sharing platforms
- Required documents to be uploaded via a document sharing platform
- Agreement on inspection time considering time zone difference
- Number of unique connection links for communication to carryout virtual inspection
- Any guidance that the agency suggest to follow during an inspection
- Limitation of access to secure systems, electronic QMS systems, and instrument servers and networks
- Requirement of translators
- Planning and participation during the opening meeting
IT infrastructure, resources, backup plan, and awareness training to SMEs on setups: Engaging an IT professional for preparation and set up is a very important aspect. Not only to setup but to ensure is that the setup up-to-date during the inspection. Firm and IT professional should ensure the following key aspects while setting up IT infrastructure for virtual inspection.
- Reliability of internet connections
- Backup facility for internet connections
- The required bandwidth for the inspection requirements
- Redundancy and Backup protocol
- Wired and wireless network setups
- Headsets and hands-free
|Wireless BT Headphone |
Good Playback Time (around 9 hrs)
Multi Connectivity Options
[Check on Amazon]
- Suitable antivirus and firewalls to ensure network security
- Connectivity and signal strength at all possible coroners where the possibility of the virtual tour by investigators
- Tablets for virtual tour outward-facing camera and inward-facing cameras
|Samsung Galaxy Tab|
8MP primary camera and 2MP front facing camera
5100mAH lithium-ion battery
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- How to give access to secure systems, instrument networks, and electronic QMS systems to auditors, by screen sharing or remote connections of the systems
- Document Camera for sharing the documents instantly. See following camera on Amazon
|Document Camera for instantly sharing documents|
Capture Size A3
High Definition Portable Scanner
English Article Recognition
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- Mock runs to ensure the working condition of all setups, video quality, sound quality, and anticipation on the potential for connectivity loss and backup plan
- Training to SMEs on awareness to use the IT infrastructure set up for an inspection
- Restricting sharing of internal networks and routine workspace for the employees
- Security/ Access to the Online Portal
Things to remember during the virtual inspections: Unlike the physical inspections, there are many things where the auditee needs to take care of during the virtual inspection.
- Very well plan for an inspection.
- One terminal (Laptop/P.C.) for discussion with one inspector in a room. If a different person wants to join in the discussion, one should use the same terminal to participate in the discussion. If another person wants to join using a different terminal, it should be in a separate room to avoid voice disturbance and echoing.
- No background or side talks in the inspection room when one person is doing a discussion with an inspector.
- Confirm with inspectors whether they can hear you loud enough and clearly.
- In case of auditee cannot listen, the auditee should inform upfront and politely regarding the issue he or she is facing in hearing the voice.
- Take care while handling the microphone to avoid sound disturbance.
- While referring to pages and documents on the desk, take care to avoid unnecessary sound, creating a disturbance.
- Know your document very well to avoid jumping on pages in the document from one page to another to find out what you are looking for.
- While doing a virtual tour, commentary and explanation are very important. You are familiar with your facility, but the inspector is not. Ensure that the inspector is following what you want to show them. Simultaneously also ensure that you are showing the inspectors what they are expecting.
- Get feedback intermittently that you are connected with the inspector, and they are following what is being explained to them.
- In the case of the aseptic area, generally, the area is designed in such a way that even during a physical audit, an inspector can witness the operation from glass windows. In the case of virtual inspections, the same approach should be encouraged that the device should keep outside the aseptic area, and glass windows should be used for visualization. This shall prevent the potential for contamination in the aseptic area.
- The firm should declare before the inspection regarding the restricted area. For example, the solvent storage areas, which are highly sensitive and vulnerable to catch fire, where the firm cannot use electronic devices.
- Wi-Fi signals should be checked in all the areas where you want to carry out a virtual tour to avoid changes of signal loss during the tour.
A proactive approach for inspection preparedness allows looking at the area of weakness and provides an opportunity to improve upon them. The firm can get a chance to rectify the weak areas and mitigate the risk of failure. SMEs will get to know the improvement areas, work upon them, and be ready with confidence to present during an inspection.
Such preparation requires investment in terms of time, effort, and resources. The investment for being proactive is worth instead of a reactive approach, which involves dealing with remediating the situation post-inspection. Remediation exercise is more painful, time-consuming, and costly. The reactive approach puts organizations on the back foot.