By Tim Sandle, Ph.D.
The 2020–2021 coronavirus pandemic has caused multiple changes across the pharmaceutical and healthcare industries. One such difference has been the move toward remote inspections. To address this new approach, both parties (regulatory inspectors, such as FDA; and inspectees, such as pharmaceutical, biotech, or medical device companies) need to make changes relating to technology and culture. Given that this model will also continue, to an extent, post-coronavirus, it is important that organizations prepare for remote inspections.
This article presents an overview of the remote inspection process and provides advice on how to prepare for and deal with the inspection on the day, as well as how to respond to any concerns raised following the audit.
Preparing For The Inspection
To make the process easier, staff should be briefed on how to engage with an inspector remotely, in addition to:
- Educating staff on applicable GMP regulations and requirements
- Notifying any significant issues to senior management prior to the inspection
- Developing an audit plan and assigning roles and responsibilities
- Ensuring that all assigned personnel are readily available to the auditor
- Emphasizing the importance of providing any information requested by the inspector prior to the start of the inspection.
- Reviewing applicable FDA and GMP guidance documents
When documents are to be submitted in advance, the following points are noteworthy:1
- All documents should be in English or in a nationally accepted language.
- Where a document is not in English or a nationally accepted language, it should be submitted with a certified translation.
- Translated documents must be accompanied by a signed and dated statement by the certified translator stating that it is a true and accurate translation of the original document.
- Documents must be the most recent and reflect current activities and practices and be dated (expired/superseded documentation cannot be used).
- Documents must provide sufficient information to cover the scope of activities for which GxP compliance is sought.
- All documents must be submitted electronically, and they are not required to be certified as original copies unless requested (such as where there is concern over the validity of the supplied documents).
Other areas to prepare for in advance include:2
- You should develop prerecorded videos of the site and operations so the inspectors can be presented with a virtual tour of GMP relevant areas.
- If the manufacturer has electronic systems for quality management system (QMS) databases, such as complaints, deviations, out of specification/out of trend, and other GMP relevant areas, the company can consider setting up a guest remote read-only login to the QMS databases for inspectors to use at the time of inspection.
- Where time zone differences need to be taken into consideration, staff, including subject matter experts, should be made available at the agreed-upon real-time communication time slots.
Overall inspection planning on both sides will take longer. This is because:
- Inspectors will need to assess and document feasibility and risks with the company.
- Both parties will need to determine the different information and communications technology (ICT) used and how they will be used.
- Time needs to be set aside to define the agenda, particularly to accommodate dispositions different from an on-site audit, such as better definition of tasks by different team members to ensure auditors audit separately and make the best use of time, more detailed definition of themes to be handled in different time slots, which will require a better and previous understanding of the processes of the organization, and so on.
- The company to be inspected needs to identify the people who will most likely be needed during the audit and ensure their availability at the specified time.
- A test on the use of ICT must be run before the inspection to confirm that there is a stable connection and people know how to use the technology.
Additionally, for clinical trials, regulatory agencies may request access to the electronic trial master file and other systems in order to assess the conduct of the trials without an in-person visit.3
After analyzing risks and opportunities, the inspectors’ conclusions will provide the basis for defining what processes are to be inspected in relation to the availability of the appropriate technology.
Anticipating The Inspection Agenda
When facing a remote inspection due to a national emergency (such as with the COVID-19 pandemic), it is likely that the pharmaceutical or healthcare products manufacturer needs to adopt special measures (which may or may not follow regulatory guidance). Exceptional variations to standard GMP will no doubt be special topics added to the inspection agenda. This may occur in the following cases, for example:4
- Where retesting of raw materials has been limited to identification only (i.e., where supplier history, material criticality, and the finished product quality control strategy indicated a low risk)
- Where product has been shipped from a manufacturing site to another suitably authorized site under quarantine while quality control tests and batch certification at the manufacturer were ongoing
- Where investigation of minor non-conformances has been put on hold
- Where supplier audits have been put on hold
- When routine SOP reviews may be extended
- Circumstances where internal audits (self-inspection) are on hold
- When corporate training, such as GMP refresher training, has been put on hold
Your company may have made modifications to distribution of product within the supply chain. The changes could impact transportation times and the required transportation parameters (such as storage temperatures). Given the criticality of transport environmental conditions, and how these stand in relation to stability studies, regulators will most probably wish to scrutinize controls in relation to good distribution practice (GDP).
Many pharmaceutical, biotech, and medical device companies will have moved away from wet signatures to make greater use of electronic documents. Where transitions have occurred, regulators may be keen to assess whether:
- Controls, proportionate to the risk considering the type of document and the methods used for distribution and approval, are in place.
- An understanding exists that a signature performed remotely should be equivalent to the handwritten signature of the signatory.
- The method of document distribution and approval has been defined to minimize the risk of error due to misunderstanding what is being reviewed/approved.
A risk assessment for electronic approval must be in place, covering such areas as:
- How the approval signature was attributable to an individual
- Whether there is a legislative requirement or GxP guidance for a signature. If there is, then the signature needs to be considered more critical and there needs to be, proportionately, greater control.
- The security of the electronic signature needs to be assessed, especially so it can only be applied by the “owner” of that signature
- Consideration of what is in place for the act of “signing,” so the document cannot be altered or manipulated without invalidating the signature or status of the entry
- Ensuring that all required associated data is available to a remote reviewer that would have been available to them if they were performing the review at a site.
Areas of regulatory concern with remote documentation approvals include:
- Document number/version not being included on the approval page
- Simply pasting in image copies of signatures
- Approving by email (which is seen as lacking appropriate controls)
- Holding approved documents in shared folders that can be accessed by non-approved personnel
There may also have been an impact upon the frequency of equipment calibrations, or the extent to which equipment modifications can take place. Here, calibrations of equipment may have been executed or undertaken remotely via digital media. However, a number of service and calibration visits may need to have been cancelled. An inspector will probably wish to review the following in relation to when a calibration has been delayed:
- The criticality of the equipment and its intended use
- The frequency of the calibration/maintenance
- Whether the delay affects an interim or annual recalibration/maintenance task
- The prior performance of the equipment, including drift between previous calibration or maintenance visits and recent breakdown history
- Performance checks that are made on the equipment prior to use
Your organization’s risk assessment should also consider additional performance checks and verifications that should be performed to monitor the compliance status of the equipment. The quality management system should document and mange delay of a calibration or maintenance task. It is important that the documentation is suitably transparent to allow the person responsible for releasing product or making a regulatory claim of compliance to make a full and accurate assessment. Demonstrate that once a calibration or maintenance task can be performed, it is conducted at the earliest opportunity once restrictions on movement are removed. Furthermore, any equipment taken out of service following risk assessment should have outstanding maintenance or calibration work completed prior to being put back into use.
Ensuring A Good Opening Meeting
Many processes, including the opening meeting, will need to be adapted to ensure that the remote inspection runs smoothly. At the opening meeting, both parties should discuss the technology and the particulars of a remote meeting setting. This also includes how documents will be presented and when to schedule breaks.
As a matter of courtesy, you should provide a list of attendees for the opening meeting, especially as not every attendee may be visible to the inspector.
How The Inspection Process Will Work
While many aspects of the inspection process will be the same as a routine inspection, there may need to be more interaction in order to explain things that the inspector cannot see and, hence, a greater reliance on interviews, presentations, and video recordings. It is important that information is shared during the inspection, including the fact that documentation requests may take longer given the additional time that may be required to retrieve and scan files. Ideally, an electronic document request form will be used and configured so it can be shared among your team and the inspection team. The inspection team may request you to keep track of all requests and provide a regular update of the electronic document created.5
During the inspection, it is generally useful to have one person discussing content with the inspector and one or more person in an assistant role, working on opening and sharing documents as well as taking notes and getting ready to prepare supplementary information. It is also preferable, assuming that it can be controlled, for a remote inspection to be conducted in segments. This allows time for the inspector to review records and generate questions and for your company to gather records, organize interviews, and formulate responses.
During the inspection, it is important to maintain trust, which can be impacted by technology. There are three obstacles that need to be addressed to establish trust in virtual environments:
- Communication of trustworthiness, which concerns how people convey ‘trust’ to one another, such as tone of voice, emotions, nonverbal signals and so on. This is easier to achieve face-to-face whereas via digital audio and video technology, the assessment made by an inspector as to the veracity of what is being said becomes harder. This can be made easier if reliable and effective information and communication technology is used, together with practices like ensuing whoever is speaking is in camera view and avoiding video screens closing down (either intentionally, in order to avoid being seen, or accidentally due to unreliable systems).
- The prior establishment of common understanding, such as how information will be conveyed (such as screen sharing, emailing documents, text chat and so on); whether some people will be out of camera vision; when a break is needed to discuss a point between colleagues; and when going on mute is acceptable. Establishing such rules helps to avoid misinterpretation of behaviors.
- Demonstrating sound ethics.
Avoid noise and other distractions, and warn your team members that when they speak, they can be heard over their microphones (the microphones on many computers have considerable range). Because remote communication is generally more impersonal than face-to-face, it is in each person’s best interest to try to be approachable and understanding. Your choice of language is also important, and it is best not to use too much technical language, field-specific jargon, or lesser-known acronyms. Instead, try to use simpler terms whenever possible.
Participating In The Closing Meeting
While the closing meeting should run in a way similar to the opening meeting, the remote aspect may prompt an assessment as to the extent of use of ICT as well as the effectiveness of its use in achieving the inspection objectives (and if the technology limited the achievement of these objectives). Both parties should agree on the processes that could not be inspected and that need to be inspected on-site at a later date. This information is important for any subsequent inspections.
As an addendum to the closing meeting, any information requested by inspectors post-inspection should be provided by the manufacturer within the requested timeframes.4
The considerations and ideas for preparing for remote inspections outlined in this article are not important only in the era of the SARS-CoV-2 virus threat, because the general success of the model may lead to remote inspections becoming part of the normal inspection process. Perhaps this will occur with regulatory agencies alternating between on-site inspections and inspections conducted over video media. If this becomes the new reality, then the points raised in this article will become ones that each quality assurance department needs to consider carefully in terms of adapting to the new regulatory approach.
This article has been adapted from chapter 6 of the book Digital Transformation and Regulatory Considerations for Biopharmaceutical and Healthcare Manufacturers, Volume 2, written by Tim Sandle and co-published by PDA and DHI. Copyright 2021. All rights reserved.
- WHO (2017) Guidance on good practices for desk assessment for compliance with Good Manufacturing Practices, Good Laboratory Practices, and Good Clinical Practices, for marketing authorization of medical products, QAS/17.713, draft document issued May 2017, World Health Organization, Geneva, Switzerland
- Das, P.C. (2020) Hosting remote inspection at pharmaceutical facilities, PRES, India
- Halloran, L. (2020) Assessing The Impact Of COVID-19 On Regulatory Interactions, Inspections, and Audits, Clinical Leader, 19th March 2020 at: https://www.clinicalleader.com/doc/assessing-the-impact-of-covid-on-regulatory-interactions-inspections-audits-0001
- Sandle, T. and Saghee, M. (2020) Virtual regulatory inspections: Part of the ‘new normal’ for pharmaceuticals and healthcare. In Saghee, M., Sandle, T. and Bid, G. (2020) Pharmaceutical Regulatory Inspections: Quality and Compliance, 2nd Edition, Euromed Communications, Passfield, UK, pp503-526
- EMA (2020) Guidance on remote GCP inspections during the COVID19 pandemic, European Medicines Agency, EMA/INS/GCP/162006/2020, Issued on 18th May 2020. Available at: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guidance-remote-gcp-inspections-during-covid-19-pandemic_en.pdf
About The Author:
Tim Sandle, Ph.D., is a pharmaceutical professional with wide experience in microbiology and quality assurance. He is the author of more than 30 books relating to pharmaceuticals, healthcare, and life sciences, as well as over 170 peer-reviewed papers and some 500 technical articles. Sandle has presented at over 200 events and he currently works at Bio Products Laboratory Ltd. (BPL), and he is a visiting professor at the University of Manchester and University College London, as well as a consultant to the pharmaceutical industry. Visit his microbiology website at https://www.pharmamicroresources.com.