GMP: EMA distant assessments – Europe – and not America – First!

The European Medicines Agency finds a solution that allows performing GMP and GDP inspections from remote.
The European Medicines Agency as the responsible agency coordinating the verification of compliance with the principles of GMP finds a solution that allows performing GMP (Good Manufacturing Practice) and GDP (Good Distribution Practice) inspections of their Member State supervisory authorities from remote.

The ongoing and culminating Coronavirus pandemic obviously urged the European Medicines Agency to be innovative and to develop a remote GMP inspection guideline, to keep up with due GMP surveillance inspections for drug manufacturers across Europe. For 3rd party auditors, this EMA Draft Guidance could be leveraged as a “template” for remote GMP audits, that are due – and usually conducted at the site, but which are currently heavily impaired during these Coronavirus pandemic times. In contrast, FDA – as of today – has not developed such a remote drug inspection guidance, and thus, other than “mission critical” inspections are postponed.

FDA rebuffs requests.

“FDA Fiddles with Remote Drug Inspections While Pharma Burns. Numerous pharmaceutical companies have pleaded with agency officials to conduct such inspections over the past several months in order to resolve manufacturing compliance issues and get critical new drugs approved, and have even offered to obtain the requisite technology, but the FDA has rebuffed such requests. The agency has not made public any plans for the adoption of this remote method of inspecting, despite multiple requests from the pharmaceutical industry to do so”, said Mark I Schwartz, who is a director at Hyman, Phelps & McNamara P.C. in Washington, D.C. and spent 13 years at the FDA and served as Deputy Director for the CBER Office of Compliance and Biologics Quality[1]

August 20, FDA (Food and Drug Administration) Guidance issued: “Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency Questions and Answers Guidance for Industry”[2]. This guidance defines “mission critical” inspections – using its COVID-19 Advisory Rating system, that provides a rationale for either conduction these mission critical inspections “on a case-by-case basis or, where possible to do so safely, resuming prioritized domestic inspections, which generally include pre-approval and surveillance inspections”[3]

In contrast to the FDA, the European Medicines Agency (EMA) faces the current and still very active Coronavirus pandemic with respect to finding a solution to performing GMP (Good Manufacturing Practice) and GDP (Good Distribution Practice) surveillance inspections from remote and recently (15 OCT 2020) issued a DRAFT Guidance: “Guidance related to GMP/GDP and PMF distant assessments. A.GMP/GDP distant assessment guidance (version 1)”[4]

Europe first!

The EMA draft guidance content on conducting distant assessments is outlined in table 1. This draft guidance information may also help 3rd party auditors performing GMP/GDP compliance remote audits, while I am assuming, that EMA is likely to rather accept those remote audit reports, whenever 3rd party auditors perform these remote – distant – virtual audits according to the EMA draft guidance (Table 1, No. 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 (14)).

Table 1: Remote – virtual – distant assessment approach EMA[5]

No.:Considerations/ ProcessEMA DRFAT Guidance EMA/335293/2020*
1EMA: Planning/ feasibility distant assessments-manufacturing sites/ dosage formsFor all types of inspections as necessary and can be performed for all types of sites and dosage forms following a careful case-by-case evaluation, taking into account the criticality of the manufacturing activities and the product(s) concerned…
2Planning/ feasibility distant assessments requested by CHMP/CVMP and coordinated by EMAThe Supervisory Authority and inspectorate (if different) together with EMA should make a case-by-case decision on whether a distant assessment is considered appropriate and feasible. For pre-approval distant assessments, the Rapporteurs should also be informed, and the criticality of the product should be taken into consideration Distant assessments should follow the applicable procedures that already exist for coordinating, preparing and conducting GMP inspections requested by the CHMP or CVMP, respectively, and should take into consideration the present guidance…
3Planning/ feasibility distant assessments coordinated by member statesIndividual National Competent Authorities (NCAs) can determine on a case-by-case basis whether a distant assessment is required, feasible and appropriate for sites on their national inspection programmes.
4IT and other practical considerationsFollowing a decision to perform a distant assessment, early contact should be made with the site to determine the feasibility. At a minimum, the following should be considered: The use of appropriate platforms to allow for the timely provision of data such as large electronic documents (e.g. access to secure cloud servers or the use of Eudralink or other secure NCA platforms). The use of teleconference/videoconference or alternative to allow for real time discussions with company personnel and Subject Matter Experts (SMEs). The capability for the live sharing of screens displaying computerized systems used at the site, or the feasibility of providing remote (read-only) access to inspectors to computerized systems. The provision of live camera footage or video recordings (e.g. smart glasses, mobile cameras, drones or cameras in place) to allow for a remote review of manufacturing operations, equipment, facilities and relevant documentation such as logbooks, if applicable. The time zones of the site and the location of the inspector(s). The language of the site. The inspector(s) may require access to a translator for parts of or all of the remote inspection…. An example of an optimal communication platform could include the following: A live videoconference platform which has the following capabilities: – Break-out rooms/conferences to facilitate separate channels of discussion between different inspectors and the site.  – Screen sharing to display site applications/electronic systems. Smart glasses or other mobile cameras which can be interfaced to the videoconference platform to provide live footage of manufacturing operations, facilities and equipment. Access to a secure cloud server to share documents
5Limited on-site inspectionsDepending on the circumstances at the time, it may be possible to conduct a limited on-site inspection of sites located in the EEA. This should only be considered if it is compatible with travel restrictions, health measures, and other restrictions/guidance issued by local or national authorities at the time and should be discussed with the site. The inspection could consist of a distant assessment of relevant documentation with a limited on-site inspection of manufacturing operations, facilities and equipment. The on-site inspection and distant assessment should be considered together as parts of the same inspection. A single inspection report and inspection outcome (e.g. GMP certificate) should be produced.
6Distant assessment durationThe principles of the Union procedures A Model for Risk Based Planning for Inspections of Pharmaceutical Manufacturers and GDP Inspection Procedure (Medicinal Products for Human Use) should be taken into account, as relevant, when determining the scope and duration required for the distant assessment. The practicalities and potential challenges associated with distant assessments should also be considered and could result in a longer duration compared to an equivalent on-site inspection. Aspects such as the communication process, site time zone and language, and location(s) of the inspectors should be taken into account.
7PreparationInspector(s) should adequately prepare for the distant assessment and familiarize themselves with the site to be inspected, in accordance with the Union procedures for Conduct of Inspections of Pharmaceutical Manufacturers or Importers and GDP Inspection Procedure (Medicinal Products for Human Use), as relevant.
8Distant assessment planIt is recommended that a plan is drafted in a manner similar to on-site inspections, outlining the areas of the site to be reviewed by each inspector. It is also recommended to share relevant parts of the plan and timetable with the site to facilitate the smooth running of the distant assessment and ensure that site SMEs are available at the requested times.
9Announcement of distant assessmentNotification of the intention to perform a distant assessment should be communicated to the site in accordance with the standard timelines for on-site inspections. In order to prevent any delays during the distant assessment, consideration should be given to requesting that electronic copies of documents and/or lists of documents are provided to the inspector(s) in advance of the distant assessment or, at least, are available for review from the start of the distant assessment.
10Communication process for the distant assessmentThe communication platform and process for the provision of electronic copies of documents and other information to the inspector(s) should be defined and agreed with the site in advance of the distant assessment. Consideration should be given to the items listed in paragraph 2.4 (i.e. No. 4 this table).”IT and other practical considerations”…
11Conduct of distant assessment/ opening meetingThe distant assessment should start with an opening meeting via videoconference, teleconference or alternative. In addition to covering the relevant items listed in the Union procedures for Conduct of Inspections of Pharmaceutical Manufacturers or Importers and GDP Inspection Procedure (Medicinal Products for Human Use), as relevant, the inspector should consider outlining the following: A brief overview of the process for communication and the distant assessment plan/timetable. Any video/audio recording of the distant assessment by the inspectorate should be agreed between the site and the inspector(s). If part of the distant assessment will be recorded, the site should be given the opportunity to appropriately inform any personnel who may appear in such video footage in accordance with any relevant local legislation.
12Performing the distant assessmentRelevant elements of the Union procedures for Conduct of Inspections of Pharmaceutical Manufacturers or Importers, the Outline of a Procedure for Co-ordinating the Verification of the GMP Status of Manufacturers in Third Countries and GDP Inspection Procedure (Medicinal Products for Human Use) should be considered to assess the compliance with GMP/GDP and with the terms and conditions of authorization(s) as applicable….
13Closing meetingThe distant assessment should end with a closing meeting via videoconference, teleconference or alternative and should cover the relevant items listed in the Union procedures for Conduct of Inspections of Pharmaceutical Manufacturers or Importers and GDP Inspection Procedure (Medicinal Products for Human Use), as relevant.
14Distant assessment reportDistant assessment reports should be written in line with the Union formats of GMP/GDP inspection reports. Appropriate clarifying remarks should be included in relevant sections of the report to make it clear that a distant assessment was performed and to indicate if physical aspects of the facility were assessed and the methods used.
15GMP/GDP certificatesIf the outcome of the distant assessment is positive, GMP/GDP certificates should be issued. For GMP distant assessments, the Type of Inspection on the certificate should indicate Distant Assessment. If a limited on-site inspection as per paragraph 2.5. (i.e. No. 5 this table) was conducted, the Type of Inspection on the 188 certificate should reflect the on-site inspection and a clarifying remark may be included to indicate that part of the inspection was performed as a distant assessment. Existing regulatory risk management principles should be used to determine the duration of the validity of GMP/GDP certificates issued following distant assessments.
16Serious GMP/GDP non-complianceFor new sites, including pre-approval distant assessments requested by EMA, if any critical deficiencies are identified during the distant assessment, the relevant application should be put on hold until an on-site inspection can be performed. For other types of distant assessments, if any critical deficiencies are identified during the distant assessment, existing processes for on-site inspections should be followed and a Statement of non-compliance may be issued if applicable.
17Planning of next InspectionOn-site inspections should be conducted once circumstances permit… A distant assessment may be considered a suitable justification to recommend a reduced interval until the next on-site inspection.
  • the list as presented is not exhaustive…!
References.

[1] Mark I Schwartz (7 DEC 2020): https://hpm.com/wp-content/uploads/2020/12/MIS-Bloomberg-Artcle-00735184.pdf, accessed 26 JAN 2021

[2] FDA Guidance (AUG 2020): Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency Questions and Answers (fda.gov), accessed 26 JAN 2021

[3] Op cit 2.

[4] EMA DRAFT Guidance (15 OCT 2020): https://www.ema.europa.eu/en/documents/scientific-guideline/guidance-related-gmp/gdp-pmf-distant-assessments_en.pdf, accessed 26 JAN 2021

[5] Op cit 4.

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Dr. Ralf Hess

Principal Management Consultant

Dr. Ralf Hess studierte Biologie an der Albert-Ludwigs-Universität Freiburg und promovierte ebenda am Institut für Virologie. Dr. Hess verfügt über langjährige Erfahrung in der Entwicklung von Medizinprodukten und Arzneimitteln sowie deren Kombination, in der Laboranalytik und deren Qualitätssicherung. Der Qualitäts-Experte hat QM-Systeme nach ISO und GxP für verschiedene Anwendungsbereiche aufgebaut, implementiert und aufrechterhalten. Das Kundendienstleistungsportfolio reicht von Herstellern klassischer und biologischer Medikamente über Medizinprodukteunternehmen und Impfstoffherstellern bis hin zu immunhistochemischen, immunologischen, molekularbiologischen und serologisch-diagnostischen Laboren. Dr. Hess ist weltweit als Auditor im GxP/ISO-Bereich tätig und hat langjährige Erfahrung in FDA Remediation Projekten sowie der regulatorischen Entwicklung von Kombinationsprodukten (Drug Device Products).
Dr. Ralf Hess unterstützt Entourage als Principal Management Consultant.

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