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GMP UPDATE 2022/2023 No36Issue 36 | Feb/Mar 2023The Ideal Mana-ged Access / Compassionate Use LegislationPharma Congress 2022Reusable wipe covers - GMP-compliant and process-safe Qualification and Validation ForumWith 5 pagesabout the latestGMP Updates!
2Publisher:CONCEPT HEIDELBERG GmbHRischerstraße 869123 HeidelbergHRB Mannheim Nr. 705125General Manager:Oliver SchmidtChief Editors:Oliver SchmidtWolfgang HeimesEditors:Dr Gerhard Becker Dr Robert EicherDr Markus FunkAnne Theresa GuensterDr Andrea Kuehn-HebeckerDr Andreas Mangel Sven Pommeranz Oliver Schmidt Wolfgang Schmitt Axel H. SchroederEditors of this Issue:ECA IMP Group Task Force Compassionate UseWolfgang SchmittDr Robert EicherMargarete Witt-MäckelSven PommeranzDr Andreas MangelRobert G. Schwarz Graphic Concept:Rebecca IlliProduction:abcdruck GmbHWaldhofer Straße 1969123 HeidelbergContact:info@gmp-compliance.orgAny reprints of text and images require specific pre-approval by the editorial office.Photo Credits:Cover/Page 4: iStock, ID: 973278302 S.10: iStock, ID: 1091863936 Page 15: iStock, ID:1170732764, Merck Page 19: Pfennig Reinigungstechnik GmbH, DurachPage 22: AdobeStock, ID: 77595184Page 27: iStock, ID: 1367696835Page 31: iStock, ID: 527883021 GMP Update 2022/2023For all employees working in the GMP area it is very important to always be in-formed about the current regulatory changes - especially, but not exclusively in the EU and USA (FDA).It is already a firm tradition that we publish an article about the GMP developments in the GMP Journal at the beginning of the year. And this year there are again impor-tant changes in the GMP environment:• The new EU veterinary medicines legislation in the EU.• Changes in the GMP Guidance Annex 1 and Annex 21• New guidelines from the FDA • Revision of ICH Q9 and Q13These are just some of the important changes all companies should be prepared for. You will find the detailed GMP Update and other interesting GMP articles in this issue.Enjoy reading!Oliver SchmidtEditoralContent44The Ideal Managed Access / Compassionate Use LegislationProposals to revise the legislation that currently governs the framework for the use of managed access concepts.10Cover story GMP Update 2022/20232022 saw a lot of new developments in the GMP environment. This article summarizes a few selected highlights. 15Pharma Congress 2022A recap of the Pharma Congress 2022, which took place on 31.5.-1.6. in Düsseldorf Neuss.19Reusable wipe covers - GMP-compliant and process-safe in useHow to maintain the specified cleanliness status of GMP cleanrooms.22ECA Qualification and Validation ForumA look back at the Qualification and Validation Forum in November 2022.27Questions and Answers to Cloud Computing in a GxP Environment - Part 2Nine experts from the pharmaceutical industry and regulatory authorities answer frequently asked questions on cloud computing.31Questions and Answers about Cleaning Validation - Part 2Speaker Robert G. Schwarz answers frequently asked questions about cleaning validation101519222731
3NEWS FROM OUR ASSOCIATION www.eca-foundation.orgEuropean QP AssociationBrenda Van Assche was winding down her responsibilities in the IMP Working Group after seven very successful years of excellent work. EQPA would like to extend their heartfelt thanks to Brenda for her outstanding service to the board and her energizing and inspiring contribution to the success of the organisation. The Com-mittee has taken the decision to appoint Katrien Himpens as Bren-da’s successor with the aim of maintaining the same spread of pharmaceutical company size. Katrien is Director Quality Assur-ance and Qualified Person JSC at Janssen, Pharmaceutical Compa-nies of Johnson and Johnson. Further details were shared during the Board Meeting on 02 Dec 2022. There also was a formal announcement at the IMP QP Pre-Conference to the 2022 QP Forum and a written announcement in the EQPA news after the Forum. Cheryl Chia was invited to join the EQPA Board of Directors. Cheryl is an independent consultant since 2019, providing advice and acting as QP if necessary to phar-maceutical companies that are developing their organisations in Europe. Cheryl was originally a hospital pharmacist in England and made the switch to Industrial Pharmacist when she moved to the Netherlands in 2002. There she worked for seven years at Organon N.V. in various roles and for ten years at Amgen Europe B.V. in var-ious roles including Production QA, QP and RP and Supply Chain. A Board Meeting was held on 02 December face to face in Berlin – with the following agenda:Open tasks from last Board Meeting incl. update to the QP Code of Practice/ EQPA Code of ConductFeedback for QP Forum 2022 and ideas for QP Forum 2023Update IMP Working GroupIWG interaction 2022 and outlook 2023 - alignment on gen-eral positionspossible political and other threats and their influence on application of GMP and whether this will need attention also by EQPAProjects: Chapter 4 and Annex 11 updateNew Professional Code of ConductDavid Cockburn, Georg Goestl, Ulrich Kissel have a finalised a doc-ument on Professional Code of Conduct (Ethics for the Qualified Person) which will become part of the current EQPA Code of Prac-tice for QPs as a new Chapter one. Publication will be done via mail-ings and video on the EQPA website, in Linkedin and in magazines.Survey on Annex 21After a rather long development phase, Annex 21 “Importation of medicinal products” was published in February 2022. It defines the different roles of manufacturers and QPs working with such manu-facturers involved in importation. Its transition period ended by 25 August 2022. With this survey sent out late in November, the EQPA wanted to learn more about the impact of this new guideline on QPs – e.g. which compliance gaps may have been identified and how successful they have been closed. That’s why the new survey particularly addresses responsibilities of QPs involved in importa-tion scenarios.QP ForumThe 17th QP Forum was held as a hybrid conference on 01/02 December. Delegates could choose whether to join live on-site in Berlin or live online on a screen.Two parallel Pre-Conference Sessions were preceding the Forum on 30 November: Investigational Medicinal Products and Quality Culture.The hybrid version of the Forum was very successful. About 350 delegates joined over the three days (approx. 2/3 on-site and 1/3 online). A five star rating was used - with five stars meaning very good and one star rather poor. The rating was very positive: The overall average rating of the pre-conference session on IMPs was 4.1 stars (result might have been influenced by the technical prob-lems online delegated were facing in the morning), the pre-confer-ence session on Quality Culture delegates rated with 4.2 stars. The overall average rating of day one of the QP Forum was 4.0 stars, day two was rated with 4.2 stars.Suggestion to amend Directive 2001/83/EC on Requirements for the Qualified PersonsDuring the GMDP Inspectors Working Group (IWG) meeting with Interested Parties, on 10 March 2022, the lack of harmonisation in the interpretation and transposition of the practical experience requirements for Qualified Persons (QPs) laid down in EU legisla-tion was discussed. A proposal was therefore made to harmonise approaches, for example through guidelines. Grasping that the underlying cause of the problem is the terminology used in the EU legislation (Dir 2001/83/EC), the Commission’s representative at the meeting invited the Interested Parties to submit a proposal directly to the European Commission in the context of the ongoing revision of the EU general pharmaceuticals legislation.The European Qualified Persons Association (EQPA), together with ECA Foundation (ECA) proposed to amend Directive 2001/83/EC on Requirements for the Qualified Persons.EU Commission DG SANTE Unit B4 will now make a proposal for the revision of article 49 taking into account the suggested changes!www.qp-association.eu In the following you can find again what the ECA’s Interest and Working Groups have been working on in the last third of 2022.Dr Afshin Hosseiny (Chairman ECA Foundation)continued on page 35
4BackgroundNumerous voices in the recent past phrased concerns about the complexity of the legal framework for Compassionate Use / Man-aged Access in the EU1,2,3. While authorities are aware of the situa-tion4, and initiatives are on the way, this appears not to be a priori-ty. Instead, we as pharmaceutical industry feel the need for change and harmonization. We see that some member states have a clear regulation; others have no regulation. At this point, patients across EU cannot con-sistently benefit from the idea of compassionate use. A clear regu-latory landscape for Pharma Companies (acting as or sponsors) is missing to allow providing such products under a standardized le-gal framework. For details regarding the experienced pain, we par-ticularly refer to our recent publication1. We, the author group, are Qualified Persons, concerned with the release of managed access medication. Our point of view is driven by GMP legislation; thus, we feel a broad overlap with the interests of our medical colleagues: We want to make unauthorized medicinal products available to patients that are suffering from life-threaten-ing, long-lasting or seriously debilitating illnesses, which cannot be treated satisfactorily with any currently authorised medicine5. Consider this paradigm be the basis for all conclusions drawn in this publication, even when not repeated.Thus, we also want to make sure that we are compliant with legal requirements. Moreover, we want to achieve the best possible as-surance for efficacy, safety, and quality of the unapproved products used in Managed Access Programs in line with their stage of devel-opment. The solution is further harmonization of the fragmented regulatory The Ideal Managed Access / Compassionate Use LegislationAbout the AuthorsThe ECA IMP Group Task Force Compassionate Use: Andreas Schwinn, Birgit Becker, Constantinos Kousoulos, Kerstin Thaele, Karoliina Nurminen, Lucia Dalvit, Pam Turner, Eveline Reininger, Scott Smith, Renate Steurer, Sara Taglialatela, Tine Wentzel Bekker
5landscape concerning Managed Access / Compassionate Use.In this paper, we want to propose the elements of an Ideal Managed Access Legislation from an Industry perspective. We want to com-bine the proven elements and best practices existing in the differ-ent member states into one new proposal. In the end, we want to achieve a revision of the Compassionate Use regulation given in Regulation 726/2004, Article 836. Encouraged by the recently completed harmonization on the legis-lation for Clinical Trials achieved with the applicability of the CTR7as of 31-Jan-2022, we want to call on to our legislators now to take care also of Managed Access / Compassionate Use.While we are primarily focussed on the EU, we suggest, that this could be of value also for PIC/S. We should note that all these con-cepts are already available in some members of PIC/S.What should be regulated?This publication will describe an industry view on what aspects of Managed Access should be regulated EU wide, defining• Accepted Compassionate Use / Managed Access types;• Interaction with authorities;• Documentation that should be submitted to authorities;• End of the program;• Manufacturing and Quality standards;• Some general Legal Framework aspects. Managed Access Concepts Regulation 726/2004, article 83, specifies the concept of compas-sionate use. This is a good start, thus, there are other widely established con-cepts across EU member states that we suggest to legally define EU wide. The list of generally accepted Access types should be:• Compassionate Use • Post-Trial Access• Named Patient AccessWhat are the differences?Compassionate usedescribes a program for a group of patients, suffering from life-threatening, long-lasting or seriously debilitat-ing illnesses, which cannot be treated satisfactorily with any cur-rently authorised medicine. Pharma companies provide unap-proved products under this concept. Typically, this requires approval of local Health authorities. Post-Trial Accessshall be a Compassionate Use Program building on existing and approved Clinical Trials. It should provide the op-tion to transition study participants straight into a follow-up pro-gram that ensures that patients stay on life-saving treatments.Currently we could supply trial medication past the end of trial if the protocol allows doing so. Thus, for multiple trials and countries, this comes with a regulatory and logistical complexity that creates highly artificial efforts. In addition, if the protocol does not foresee an open label extension that allows patients to stay on treatment, Post-Trial Access would solve the problem. With the concept of Post-Trial Access, as an alternative to the pro-gram for a group of patients, regulators could provide additional support for the pharmaceutical industry. Finally, a patient’s pros-pect of continued supply could speed up enrolment and thereby shorten development timelines.Named Patient Accessis an option to treat single patients. In con-trast to a program, the responsibility is solely with the medical doc-tor, whereas the Pharma Company would ‘only’ supply medication based on a specific request of the physician. The ‘only’ indicates the difficulties arising from this concept not be-ing consistently allowed or officially regulated in all member states. We as QPs are facing particular difficulties when requested to re-lease and confirm compliance for the use of a product batch in such context. What is supposed to be considered to certify medication for a Named Patient Access? We would appreciate a harmonized regulatory framework in which release concepts are reflected to define the minimum requirements to clarify certification/confirmation requirements for the QP. Qualified Person Education Course Module A PLUS IMP Pre-Course Session 26-28 April 2023 in Hamburg, Germanygmp-compliance.org
6All three concepts should be defined in the Regulation (EC) 726/2004. Named Patient Access and Post-Trial Access should therefore be added as an amendment.Health Authority InteractionAll Managed Access Scenarios should require a specific interaction with the pertinent Health Authority. Please see our proposal below:Compassionate Use Program for a group of patients• There should be a formalized submission by the Pharma Com-pany (see below for submission requirements) to a Health Au-thority8.• The program should be formally approved (or non-objection confirmed)Post-Trial Access• There has already been an approval for the Clinical Trials – or several ongoing Clinical Trials - that are to be continued under such concept.• Accordingly, the Health Authority interaction should be signifi-cantly easier than for a program for a group of patients.• We imagine a simple request mechanism where we refer to the study outcome and confirm a positive Risk-Benefit Ratio.• Accordingly, the approval mechanism should be simple as well - to allow patients to remain on treatment• Since Clinical Trials are approved centrally, imagine the bene-fits of doing so for a Post-Trial Access Program. The first step must be to have Post-Trial Access be allowed in all member states as per EU law.Named Patient Case• The common concept of the Doctor’s privilege allows the use of unauthorized products. Thus, there is a great variety in ap-proaches in member states regarding the submission and ap-proval for named patient access. We would expect a formal-ized notification by the Health Care Professional to a Health Authority or Ethics Committee. We do not expect a formal ap-proval, thus, evidence of receipt or at least the submission are helpful. Looking at the variety of different processes at mem-ber state authorities at this point in time, we tend to leave it to the member state to decide, which authorities are appropri-ate. To start with, the concept should be permitted in all mem-ber states by regulation.Submission Documentation RequirementsThe different scope of the three proposed access types, should be adequately accompanied by submission packages in line with the number of patients exposed and the corresponding potential risks of administering an unapproved product to patients.Compassionate Use Program• For a Compassionate Use Program, the submission should contain comprehensive Chemistry, Manufacturing and Con-trols (CMC) data. This can be achieved with an IMPD-type document, or more easily with a cross-reference to a Clinical Trial in the EU or a cross-reference to a submitted MAA. It should also be possible to submit an IND or a CMC dossier from another MRA country. • We propose the following documents, as evidence that these products fulfil basic Quality and GMP expectations, to be ob-ligatory components of such a submission:-Manufacturing and Import Authorization (MIA) /GMP cer-tificate of the importer/manufacturer, -QP declaration,-Product Label9.• Medical information: For an unapproved medicinal product, a clear focus should be on medical information: This should in-clude e.g. -Description of the medical condition, -Assessment that no other treatment options exist, -Risk-benefit assessment,-Patient inclusion criteria, -Treatment plan, -IB/Draft SmPC, -Informed consent, -Qualification requirements for Health Care Professionals (HCPs).Post-Trial Access• The concept of Post-Trial Access builds on existing Clinical Tri-als. • The submission requirements should accordingly be limited to a cross-reference to the existing trials in exchange to other CMC and Medical information, with one exception:• The core of this submission should be the justification to con-tinue treatment via an updated risk-benefit assessment taking into account the new study results10.• Note: Our expectation is that in a Post-Trial Access scenario, no substantial CMC changes occur in comparison to the trial that the application refers to.• Named Patient Access • Typically, submission requirements for a Named Patient Ac-cess are lower (if they exist at all).• Still, the documentation should contain the following:-Identification of the product(s): This sounds self-explanato-ry, thus, as these documents are typically not compiled by the Pharma Company, you would today be quite pleased if the product name, strength, and dosage form are provided correctly. An easy way to include a more precise product European GMPs and the Role of the Qualified Person (QP)Live Online Training11/12 July 2023The Impact of EU Legislation on the Supply ChainLearn more about this course:www.pharmalab-congress.com
7information, though indirect, would be by adding a cross-reference letter to a clinical study.-There should be a formalized requirement that Named Pa-tient Access medication is manufactured according to GMP and released under a MIA, and that systems need to be in place that assure the Quality of the unapproved product. However, we do not expect the submission package to in-clude a MIA or a QP declaration. • Medical information of such a submission should include:-Justification of Treatment, -Treatment plan, -A Statement that the HCP is solely responsible for the treatment of this patient.Approval TimelinesFor different reasons, it can take a significant amount of time be-tween when a patient is identified to be eligible for a Managed Ac-cess until he actually gets treated. An important factor are author-ity approval timelines. We recently observed that official approval timelines within EU member states vary between 1 and 60 days with upwards excursions1.Such period should be harmonized and limited to account for the high medical need. Accordingly, we propose the following approval periods • Compassionate Use Program for a group of patients: maximum 30 days• Post-Trial Access: maximum 30 days• Named Patient Access: No approval should be requiredAs stated above, and as a visionary outlook, we are drawing a men-tal picture where the landscape for Managed Access Legislation is completely harmonized within the EU and we apply centrally through an electronic portal.Amendments to CMC DocumentationInformation that we submitted might need to be amended when-ever there are substantial changes. This applies to Compassionate Use as well and should be stated by our envisioned new legislation. The existing guidance for Clinical Trials could be referred to.End of Program Commercial availability marks an endpoint as per Regulation 726/2004. Interestingly, this requirement was translated into national legisla-tion in different ways, so that the endpoint condition could either be the• Marketing Authorization Approval,• Commercial Availability,• Reimbursement.Commercial Availability might differ significantly between member states. Note: commercial availability refers to a specific member state. Availability in one member state should have no impact on the con-tinuation of Managed Access in another country. For some countries, reimbursement arrangements take years to be in place. Only with reimbursement, medication can be assumed not only as “commercially available”, but also “practically available” to patients.We do by no means intend to question the member states sover-eignty on Pricing and Market Access. Thus, the logical conclusion would be to generally allow the continuation of all three Managed Access concepts until Reimbursement is achieved. Note: Several member states allow to do Compassionate Use Pro-grams in an unapproved indication, in other countries it is specifi-cally forbidden. We tend to leave it to the law makers discretion how to decide here, but we expect a harmonized approach within the EU.Period of validity of an approvalMany national Managed Access concepts limit the approvals to a certain period of time or a certain amount of drug product. We understand that authorities have an interest to limit the dura-tion due to the implications of using an unapproved product. On the other hand, it is in the self-interest of the Pharma Company to finish Managed Access and to achieve Marketing Authorization ap-proval as quickly as possible11.A compromise would be, to limit the validity to one year, and estab-lish a simplified – e.g., one page – reapplication process.Another interesting question: What happens, if we do not reach a reimbursement agreement in a certain country? Logically, it should be allowed to continue treatment under Compassionate Use.The Free-of-charge paradigmCompassionate Use Medication should be free of charge from a moral and ethical standpoint and in the sense of the meaning “com-passionate”.In particular, Compassionate Use medication should be free of charge prior to Marketing Authorization Approval. Some member states extend the concept of Compassionate use af-ter Marketing Authorization approval and commercialization. Other countries instead, explicitly prohibit the dispensing of com-mercial medicinal products free of charge. In contrast to the above, in several member states, specific reim-bursement options for compassionate use exist that are independ-ent of a general reimbursement agreement after commercializa-tion. This facilitates access to medication for patients in urgent need, and member states may certainly do so. There should be a general agreement across industry that the con-cept of Compassionate Use is not meant to create additional reve-nue streams. On the other hand, there might be situations where a company might find it financially unreasonable or difficult, e.g., for a start-up company, to perform a compassionate use program.
8It might be difficult to find a compromise here. Our proposal is:Compassionate Use Medication should by default be free of charge and remain so until reimbursement agreements are reached. If ad-ditional reimbursement concepts exist for compassionate use on a national level, they benefit patients and industry and should be used. Development product may be supplied under a compassionate use label until commercial product is available. Commercial products may be used in their national make-up. If they are given away free-of charge, we propose an additional label “For Compassionate Use only!”. Labelling RequirementsA new Compassionate Use legislation should also include harmo-nized labelling requirements for Compassionate Use, Named Pa-tient Access, and Post-Trial Access. The important elements are:• Basic requirements, similar to CTR Annex VI, should be de-fined;• English is the preferential language to be used in a hospital setting;• For home administration, booklets should be the labelling of choice. They should contain languages rather than countries, as there is no predefined country list. Local special regulations, e.g., adding a program code that is com-municated via the program approval to the pharma company, should be avoided by all means. Such a requirement means that the labelling will not start until after program approval. Such regula-tions illustrate a complete disregard for industry supply logistics. We do certainly not assume the intent to delay or prevent treat-ment, thus, such a requirement might mean preventing treatment in many situations where compassionate use is typically applied. This again illustrates the urgent need for revising and harmonizing the Compassionate Use regulatory landscape.GMP complianceAs QPs, it is our job to assure product quality and GMP compliance for the products that go into Managed Access programs. However, we believe that this should be a prerequisite for every legally de-fined Access mechanism. Accordingly, we believe that the manufac-ture and import of Managed Access medication should occur under a MIA covering Managed Access / Compassionate Use and the re-quirement for certification by a QP should be stated in the law. There needs to be a Quality System in place to assure compliance, e.g.:• The respective Managed Access Mechanism must be ap-proved;• Each batch must be certified by a QP for this certain access mechanism;• Products have to match the information submitted to and ap-proved by the authorities;• In addition to QP release, there must be a second release step to assign the released stock to a certain patient. Distribution and ImportTo enable fast access to medication, distribution of medication un-der an approved Managed Access concept should not require addi-tional licenses for involved wholesalers, pharmacies, or HCPs. The new legislation should make provisions to allow distribution direct-ly to HCPs when they are not associated with hospital pharmacies.Import should happen under a MIA and involve QP Release.In some countries (e.g., Bulgaria, Ireland, Iceland, and Latvia1,12) compassionate use is based on importation via a wholesaler and we acknowledge the conflicting requirements and interests:The authors see the existence of a MIA and QP release as the basis to assure compliance to GMP and the necessary quality of a me-dicinal product. Some legislations put this obligation on the whole-saler who has to e.g., retrieve a certificate of release (Bulgaria12).Of course, a wholesale license is needed in addition to a MIA to al-low distribution of medicinal products. Requiring both, a MIA for the import and a wholesale license for the distribution, might be the possible compromise between the differ-Qualified Person Education Course Module B PLUS “Interpersonal and Soft Skills for the QP” 21-23 June 2023 in Hamburg, Germanygmp-compliance.org
9ent approaches. This discussion also shows how difficult it may be to navigate between the pitfalls of our current Compassionate Use legislation.Pharmacovigilance and ComplaintsThere must be systems in place to report and monitoring com-plaints and safety signals.Other ConsiderationsCompassionate use programs are published by the competent au-thorities and any form of advertisement should not be allowed. The concept of the “unsolicited request” from Health Care Providers should remain.In cases where an MAA was not granted this should not imply that Compassionate Use programs are to be stopped. Accordingly, if a company decides to withdraw an MAA due to not reaching a reim-bursement agreement, we suggest that a continuation of Compas-sionate Use Programs should be allowed. Concepts out of scopeWe want to make three known concepts of Managed Access to be included under the Compassionate Use umbrella and legally de-fined for the EU as a whole: The Program for a group of patients, Post-Trial Access, And Named Patient Access.We do not want to touch other existing Managed Access concepts that in some member states might be closely related to Compas-sionate Use. These concepts may remain legally defined in national legislation; thus, we did not want to propose them to be included in the EU’s harmonized Compassionate Use framework. Such con-cepts are therefor out of scope of this publication, e.g.:• Off-label use - prescribing a product to a patient in an unap-proved indication is in general legally possible in all member states. Thus, we do not see it as Managed Access. Testing a medicinal product in a new indication should be done in clini-cal trials.• Import of a product approved in another country by a public pharmacy based on a prescription. This is possible in many countries. In some countries, this is labelled Compassionate Use. The authors appreciate the value of the concept: It allows single patients access to medication that is already approved in another country, often the US, while the product is not yet approved in the EU. Thus, we do not see it as a desirable con-cept to organize compassionate use.• Managed Access Concepts that involve Compounding or Phar-macy operations, are considered out of scope as well.• Reimbursement and Market Access arrangements.ConclusionThis publication defines the cornerstones of what the author group considers the ideal of a future harmonized EU legislation. We do not have answers to all questions thus, we know that this already would be a big step forward. Accordingly, we want to herewith re-quest EU legislators to initiate the revision of the current legislation defined in regulation 726/2004, Article 83. And we want to make it clear that we believe that this call for har-monization is urgent!1 GMP Journal 22.11.2021: https://www.gmp-journal.com/current-articles/details/compassionate-use-and-other-managed-access-concepts.html2JAMA Health Forum 15.04.2022: https://jamanetwork.com/journals/jama-health-forum/fullarticle/27911973Regulatory Rapporteur, Sep 2020 (members only): https://www.topra.org/TOPRA/TOPRA_Member/REGRAP/Public/Regulatory_Rapporteur_Issue_Detail_Public.aspx?IssueID=533884&ID=572214HMA – Timely Access Group, 01/2020: https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/Timely_Access/2020_01_Timely_Access_SG_Mapping_of_national_frameworks_for_Eap_16_01.pdf5 As per the purpose of Compassionate use defined by the EMA under https://www.ema.europa.eu/en/human-regulatory/research-development/compassionate-usehttps://www.ema.europa.eu/en/human-regulatory/research-development/compassionate-use6REGULATION (EC) No 726/2004 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency.7REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC.8We do not want to be too bold and request a centralized submission and approval within the EU, knowing that it took twenty years to achieve this for Clinical Trials from Clinical Trial Directive 2001/20/EC to CTR 536/2014 becoming applicable on 31_Jan-2022. 9If the proposed new legislation would provide an EU wide definition of such label text, the requirement of this to be filed could be reconsidered. National peculiarities, like adding the program number from that is pro-vided with the approval must be eliminated. CTR, Annex VI requirements are a good start, thus, do not fully match. It would also be beneficial, if a general acceptance would exist, that an English label text is sufficient for a hospital setting.10As a vision, we imagine Post-Trial Access being an amendment to the respective Clinical Trials – thus, for the moment we settle for it being a legitimate EU wide concept. 11Please be aware that there are also access concepts in EU member states where products are used for years without the potential MA holder even aiming for approval. We want to note, that we do not consider this as Compassionate Use and outside the scope of this publication.12Regulatory Requirements for Managed Access in Europe, collected by the Managed Access Taskforce of the EQPA, https://www.qp-association.eu/download_imp%2FCompassionate-Use-Landscape-Jan2021.xlsxGMP and Quality Requirements for Radiopharmaceuticals Vienna, Austria13/14 June 2023Development of radiopharmaceutical regu-lations and experiences in inspections.Learn more about this course:www.gmp-compliance.org
102022 saw a lot of new developments in the GMP environment. The following article summarizes a few selected highlights. New veterinary medicines legislationRegulation 2019/6, commonly known as the new veterinary regu-lation ("NVR"), governs the authorization, use and supervision of veterinary medicinal products in the European Union. The legisla-tion entered into force on January 28, 2019, and has been applied in all EU member states since January 28, 2022. The aim was to de-velop a fit-for-purpose veterinary medicines legislation that is no longer based on the corresponding requirements for human medi-cines.As an EU regulation, the EU Veterinary Medicinal Products Regula-tion (Regulation (EU) 2019/6) applies directly in the member states and replaces the previously applicable Veterinary Medicinal Prod-ucts Directive 2001/82/EC. In this context, the European Medicines Agency (EMA) has adapted the answers to frequently asked questions on Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP)1on its web-site. The new chapter deals with requirements for active substanc-es used as starting materials for the manufacture of veterinary medicinal products.EU-GMPAnnex 1After more than five years and two public drafts for comment, the European Commission published the final version of the new An-nex 1 to the EU GMP Guidelines in August 2022. The new Annex 1, entitled "Manufacture of Sterile Medicinal Products", will enter into force on August 25, 2023, one year after publication in Eudralex Volume 4. Only with regard to Chapter 8.123 "Product transfer / loading/unloading areas for freeze dryers", the deadline is two years and ends on August 25, 2024.GMP Update 2022/2023About the AuthorWolfgang Schmittis Vice President at CONCEPT HEIDELBERG and organises and conducts courses and conferences on behalf of the ECA Academy in the areas QA and GMP. He is also Administration Manager of the European QP Association.
11Which changes/additions compared to the second draft version of 2020 are obvious?Annex 1 has become even more extensive. The number of pages has increased from 52 to 58.In addition to the increased importance of Quality Risk Manage-ment(QRM) and the discussion of Pre-Use, Post-Sterilization In-tegrity Testing (PUPSIT) of filters, it is particularly striking that for the first time, an overarching recording and coordinated manage-ment of contamination control measures is required, called "Con-tamination Control Strategy" (CCS) in the draft. The CCS is intend-ed to link various measures such as personnel hygiene, clothing specifications, cleaning and disinfection processes, environmental monitoring and ventilation technology.Furthermore, there are a few deletions in addition to rewordings in many chapters.Annex 21The final version of Annex 21 to the EU GMP Guidelines ("Importa-tion of medicinal products") was published in EudraLex Vol. 4 in February2. The new annex has been valid since August 21, 2022.Besides editorial changes and adaptations to Annex 16, there were a few important additions and clarifications:• Clinical investigational medicinal products are now explicitly included. Advanced Therapeutic Medicinal Products (ATMPs) and medicinal products that do not have a marketing authori-zation in the EU / EEA and are directly re-exported were not included. • "Fiscal transactions" (physical retention of the product in the EU but change of ownership to a third country and vice versa) remain explicitly excluded.• Full batch documentation must be available to the MIA holder responsible for QP certification or confirmation of the batch, as appropriate, at the time of certification or confirmation of the batch. • QP certification or confirmation of the batch now also requires a packing list, shipping documents or an import customs dec-laration. The certification of a batch can therefore only take place after the physical import and customs clearance.Guidance on quality and specifications for herbal medicinal productsThe European Medicines Agency (EMA) has published final guide-lines (Revision 3) on quality and specifications for herbal medicinal products (HMPs). Among other things, a written GACP confirma-tion for the herbal starting material is to be submitted. In addition, the EMA's Committee on Herbal Medicinal Products (HMPC) re-cently published a concept paper on revising the GACP guidance. The deadline for comments was June 1, 2022.Remote CertificationIn May, the EMA opened a brief, one-month public consultation on a draft question and answer document on remote batch release (remote certification) by the Qualified Person (QP): "Public Consul-tation concerning the Physical Attendance and the Location of Person-al Residency of The Qualified Person" (EMA/INS/169000/2022).Questions to be clarified here are:• Is remote batch certification by the QP routinely permitted?• What conditions should apply?• Does the QP need to be located in the Member State where the approved site is located?• What are the technical requirements for remote access and signature?Nitrosamine impurities: further update of EMA's question-and-answer documentThe question-answer document developed by EMA and CMDh is updated at irregular intervals to reflect the latest knowledge. On October 12, 2022, the EMA published a new update of the Q&A document "Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products"3on its "What's new" website - the 14th revision. New issues discussed are current limits and novel nitrosa-mine impurities.Clinical investigational medicinal productsValidity of the Clinical Trials RegulationOn January 31, 2022, the Clinical Trials Regulation 536/2014 (CTR) became applicable for the first time. For clinical trials in Europe, there were thus some significant changes with regard to the pro-cesses and procedures for authorizing, conducting and terminating clinical trials. A total transition period of three years is now ongo-ing, during which both the contents of the CTR and the current legislation for clinical trials apply.In parallel, the European Commission has published an updated version of the draft Questions and Answers (Q&As) to the Clinical Trials Regulation (EU) No. 536/2014 (CTR). However, certain sec-tions of the Q&A document are not yet complete and updated ver-sions of the Q&As will be published gradually4.Final EMA Guidance on Quality Requirements for IMPsThe final EMA Guidelines (Rev. 2) on Quality Requirements for In-vestigational Medicinal Products ("IMPs") have been published on the EMA website, together with an overview of comments received on the draft guidelines published last year5. The coming-into-force date has been set for January 31, 2022, same as for Regulation (EU) No. 536/2014 on clinical trials (CTR).According to the EMA, a clear distinction should be made between the requirements for an investigational medicinal product dossier ("IMPD") for a clinical trial ("CT") and for a marketing authorization dossier. For further information, please refer to the two EMA Guidelines (Rev. 2) on chemical and pharmaceutical quality docu-mentation requirements for investigational medicinal products6and on quality documentation requirements for investigational bi-ological products7.
12News from the FDANew Guidance on Out-of-Specification (OOS) FindingsIn May 2022, the U.S. Food and Drug Administration (FDA) released a new version (Revision 1) of its Guidance for Industry titled "Inves-tigating Out-of-Specification (OOS) Test Results for Pharmaceuti-cal Production"8. The original version of the document was issued nearly 16 years earlier, in October 2006.Compared to the 2006 version, the following adjustments were made, among others:• Editorial changes.• The term "quality control unit (QCU)" was replaced by "quality unit (QU)".• Addition or updating of references in the main text and foot-notes to refer to the latest version of other relevant guidance, USP chapters, CFR paragraphs, etc.• Additions to "Outlier Tests" and "Averaging results from same final sample preparation".New Guidance on RecallsFDA has finalized its guidance on voluntary recalls to assist indus-try in promptly initiating recalls of defective products ("Initiation of Voluntary Recalls Under 21 CFR Part 7, Subpart C")9. The guidance applies to voluntary recalls of food, drugs, medical devices, cos-metics, biological, and tobacco products. The agency has made only minor changes from the draft version published in April 2019.The document includes recommendations in the following three key areas:• Proper training of personnel• Record keeping• Written procedures for initiating recallsHow many FDA inspections are still taking place in Germany?Since July 2019, the MRA (Mutual Recognition Agreement) between the EU and the FDA has been fully in force. One of the main goals was to mutually recognize each other's GMP inspection systems and reduce the number of mutual inspections.But has the number of FDA inspections actually decreased? A very good source is provided by the FDA Data Dashboard10. This detailed overview of FDA activities performed provides easy-to-use and un-derstandable tables and graphs for comprehensive analysis.According to the dashboard, for example, ten "drug quality assur-ance" inspections of German companies were completed in 2021 alone - despite the pandemic and MRA. And pre-approval inspec-tions aren't even listed here. The year before (2020), there were 27, and in 2019 there were 68. No warning letters were issued in this regard.In addition to on-site inspections, FDA has also conducted so-called "Remote Interactive Evaluations" (RIE). While these remote evaluations do not meet the legal definition of an inspection, ac-cording to FDA, and effectively serve only as a supplement to an inspection, a Warning Letter was issued in early 2022 to a firm in Poland11. And this happened after a purely remote inspection. In fact, according to the FDA Dashboard, no on-site inspection has ever been conducted there. The company manufactures over-the-counter drug products (OTC) and distributes a homeopathic cream in the USA. FDA reviewed documents submitted in response to a June 2021 agency request as part of the remote assessment de-scribed in the warning letter.FDA expands remote assessments - even after the pandemicThe FDA wants to use Remote Regulatory Assessments (RRAs) not only during the COVID-19 pandemic, but also beyond it to evaluate sites and regulatory applications and has published a Draft Guid-ance for Industry "Conducting Remote Regulatory Assessments - Questions and Answers"12.FDA has also updated two Compliance Program Guides (CPGs) on GMP inspections13. CPGs are primarily for FDA staff and assist them in evaluating and enforcing regulations for industry. Many details and interpretations found there that are not covered by existing FDA laws, regulations or guidances. Chapter 46 - New Drug Evalua-tion addresses pre-approval inspections (PAIs) and Chapter 56 - The GMP-Auditor14-16 June 2023 in Copenhagen, Denmarkgmp-compliance.org
13Drug Quality Assurance addresses routine surveillance inspections.FDA plans evaluation system for companiesFDA's CDER continues to work on its vision for 21st century phar-maceutical quality and supply chain assurance. To that end, it has produced a white paper titled "Quality Management Maturity (QMM): Essential for Stable U.S. Supply Chains of Quality Pharma-ceuticals."14In principle, this paper deals with ways of objectively assessing the "quality management maturity" of pharmaceutical production sites. A central aspect of this is a so-called "QMM Rat-ing System", a program for evaluating and rating the QMM of pro-duction sites using monitoring data and the participation of the companies.Central elements of the program are:• Quality Culture as a basis with common business and quality objectives.• Objectivity of the QMM assessment tool• Incentives for the industry• TransparencyDraft Guidance on Computer Software Assurance (CSA)In September 2022, FDA published the draft Guidance for Industry "Computer Software Assurance for Production and Quality System Software"15. The comment period already ended on November 14, 2022. According to FDA, the document will describe "Computer Software Assurance" as a risk-based approach in the course of ad-vancing automation in production or quality systems. When final-ized, this Guidance for Industry will complement the FDA Guidance "General Principles of Software Validation." The section on "Valida-tion of Automated Process Equipment and Quality System Soft-ware" will be replaced.News from ICHDraft revision of ICH Q9 Quality Risk Management Guideline published in 2022With 33 pages, the draft was significantly more extensive than the previous version with 19 pages16. However, this is due to the fact that each line is numbered for better commenting and the line spacing has thus become larger. However, there are also new pas-sages. This is partly reflected in the table of contents, which con-tains new elements in the form of subchapters 5.1 Formalities in quality risk management and 5.2 Risk-based decision making and II.9 Quality risk management as part of supply chain control/man-agement.The most extensive changes are also pointed out in the introduc-tion. For example, the issue of "subjectivity" is addressed in the context of risk management activities and the resulting decisions. Furthermore, appropriate risk-based decision-making during the product lifecycle and formality aspects related to quality risk man-agement are addressed in the introduction. Then, on June 14, 2022, FDA also published the draft document as "Draft Guidance for Industry" on its website. Comments could be submitted online or in writing to the FDA. In the meantime, the revision (R1) was published on the ICH website.ICH Q13: Guideline on Continuous ProductionAs early as 2018, ICH had begun work on a Guideline entitled "Con-tinuous Manufacturing of Drug Substances and Drug Products," which describes the requirements for the continuous manufactur-ing of medicinal products. A draft was published in mid-2021. In 2022, ICH adopted the final version17.Guideline ICH Q13 describes scientific and regulatory considera-tions for the development, implementation, operation, and life cy-cle management of continuous manufacturing. ICH Q13 is applica-ble to the manufacture of active pharmaceutical ingredients and drug products (small and large molecules). It applies to new prod-ucts (e.g., new drugs, generics, biosimilars) and the conversion of conventional batch manufacturing to continuous manufacturing for existing products. Aspects of development, GMP and regulatory affairs are addressed.News from the PIC/SAnnex 1 (Manufacture of Sterile Medicinal Products)Almost simultaneously with the EU Commission, the PIC/S (Phar-maceutical Inspection Co-operation Scheme) also published the revised Annex 1, which is identical to the new Annex 1 of the EU GMP Guideline, with the exception of a few minor corrections in the wording.The PIC/S has also adopted EU-GMP Annex 16 (Certification by a Competent Person and Batch Release) and refers to it as "Certifica-tion by the Authorised Person and Batch Release". Previously, PIC/S had not adopted EU Annex 16, even in an adapted form. Initially, PIC/S felt that the Annex was too EU-specific and difficult to implement for PIC/S purposes. However, after a consul-tation with the participating PIC/S authorities in 2017, it was then decided to proceed with an implementation of EU Annex 16. The background was also the international harmonization efforts. The Annex was adopted by the PIC/S Committee on January 26, 2022 (together with an adapted Annex 13 for investigational me-dicinal products) and entered into force on February 1, 2022. All authorities in the PIC/S (outside the EU and EEA) were encouraged to adopt the annexes into their own GMP guidance documents. It will be interesting to see how these authorities (which include, for Quality OversightLive Online Training16/17 May 2023Supervision of the Pharmaceutical Quality System: Challenges and OpportunitiesLearn more about this course:www.gmp-compliance.org
14example, the US FDA) approach possible implementation.OutlookThe EMA has published a three-year plan18. A large part of the IWG's work plan is derived from the experience with nitrosamine con-tamination issues ("Nitrosamines Lessons Learnt Exercise" - LLE) and includes plans to revise the EU GMP guidelines:Chapter 1 (Pharmaceutical Quality System)Submit final text for the revised chapter to the European Commis-sion to encourage industry to adopt risk-based approaches to pre-vent shortages, taking into account initiatives such as the HMA-EMA Taskforce and industry inter-association guidance.Chapter 4 (Documentation) and Annex 11 (Computerized Systems)Submit final texts for the amended chapter and annex to the Euro-pean Commission to ensure data integrity related to GMP.Then on November 16, 2022, EMA published a 5-page "Concept-Paper on the revision of Annex 11 of the guidelines on Good Manu-facturing Practice for medicinal products - Computerised Systems" (comment period until January 16, 2023)19. This is not yet a new draft, that should probably come in 2025. In 33 points, based on the structure and chapters of the existing Annex 11, new points to be included and topics to be updated are presented.Annex 4 (Manufacture of Veterinary Medicinal Products other than Immunological Veterinary Medicinal Products)Review comments received during stakeholder consultation on the concept paper and draft updated text. Annex 15 (Qualification and Validation)Review the Annex in light of new technologies in facilities, prod-ucts, and processes and consider whether updates are needed. Also reviewing whether the scope can be expanded to include APIs.Annex 16 (Qualified Person Certification and Batch Release)Following the LLE recommendations, consider revising the Annex to provide additional guidance on batch traceability.GMP and Marketing Authorization HoldersRevise paper in line with LLE recommendations to align guidance for MAHs regarding appropriate quality agreement with manufac-turers.1 https://www.ema.europa.eu/en/human-regulatory/research-development/compliance/good-manufacturing-practice/guidance-good-manufacturing-practice-good-distribution-practice-questions-answers#requirements-for-active-substances-used-as-starting-materials-in-ve2https://ec.europa.eu/health/system/files/2022-02/vol4_annex21_en.pdf3https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-questions-answers-marketing-authorisation-holders/applicants-chmp-opinion-article-53-regulation-ec-no-726/2004-referral-nitrosamine-impurities-human-medicinal-products_en.pdf4https://ec.europa.eu/health/system/files/2022-02/regulation5362014_qa_en_1.pdf5 https://www.ema.europa.eu/en/requirements-quality-documentation-concerning-biological-investigational-medicinal-products-clinical6https://www.ema.europa.eu/en/requirements-chemical-pharmaceutical-quality-documentation-concerning-investigational-medicinal7https://www.ema.europa.eu/en/requirements-quality-documentation-concerning-biological-investigational-medicinal-products-clinical8https://www.gmp-compliance.org/gmp-news/fda-updates-guidance-on-investigating-out-of-specification-oos-test-results-for-pharmaceutical-production9https://www.fda.gov/media/123664/download10https://datadashboard.fda.gov/ora/cd/inspections.htm11https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/dr-retter-ec-wladyslaw-retter-619881-0314202212https://www.fda.gov/media/160173/download13https://www.gmp-compliance.org/gmp-news/fda-new-inspection-guidance14https://www.fda.gov/media/157432/download15https://www.fda.gov/regulatory-information/search-fda-guidance-documents/computer-software-assurance-production-and-quality-system-software16https://www.gmp-compliance.org/gmp-news/draft-revision-of-ich-q9-quality-risk-management-guideline-published17https://database.ich.org/sites/default/files/ICH_Q13_Step4_Guideline_2022_1116.pdf18https://www.ema.europa.eu/en/documents/work-programme/work-plan-good-manufacturing-practice/good-distribution-practice-inspectors-working-group-2021-2023_en.pdf19https://www.gmp-compliance.org/gmp-news/revision-of-the-eu-gmp-guide-annex-11-computerised-systems-presentation-of-concept-paperGMP Forum 20 – 21 June 2023 GDP Forum21 – 22 June 2023Barcelona, Spainwww.gmp-conference.org
15After two long "pandemic years", the Pharma Congress Manufac-turing & Technology finally took place on site again in Düsseldorf Neuss on 31.5.-1.6. A total of 705 participants, 55 speakers and 71 exhibitors had come together to exchange ideas. One major change before the congress moves to Wiesbaden next year has already taken place. For the first time in 2022, the Pharma Congress was 100% international, i.e. all conferences were held in English.However, in the conference "Facility and Technology Projects", the former "Pharmatechnik-Konferenz" (German; Pharma Technology Conference), everything still revolved around investment projects, i.e. construction and conversion projects of recent years. Thomas Zlabingerkicked things off by reporting on Boehringer In-gelheim's Large Scale Cell Culture (LSCC) project in Vienna. In his role as validation manager, he was responsible for the execution of all related commissioning and qualification activities. A total of five new buildings were constructed as part of the impressive €700 million project: the LSCC Main Building, a Biopharma Logistics Center, a Quality Building, a Power Supply Building, and a Fire Sta-tion. Mr. Zlabinger called it the "new landmark of Vienna." In total, more than 40 individual building permits had to be issued by the authorities, digging at the site accounted for 6900 truckloads and 10 tower cranes were required. A challenging aspect of the project were the three rail tunnels that run under the new buildings and the vibrations this created, which had to be taken into account during all phases of the project.The new logistics center includes several storage areas. The 20 °C high-bay warehouse offers 4000 pallet spaces, cold storage at +2/+8 °C with 450 spaces, and underground deep-freeze ware-houses for -20 °C and -70 °C with 300 and 50 pallet spaces, respec-tively. Sampling and weighing is carried out in ISO classes 8 and 7.The building for the quality unit (QA and QC) has a floor area of 2000 sqm and a usable floor area of 13,000 sqm including a terrace on the 2nd floor. The quality building required attention to two of Pharma Congress 2022About the AuthorDr Robert Eicher is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy around pharma tech-nology.
16the railroad tunnels at once, one directly under the building, and one running along the side.The LSCC main building is a Biopharmaceutical Multiproduct Facil-ity and is served by the Boehringer Ingelheim Launch Plant in Bib-erach. There are 2x80 L, 4x 400 L, 4x 2000 as well as 6x 15,000 L fermenters available as well as space for others. Mr. Zlabinger mentioned the many utility systems needed for GMP production. For media and utilities alone, 60 km of piping were laid. Two 20 m3/h PW generators and two 7 m3/h WFI generators are available for water supply. The cleanroom classes of the total of 414 cleanrooms include CNC (Controlled, not classified), ISO 8 (D) and ISO 7 (C). An elevator in the building in cleanroom class ISO 8 is also in use. For the main building, 4 ventilation systems are in use, two in the basement and two on the top floor. Mr. Zlabinger also discussed the qualification of the premises. The sequence was established: IQ, OQ (technical), basic cleaning, OQ (classification) and PQ. A complicating factor was that the global Boehringer Ingelheim guidelines for cleanroom qualification changed during the project. According to Thomas Zlabinger, in order to keep the extra work under control, it was pos-sible to use the HeRo software, which he had programmed himself. As a result, efficiency in the creation of planning documents in-creased by 77%, and in the creation of reports by as much as 97%. Transition monitoring could also be avoided, resulting in a saving of about 33% of microbiological samples.In their joint presentation, Dr Daniel Minör (Senior Manager Produc-tion at IDT Biologika) and Dirk Steinhäuser (Glatt Ingenieurtechnik) reported on the new vaccine production at a facility in Dessau. The initial situation was the increase in demand for viral vaccines. The goal was to build a flexible multipurpose facility for the production of recombinant live viral vaccines and gene therapeutics, which would be established in less than four years (until the manufactur-ing license was obtained). It was clear from the outset that there would be increased reliance on single-use technology, both down-stream and upstream.The project was implemented as a fast track project. Time in con-struction could be saved by using precast concrete elements and by simultaneous construction and commissioning activities on dif-ferent sides of the building. The required flexibility was achieved by means of four flexible production units in a house-in-house con-cept. The cleanroom zones of the four areas can be flexibly changed from CNC to C to B.Ultimately, a time for construction and commissioning of 20 months was achieved, the total time was only 24 months with an investment sum of 23 million euros. The new production building for manufacturing under Biosafety Level 2 (BSL2) contains approx-imately 900 m2 of class B and C cleanrooms. Interestingly, a Class D was omitted, and entry to C is directly from the CNC area. The authority had no problems with this, according to Dr Minör. How-ever, the introduction of a class D is also possible without any problems. What was difficult, due to Covid, was the delivery time for the single-use production equipment, Dr Minör concluded. But that, too, was successfully resolved.CSL Behring's "Brownfield Project" in Marburg was also about ex-panding capacity. In this case, an expansion of the freeze-drying capacity, because the 10-year forecast had indicated a bottleneck in 5 years. Also, a utilization of the production capacities of more than 80% was to be avoided, including the times for shutdown or maintenance. Matthias Klein(member of the Site Operations Lead-ership Team) and Steffen Mörler(Deputy Director Project Excel-lence) were the speakers. Matthias Klein opened his presentation by saying that there were a total of four options for responding to the forecast bottleneck. Weighed against each other were a new building, the use of external suppliers, a "do nothing" option, and the aforementioned brownfield project planning, i.e., a capacity ex-pansion at the Marburg site, which was ultimately chosen. In addi-tion to cost and time, the use of the already existing modern filling lines was also a crucial factor in the implementation of the project in Marburg.The goals were fully automatic loading of the freeze dryer, approv-al in the EU and USA, and one bulk batch per load at approx. 500L drying capacity. According to Matthias Klein, it was also important to avoid shutdown periods in order to be able to continue produc-tion in the building. Difficult, because the new space is in the mid-dle of the 3rd floor of the production building that is in operation. Also, the accuracy of the existing building plans was not known which was problematic given the simultaneous space constraints of this remodeling project. This was solved by laser scanning the building and creating a 3D model, explained Steffen Mörler. In this way, collision checks could be carried out, which prevented prob-lems when bringing in the new freeze dryers, for example. These were brought in through an opening in the building from the out-side. This could be accomplished in one day, as could the removal of interfering ventilation ducts. Another key point that contributed to the success of the project, both speakers agreed, was the early involvement of operational production staff in the project. They were involved from layout planning to mock-up, which meant that no design changes were required after the detailed design. The pro-ject was successfully completed as planned after 32 months and seven PPQ batches.Dr Markus Weigandt, Executive Director Pharmaceutical Technolo-gies at Merck, began his presentation with Merck's pipeline. Phas-es 1-3 include oncology, immunology, neurology and other drugs - sterile as well as solid forms. And this is constantly changing, Dr Weigandt said. So it's difficult to predict what production technol-ogies will be needed in five years. But for the task of setting up a modular GMP facility for clinical trials, this is definitely important. The need for isolators to be able to manufacture the OEB 3/4 and 5 products in the pipeline was foreseeable. In addition, future tech-nologies such as continuous manufacturing and paperless produc-tion should also be taken into account, as well as space for QC analyses. A crucial question needed to be answered: would all this fit on the 4th floor of the development building already erected in 2012 at the Darmstadt site? The 1200 m2 available are also sepa-rated by a firewall and contain two building cores with staircases, only one of which has so far provided GMP access.The answer is "yes, it fits". A ballroom concept continued to be weighed against dedicated rooms per unit operation. The disad-vantage of the dedicated suites is of course the lost space, due to the airlocks needed per suite. However, the ballroom's disadvan-tage of not being able to use the rest of the room when using a manufacturing unit then outweighed this, so Merck decided on
17four separate production suites. Three suites for the production of solid forms (called Solar Suits) and one suite for the production of parenterals (Lunar) were built. The expansion was carried out in partial steps, but access was always from the outside of the build-ing. In the first step, the production suites Solar 1 (coated tablets) and Solar 2 (for new technologies) were built. The Lunar Suite for parenterals was started about one year later, and Solar 3 (conti) and Solar 4 (melt extrusion) were started in a common suite even before the PQ of the other suites. The Solar units are connected by a central Clean Corridor. Media Supply and Engineering sit above clinical production on floors 5 and 6. Merck chose Class C for the isolator environment in the Lunar Suite. Flexibility is a key aspect in development and clinical sample man-ufacturing. Thus, 12 different manufacturing paths for coated tab-lets are possible in Solar (sieving, granulating, mixing, tableting, coating). Granulation is possible by fluid bed or dry granulation. It is already quite full, added Dr Weigandt, but there is still room, for isolators, for example. The production of highly active drugs is de-signed for OEB 5. This is made possible by completely closed sys-tems during production and transfer until decontamination. The secondary containment is the room which is operated in negative pressure. Exhaust air is cleaned via H14 filters.Qualification was based on four separate pillars: cleanroom, venti-lation system, cleanroom monitoring system and process equip-ment.Sustainability was also important in this project for Merck, as it was for Dr Weigandt. For example, the CO2footprint was kept low by integrating the new clinic manufacturing into the existing build-ing. Also, future routes for production transfers are short. Develop-ment and GMP clinic sample production sit in the same building, Commercial Manufacturing is across the street.Boehringer Ingelheim's presentation focused on the construction of a new launch facility for solid dosage forms. The speakers Volker Glück(Boehringer Ingelheim) and Ilka Rudzio-von Arx(Pharmaplan) jointly presented the 90 million investment project. The starting point for Boehringer Ingelheim was the need for a global launch site. The Solids Launch Facility (SOL for short) was realized with an area of 3200 m2 and two production lines (A and B) in Ingelheim. Production is on the first floor. A mezzanine floor contains the me-dia distribution, and the ventilation systems and offices are located on the upper floor. The exhaust air unit sits on the roof to save space in the technical area for later installations.Production line B is designed for small-scale production of highly potent drugs in OEB4, i.e. 1-10 µg. Isolators (weighing, IPC, tablet-ing) as well as closed containers and systems with e.g. butterfly valves serve as primary containment. Class D rooms form the sec-ondary containment with positive pressure in the airlocks (+) and the surrounding corridor (++). Process and wash water from the WIP systems is collected and directed to separate tanks for non-contaminated and contaminated water.Digitalization was also important for the SOL project. In addition to an MES, a Room Information Systems (RIM) and a Media Informa-tion System are in use. With the system developed by Boehringer Ingelheim, the room signage has gone digital and is connected to the MES. The logbooks are also digital, as is a training system (called "Virtual Helmut").In terms of sustainability, the two speakers cited the ramping down of air exchange rates during non-production periods, heat recovery systems, and local sourcing of equipment whenever possible. It's worth mentioning that Ingelheim is a wine region, so wine tanks from local suppliers are in use for water disposal.John Honey(Head of Engineering) and Alois Probst(Project Engi-neer) from Roche in Penzberg spoke of project work at a particular speed. The driving force was the Covid pandemic and the greatly increased demand for Roche as a supplier of PCR tests. Short-term measures such as shift work, seven-day weeks and overtime were not enough to cope with the situation. In order to make the neces-sary contribution in the fight against the pandemic, more than 20 projects were started per year and more than 60 projects were pro-cessed simultaneously with an annual CAPEX of 200 million euros. John Honey and Alois Probst explained the EMGP2P project as an example. This is the expansion project for the production of mag-netic glass particles (MGP), which are required for PCR tests and are produced exclusively in Penzberg. Time was of the essence, emphasized John Honey. The goal was to complete the project as quickly as possible and in less than a year. It was clear, added John Honey, that this would not work with the classic "milestone" ap-proach. There was no time for a new building, so a suitable space within the site had to be found for the expansion. Project approvals also ran tremendously fast. For example, Friday funding requests were ap-proved as early as Monday, a process that can otherwise take weeks. Ultimately, two factors led to success: the project strategy and the project team, meaning communication and mindset.Parts and equipment with long delivery times were ordered early and at risk, often based only on preliminary planning. Orders were often placed when specifications were only 90% finalized. For ex-ample, HVAC equipment was ordered in a design that was clear it would not fit. Adjustments to the planning were not addressed un-til after the order was placed. Suppliers were thus brought on board as early as possible, and penalties for late delivery were of-ten not formulated. However, due to the importance of the "pan-demic" projects, resources were diverted from other Roche pro-jects. Overall, the speed added about 15% to costs. The planning phase or meetings were purely virtual. Also, no un-necessary meetings were held. For example, there was only a short daily meeting, with additional meetings only when needed. Project documentation was available to the team on a cloud-based sys-tem. The open error culture was important. It was clear to manage-ment as well as the team that some decisions could be wrong. What was important then was the fix not the finger pointing. The key was to keep the team motivated by the one, common goal: we were fighting the pandemic. We wanted a productive plant, not a perfect one, John Honey explains. The pandemic has changed the way we work.Outlook for 2023: On March 28-29, 2023, the congress will be held for the first time at the Congress Center in Wiesbaden.
#sharing challenges and solutions in practice28/29 March 2023, RheinMain CongressCenter Wiesbaden• Europe´s largest Congress of its kind celebrates its 25th Anniversary!• Over 80 Speakers from Pharmaceutical Industry and Regulators – over 100 Exhibitors from leading PharmTech companies• 7 Conference Tracks:European Aseptic ConferencePUPSIT: Complying with the Main Annex 1 ChangesNew Developments in Barrier Systems & RoboticsGMP for Pre-Filled Syringes (PFS)Image: MerckSupported byPharma 4.0 & DigitalisationHandling of Highly Active Products ATMP – Manufacturing, Quality & Safetypharma-congress.com
19Wipe covers are used for manual cleaning and disinfection of larger room surfaces (floor, wall, wall elements, outer surfaces of equip-ment, ceiling, etc.). Cleaning and disinfection of these surfaces re-moves contaminants that can negatively affect the quality of the products manufactured in the room as well as the processes taking place there, and maintains the specified cleanliness status of GMP cleanrooms. The "cleaning" and "disinfection" measures are thus processes which impact the quality and therefore an important part of the contamination control strategy. However, the cleaning and disinfection measures can also lead to contamination risks if not carried out properly. Therefore, it is necessary that the cleaning and disinfection measures are not only systematically planned, but also implemented in a practical manner and tested for their effi-ciency. It must also be ensured that the individual components are coordinated as well as suitable for the respective process in the respective cleanroom, that the personnel is trained, and that all necessary documents for implementation and verification are available. If operating equipment and disposables are used several times and reprocessed for this purpose, the suitability and fitness of these agents and materials must be ensured over the entire pe-riod of use. In particular, the high levels of contamination in the washing and sterilization processes and through use must be eval-uated.Process description: Cleaning and disinfecting by wipingCleaning is the targeted removal of unwanted contaminants by overcoming the adhesive forces between the contaminant and the surface to be cleaned, and the complete removal of the released contaminants. The efficiency of the cleaning process is based on a combination of mechanical removal by the wiper cover and the chemical action of the cleaning agents. During disinfection, bioc-idal agents are applied to the contaminated surface to inactivate and kill any pathogenic and product-damaging microorganisms present. For this purpose, the active ingredients must be applied in sufficient quantity to the entire surface to be disinfected via the saturated wipe cover. The prerequisites are valid absorption and Reusable wipe covers GMP-compliant and process-safe in useAbout the AuthorMargarete Witt-Mäckel has been working as a coach and consultant in hygiene and quality management since 2012.
20consistent dispensing of the active ingredient solution as well as wetting of the surface. The mechanical action during wiping sup-ports the germ-reducing effectiveness.The cleaning and disinfecting of room surfaces is carried out using the so-called "wet wiping" method. Wet wiping is a process to re-move adherent soiling and/or to achieve a germicidal effect. Con-fusingly, the term "wet" does not mean "dripping wet", but rather the wetting of the surface with a uniform film of liquid. As a rule, the process is carried out in a single step: In this process, the sur-face is wiped in one step with a saturated wiper cover, and the re-sidual liquid dries off without re-wiping. In the same step, active substances are applied and soiling and residues are carried away by the wiping cover. The one-step method is combined with the so-called cover change method: Each wipe cover is used only once to prevent contamination from being carried over via the covers and, depending on the application method, via the solution used.As a rule, cleaning agents and disinfectants are used in the GMP environment once their efficacy has been proven. However, the ac-tual efficiency only becomes apparent when the entire process is evaluated. The process description shows that the wipe cover plays a central role here, in close interaction with the preparation or saturating system via which the solution is made available to the wipe cover. Requirements for a GMP-compliant wipe coverThe following tasks for the wipe cover result from the process de-scription:• absorption of the active ingredient solution, • transport of the active ingredients to the contaminated sur-face, • dispensing of the active ingredient solution and wetting of the surface, and • carrying away and removal of the contaminants by wash-off and mechanics.The functionality to perform these tasks is complemented by other application-specific properties such as chemical resistance and surface performance. In addition to the properties resulting from use in the wiping process, wiping covers themselves must not be sources of contamination and must not promote the accumulation of microorganisms. The totality of all requirements is also de-scribed by the term "cleanliness suitability", which specifies that a wiping cover must be suitable for the respective use and process in the respective cleanroom1. Since the use depends on the company-specific cleanliness re-quirements, processes and uses, the requirements for the wipe cover must be defined by the user for his area of application. For the GMP cleanroom, however, it is possible to assume a perfor-RequirementCleanliness specificProcess-specificApplication-specificFluid absorption capacity and fluid holding capacityXXLiquid release capacityXSurface wettingXCleaning efficiency, absorption and holding capacity of contaminantsXXXSurface performanceXChemical durabilityXActive ingredient adsorptionXParticle release and abrasion resistance (saturated wipe cover)XXWashing resistance and wear resistanceXSterilizabilityXXThermal resistanceXExtractable residuesXXOutgassing (AMC)XXHygienic design and handlingXRequirements are influenced by the cleanliness requirements of the room environment, the production process and by the users:Cleanliness specificRequirements by the air purity class and surface cleanliness class.Process-specificRequirements imposed by the production process on the cleanroom environ-mentApplication-specificRequirements due to the type of applicationTable 1: Overview of requirements due to the general use for cleaning and disinfection in the manual wiping process in the GMP cleanroom, based on VDI 2083, sheet 9.2, tab. 23
21mance profile as standard, since many requirements for wipe cov-ers are specified on the basis of the applicable regulations. The specification and qualification of a GMP-compliant wipe cover is based on the EU GMP Guide, the standard DIN EN ISO 14644-5, the guideline VDI 2083, sheet 9.2, and various textile testing standards (including the DIN EN ISO 9073 and IEST-RP-CC-004.3 series of standards).Process reliability through validationValidation provides documented proof that the cleaning and disin-fection process actually leads to the expected result in a reproduc-ible manner. Process reliability in cleaning and disinfection using the wiping method is achieved when• the liquid absorption of the wipe cover is constant and repro-ducible; prerequisites for this are a valid preparation method or saturation system and a valid liquid absorption capacity of the wipe cover, • the surface is uniformly wetted with a continuous liquid film, which requires a constant liquid release capacity of the wipe cover, • a release of microbial agents in sufficient quantity to the sur-face, taking into account possible agent adsorption, and • complete entrainment of all contaminants without carryover (cleaning efficiency), • the compatibility of wiping textile and chemistry is given, i.e. the evaluation of a possible active substance adsorption and testing of the chemical resistance, • the efficiency and stability of the working solution over the service life, and• the hygienic safety of the entire process is given, as well as • the typical signs of aging and wear of the wipe covers and the operating materials that are reprocessed for reuse are taken into account.Evaluation of process safety with regard to agingApplication with chemical agents, abrasion in use, interactions with residual soiling and residues, and reprocessing operations can negatively affect the textile structure and thus the functionality of wipe covers and thereby reduce the suitability of a wiper cover over time. Material fatigue and material breakdown also pose the risk of undesirable release of fibers and filaments from the textiles. Due to the changes that cannot be ruled out as a result of regular loads and the associated wear, a reusable mop cover can become a contamination risk. Therefore, the maximum duration of use must be determined by the number of reprocessing cycles. Based on studies2and empirical values from industry and cleanroom laun-dries, recommendations are available for the number of application cycles for reusable wipe covers. The aging phenomena evaluated here were caused by influences that are generally to be expected in a GMP cleanroom. However, this recommendation does not re-lease the user from an individual suitability and compatibility test and, if necessary, from adapting the application cycles to specific application conditions. ConclusionReusable wipe covers GMP-compliant and process-safe in use, in summary, means that they must be qualified for the intended use with regard to the requirements of the GMP regulations, must not pose any risk of contamination, and must ensure safe implementa-tion of the processes "cleaning" and "disinfection" through the giv-en functionality over a defined period of use. The evaluation of the wipe cover is part of the disinfection validation and thus of the contamination control strategy. 1 VDI 2083 Blatt 9.2 (2017). Reinraumtechnik – Verbrauchsmaterialien im Reinraum. Berlin: Beuth.2 Schmeer-Lioe G, Witt-Mäckel M et al (2016). Wiederaufbereitung reinheitstauglich! Analysen zur Alterung von Mehrweg-Wischbezügen für Reinraumanwendungen. Reinraumtechnik 05/2016, S. 48–53. Weinheim: Wiley-VCH.Microbiology for Non-MicrobiologistsLive Online Training on 4/5 April 2023gmp-compliance.org
22After the publication of version 2.1 of the ECA Good Practice Guide "Qualification and Validation - A guide to effective qualification based on Customer - Supplier Partnership" in 2021, the new ver-sion 2.2 was due to follow. It was presented for the first time at the forum. Authors and users of the guide explained its content and applica-tion possibilities to 39 participants from 12 different countries. At the beginning of the event, the current head of the ECA Validation Group, Ralf Gengenbach, gave an overview of the Guide and men-tioned the changes to version 2.1. The aim of the Guide is to outline practical solutions with regard to "lean qualification", to include case studies and to describe prime examples. The guide combines the requirements of Annex 15 of the EU GMP Guide with the FDA Process Validation Guidance and the approach of ASTM Guideline 2500. This approach can be used to address the most common problems in device qualification, see Figure 1. Finally, Ralf Gengenbach showed that the ECA Guide is well in line with the ISPE Guide "Commissioning and Qualification" 2nd edition (2019). The ISPE focuses on the process flow, the ECA Guide fo-ECA Qualification and Validation Forum November 15-16, 2022 in Heidelberg, GermanyAbout the AuthorSven Pommeranz is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the area validation.Figure 1: Challenges in device qualification
23cuses on the different parties and their tasks involved in the equip-ment qualification. Next, Dr Rainer Gnibl,Government of Upper Bavaria, a European GMP inspector, gave a presentation. Dr. Gnibl explicitly pointed out the flexibility that Annex 15 allows. Especially in the context of FAT, many of these tests can be included in the qualification without having to be explicitly repeated again - if the framework conditions are right. That is, appropriate documentation and a science-based approach as rationale are in place, see Figure 2.Rainer Gnibl is also positive about a categorization of equipment to facilitate qualification activities. But a separate presentation on this point followed later. Ralf Gengenbachagain took up the topic of Good Engineering Prac-tice and went into it in greater depth. Ralf Gengenbach sees the great advantages of GEP in the clearly defined "milestones" and the clearly defined workflow. Both lead to precise project plans. Using practical examples, he then showed possible implementations of the most important GEP documents:• Process documents• Engineering documents• Management specifications• Commissioning documents A presentation by Dr Clemens Borkenstein, ZETA GmbH, and Rolf Bauer,Syntegon Technology GmbH, on the subject of remote test-ing was discussed in great detail. The two speakers - Clemens Borkenstein heads the Remote Testing subgroup of the ECA Valida-tion Group and Rolf Bauer is a member of this subgroup - pointed out that the ECA Guide is the first guide to address the "remote topic" in equipment qualification. They then presented in great de-tail a checklist of what to look for before, during and after a remote test. They then showed in practical examples, including video ani-mations, how remote tests are carried out at ZETA and Syntegon. The presentation then led into advantages and disadvantages of remote testing, see Figures 3 and 4. Examples of both cases then came from the auditorium. In one case, remote testing went "com-pletely wrong" because the framework conditions were simply not correct. In the other case, testing went smoothly, precisely be-cause of good preparations and different camera positions.At the end of the day, Jörg Zimmermannfrom Vetter Pharma-Ferti-gung GmbH & Co KG and Immediate Past Chair of the International Board of Directors of ISPE picked up on Ralf Gengenbach's state-ment about the compatibility of the ECA with the ISPE Guide and talked about the current version of the ISPE "Commissioning and Qualification" Guide. He presented the benefits of Revision 2:• Definition of user requirements including "fitness for use" and differentiation between requirements (what) and specifica-tions (how).Figure 2: Single performance of tests, checks, reviews...Figure 3: Pros (for Live stream FAT)Figure 4: Cons (for Live stream FAT)Ongoing/Continued Process VerificationLive Online Training23/24 May 2023OPV/CPV from Control Strategy to Product Quality Review.Learn more about this course:www.gmp-compliance.org
24• Distinction between impact on product quality and no impact on product quality. • Risk assessments to identify Critical Design Elements (CDE's).• A streamlined Design Review/Design Qualification process with focus on CDE's• A clear Commissioning and Qualification (C&Q) planning pro-cess including a document release matrix• A lean structure for test execution, including distinctions be-tween engineering and quality aspects, specifying minimum requirements for testing• The tracebility matrix as a project management tool• A lean, risk-based "periodic review" approach • Integration of supplier tests with few test repetitions• Differences in engineering change management to routine change control• Current/simple examples of all steps in the Commissioning and Qualification process.With the inclusion of quality risk management (QRM), the ap-proach leads to faster market access, as Jörg Zimmermann report-ed as a result of practical experience at Vetter (Figure 5).This marked the end of the first day of the conference.Day two began with a presentation by Maik Guttzeitfrom Bayer AG. He leads the subgroup on categorization in the ECA Validation Group. Using two examples, a scale and a freeze dryer, he showed the difficulties that supposedly simple devices could show in a cat-egorization. His first conclusion was that there are no simple and clear answers to categorization. He then presented a three-tier categorization model, with the distinction into:• Non-critical• Low-critical• Critical and supported these categories with examples regarding qualifica-tion activities. Maik Guttzeit then showed simplifications regarding DQ and IQ for devices that come "off the shelf" ("commercial off the shelf", COTS). Finally, he gave an outlook on the further develop-ment of Annex 9 of the ECA Good Practice Guide, which deals with categorization. It is planned to present different approaches on how to do: • A matrix approach with a traffic light system (red, yellow, green), see Figure 6.• A decision tree approach • A tabular approach His conclusion was: Categorisation can help to reduce qualification effort - but should never reduce quality.Holger Frey from Merck in Darmstadt then presented a case study of supplier involvement in a qualification project. The project in-volved the replacement of an optical inspection line for vials with integrated leak testing. The project had a value of more than 3 million euros and was planned for a period of 2 years. Docu-mentation from the supplier was also very inten-sively involved in the project:• FMEA• Pre-FAT and FAT I and II• IQ, OQIn fact, the involvement of the supplier already started with the requirements specification, see Figure 7.Interestingly, environmental, health and safety (EHS) aspects were integrated into the user re-quirements, but as non-GMP-relevant. Thus, they Figure 5: Traditional vs QRM Approach Figure 6: Categorization - Matrix ApproachProcess ValidationLive Online Training24/25 April 2023Learn more about Validation as a „Life Cycle Process”.Learn more about this course:www.gmp-compliance.org
25were also not test relevant in the qualification. Especially in time-critical project phases, the FAT activities were integrated into the qualifi-cation to avoid duplicate testing. The proce-dure was carried out in accordance with an SOP and was coordinated with quality assur-ance, see Figure 8. Igor Krasulafrom Valicare, member of the sub-group "electronic documentation" of the ECA Validation Group, then presented the content of the revised chapter on electronic documen-tation and gave further tips on how to deal with electronic documentation systems in the context of qualification and validation. This topic also met with great interest. As advan-tages of electronic documentation he men-tioned among others:• Better readability of reports and easier translation options, if required • Improved data integrity • Easier sharing of documents (e.g., to ob-tain approvals) • Faster documenting and more consistent terms (when using standard terms)• Electronic approvals (e.g., via electronic signatures) • Direct integration of test data (from the equipment itself, from cameras, control panel printouts, etc.) • Simpler and cheaper archivingHe then went on to discuss a "traditional ap-proach (scanning paper documentation) and an "advanced approach." In this "advanced ap-Figure 7: Qualification Project - procedure qualification projectFigure 8: Qualification Project- qualification stepsFigure 9: Advanced Approach
26proach", qualification/validation documents are generated elec-tronically, the tests are entered there, and the whole package is released electronically, see Figure 9.It was very important to him that electronic systems fulfill the data integrity aspects according to the ALCOA+ and ALCOA++ princi-ples. Mr. Krasula expects it to take 1.5 - 2 years until such a system is implemented and can be used. A survey in the auditorium showed that this period is absolutely realistic. The highlight was the live presentation of such a system. It became clear in a very impressive way that sources of error due to incorrect entries can be prevented by appropriate programming of the fields to be filled in. Axel Heueis, from Drees und Sommer, then took the participants into a somewhat different world, the world of construction, with "3C Management". "3C" stands for Construction-Commissioning-Compliance. It was about construction projects in which GMP re-quirements (compliance) are integrated in good time from the out-set during planning and construction and then during technical testing (commissioning). Mr. Heueis asked the rhetorical question, when should GMP be started in a construction project? His answer was quite simple: the moment the project starts! He then present-ed a very impressive example regarding concaves between floor and wall in the context of the construction of a cleanroom, which were realized via Pharma-Terrazzo. However, this meant that the freedom to flexibly position cleanroom walls was lost. In order to clarify such coordination issues at an early stage, appropriate pro-ject management is necessary, with the corresponding (GMP) in-terfaces, see Figure 10. Finally, Ralf Gengenbachonce again presented what he considers to be the six most important errors in a device qualification:1. GMP and GEP activities are not well combined with each other2. user requirements are mixed with technical specification 3. risk assessments are not used efficiently4. integration of suppliers is not well solved5. FAT, SAT are not used to a sufficient extent 6. GEP is not well established In explaining point 6, he contrasted testing with qualification. In his sense, it means that qualification is not testing. Qualification is just testing. If one tests during qualification, this can lead to technical defects then having to be corrected during qualification. This in turn leads to increased costs, see Figure 11. Conclusion: The new ECA Good Practice Guide "Qualification and Validation - A guide to effective qualification based on Customer - Supplier Partnership" was very well received in the new version 2.2. Many discussions, also at the social event in the old town of Hei-delberg, showed the advantages of a face-to-face event. One wish for improvement was to make the guide also available in a simple edition, for (still) less experienced suppliers in the GMP environ-ment. The ECA Validation Group will work on this in the next step. The guide is available free of charge for members of the validation group, see www.validation-group.org.Figure 10: GMP Documents Interfaces and Responsibilities Figure 11: Missing GEP increases the costs and time delay
27The trend in the pharmaceutical industry is also moving towards cloud computing. Financial but also organizational advantages speak for the cloud. At the same time, however, potential dangers and regulatory restrictions should also be taken into account. Nine experts from the pharmaceutical industry and regulatory authori-ties answer a comprehensive catalog of questions from the follow-ing GxP-relevant topics: • Basics of Cloud Computing Technology • Regulations and Expectations of Inspectors • Customer-Supplier-Relationship • Requirements for Cloud Service Providers (CSP) • Requirements for Supplier Evaluation and Supplier Audits • Requirements for Qualifcation / ValidationThe experts:Frank Behnisch, CSL Behring GmbH, MarburgKlaus Feuerhelm, formerly Local GMP Inspectorate /Regierungsprä-sidium TübingenOliver Herrmann, Q-FINITY Quality Management, DillingenEberhard Kwiatkowski, PharmAdvantageIT GmbH, NeuschooStefan Münch, Körber Pharma Consulting, KarlsruheYves Samson, Kereon AG, BaselDr. Wolfgang Schumacher, formerly F. Hoffmann-La Roche AG, BaselDr. Arno Terhechte, Local GMP Inspectorate / Bezirksregierung MünsterSieghard Wagner, Chemgineering Germany GmbH, Stuttgart7. Requirements for Supplier Evaluation and Supplier AuditsCan we assume that if there is an appropriate QMS implemented and if the CSP acts in compliance with this QMS (as a result of an audit), the service provided functions in accordance with the specification and the operational controls are carried as described in the CSP's internal pro-cedures?In accordance with Annex 11 the use of computerised systems may not result in a decrease in quality assurance. The assessment of a Questions and Answers to Cloud Computing in a GxP Environment - Part 2About the AuthorDr Andreas Mangelorganises and conducts courses and conferences for the ECA Academy in the areas sterile production and computer validation.
28service provider includes the evaluation of its quality assurance system. In addition to this initial assessment Chapter 7 requires the RU (regulated user) to continuously monitor the service provider by means of the supervision of KPIs. In the case of an applied and appropriate QMS it can be assumed that operative controls defined in the QMS will be carried out and that results not compliant with the specifications will be addressed within the meaning of deviations / OOS.The RU is nevertheless required to continuously evaluate compli-ance when implementing the QMS. Chapter 7 of the EU Guidelines to Good Manufacturing Practice specifies: “The Contract Giver is ultimately responsible to ensure processes are in place to assure the control of outsourced activities.” Type and extent can be de-fined on the basis of risk, and they are influenced by the experi-ences from the continuous monitoring of the service provider.8. Customer-Supplier-Relationships Which contents must be covered by the service provider’s change con-trol and in which way must the contract giver be integrated into this system?Though the regulated company’s responsibility for patient safety, product quality, and data integrity cannot be delegated to the cloud service provider (CSP), the CSP nevertheless plays an impor-tant role and takes over important tasks such as specification, verification, and documentation of changes (in addition to their implementation), be it at the infrastructure (IaaS), the platform (PaaS), or the application (SaaS) itself. One of the goals of the regu-lated company is maintaining the validated and compliant state of a system. This requires corresponding validation measures (impact analysis, risk assessment, and further test and documentation ac-tivities, if appropriate) that typically require knowledge regarding the changes carried out by or at the CSP (see also question 9).Therefore, the following elements of a validation concept are rec-ommended:• The regulated company verifies whether the CSP has estab-lished a high-quality and compliant change control process (for instance by means of an audit).• A service level agreement (SLA) ensures to obtain information (and documentation) on planned and required changes on time and to the extent necessary allowing the regulated com-pany to perform a (risk) assessment and to plan the required measures, as appropriate.9. Principles of Cloud Computing Technology The multi-tenant provision of SAAS is accompanied by a source code basis for all customers. This implies that all customers must have the same software version irrespective of whether or not a customer ac-cepts a certain change. Is this compatible with GxP?A regulated company strives to avoid extensive and risky changes of an application that might potentially challenge the validated and compliant state of a system. This is even more the case if the changes have no or only a minor benefit for the regulated company but may cause additional validation effort.However, the relevant SaaS changes formally do not constitute a violation of GxP. Otherwise, it would not be allowed to update any operating system if the update introduces a new but unused func-tion. It is required that corresponding measures (impact analysis, risk assessment, further test and documentation activities, if ap-propriate) are performed to maintain the validated state, as for any other change. Since these measures are also required for ordered / deliberate changes the procedure must be described in the SOPs or in the validation protocol, anyway. Hence, it makes sense to con-tractually ensure the timely provision of the corresponding infor-mation with the CSP (cloud service provider) (see also question 8).10. Requirements for Supplier Evaluation and Supplier Audits Which persons (functions) should participate in the audit of a CSP and which topics should (must) be addressed?According to the vote 1100202* the following applies:Persons are to be included in the audit who are sufficiently experi-enced in this special technology. In principle, at least one person should come from IT. The lead auditor will normally come from quality assurance. According to the vote the following topics should be addressed:Computerised System Validation: Introduction to Risk Management & GAMP 5 Approach25 April 2023, Vienna, Austriagmp-compliance.org
29• Security of the data centre• Server security• Network security• Application and platform security• Data security• Encryption and key management• ID and rights management• Selection and training of staff• Validation and qualification• External services and subcontractors• Maintaining the validated state (change management, config-uration management, patch management, monitoring and re-porting, incident management)*www.zlg.de – Vote V1100202 of the group of experts 11 „Anforderun-gen an die Aufbewahrung elektronischer Daten“ (Requirements for the storage of electronic data)11. Requirements for Supplier Evaluation and Supplier Audits How many days must be planned for the audit of a CSP? Is it also pos-sible to carry out a remote audit?If activities of the pharmaceutical entrepreneur are outsourced to third parties the contractors are to be qualified. This applies to the outsourcing of the manufacture of active pharmaceutical ingredi-ents, finished medicinal products and medical devices - as has been common practice for decades - as well as to the outsourcing of services in the area of IT, including cloud service providers. In the first place a cost-saving questionnaire that is sent to the service provider via email and evaluated subsequently would be useful as concerns qualification. In doing so, it is nearly impossible to assess the correctness and truthfulness of the answers given. An increasing number of remote audits of IT service providers has been carried out for some years now. These audits are very de-manding for the auditors since video technology reaches its limits when analysing the reactions and body language of the audited party and the reading and assessing of large documents are in-volved and when taking a tour to the premises (e.g. the data cen-tre). The best solution is the well-known audit on site where the auditor can get an objective impression of the quality and performance of the future contractual partner.Depending on the scope of services one or two days on site can be sufficient for an audit of IaaS. In the case of SaaS applications, a very detailed control of the cloud service provider needs to be car-ried out since this service provider also takes over crucial parts of validation. Here, an audit duration of 5-7 auditor-days is quite com-mon.Depending on the services outsourced the lead auditor should call in further experts (for instance from the area of security) in order to obtain a complete impression.For carrying out the detailed planning of the audit the service pro-vider usually obtains a plan which clearly displays the content of the audit. This audit plan can also be integrated into a time sched-ule. It is recommendable, however, to leave the detailed schedule up to the company audited since the temporal availability of the staff has to be assured for the specific audit topics.The following is an extract from a SaaS audit plan. On this plan the service provider can see the potential topics so that he can make the corresponding staff and management available for the inter-views.Audit Participants• Lead Auditor• Further AuditorsObjective• Audit History - Follow-up of last audit• CAPAsScope• QMP,CSV, SOP's available and followed• Training of personnel on QMS including updates• Incident management• Change management• Documented baseline configuration• Software release process• Release testing, Patch testing• SDLC process• Traceability of requirements• Project methodology• Functional testing• Third Party management, Security of third parties• Back-up/Restore, Disaster Recovery and Business Continuity test evidence• Service Level Agreements (SLAs)• Security/Access Control• Data EncryptionStandards• 21 CFR Part 11• 21 CFR Part 58• 21 CFR Part 210/211• 21 CFR Part 820• GDPR• ICH E6 Good Clinical Practice• EU Annex 11• ISO 27000 series• GAMP5 and GAMP Good Practice Guide12. Requirements for Supplier Evaluation and Supplier Audits Will it be sufficient to send a check list for the assessment of the CSP – for instance Amazon and Microsoft?Cloud service providers are among the most important quality-relevant suppliers a pharmaceutical company has to assess in the course of the supplier qualification. This places heavy responsibili-ty on the quality assurance or on the audit department as concerns the qualification of auditors and the availability of the required in-formation at the supplier’s: For each cloud service provider the re-quest for an audit signifies the introduction of comprehensive co-ordination activities for the audit carried out on site or for answering long questionnaires. Both are rather unpopular since they bind a lot of resources. That’s why cloud service providers of-ten ask for cost sharing for audits carried out on site hoping that then the audits won’t be carried out at all. Obviously, the quality department of the cloud service provider isn’t very pleased about
30questionnaires full of open questions either, when answering these questions might require several days.In order to assess a SaaS cloud service provider offering a quality-relevant application it is strictly necessary to carry out an audit - it would be best on site - since the documentation on the develop-ment and validation of the system must be assessed considering GMP aspects. In case only a remote audit would be possible it has to be guaranteed that there is sufficient time for reading the docu-mentation made available online. The auditor should try to receive a copy of the quality-relevant documents for examination before the actual remote audit takes place. Most suppliers will refuse this for confidentiality reasons, however.The quality assessment of global service providers in the area of IT infrastructure (IaaS service provider) often poses bigger problems as such companies (for instance Microsoft, Amazon) simply ignore such requests. In this case, the pharmaceutical entrepreneur is re-quired to assess general documents made available on a broad ba-sis. Microsoft provides a comprehensive quality manual (Microsoft Azure GxP Guidelines, © 2020 Microsoft Corporation, 99 pages) which can be downloaded from the Microsoft website. Here, the auditor finds answers to a number of questions she/he would want to discuss in the course of the audit. Amazon also provides a number of documents on the relevant sub-ject areas in the form of not contiguous fragments which are made completely available to the auditor only after signing the delivery contract, however, so that they are not suitable for the initial as-sessment of the supplier.The auditor should absolutely try first to send a questionnaire with the request for replies also to these global companies in order to leave nothing undone. In this context it should be noted that I’ve sent a request to Amazon recently and have received an almost completely answered questionnaire which allowed me an assess-ment.It is very important for the pharmaceutical company to include the option of regular audits (without additional costs) into the contract with the service provider. Furthermore, the bundling of audits ac-tivities of several pharmaceutical companies (joint audit) with sharing of the costs should be considered. This would have a lot of advantages and win-win situation for both parties - the customer as well as the service provider - since time and costs could be saved.13. Customer-Supplier-Relationships A cloud service providers refers to SOC reports when assessed, espe-cially to the SOC2 report. Would this report be sufficient as concerns the requirements of the assessment and could it be used?The SOC2 report can be used for the requirements we have in the GMP/GLP environment. It should be noted, however, that the SOC2 report must meet the requirements of the financial sector. This does not fully cover the requirements of the pharmaceutical sector. For example, we reviewed the change process in the SOC2 report and there remain some requirements that have not yet been answered.Conclusion: The SOC2 report alone is not sufficient for the Evalua-tion of a CSP.ECA GMP/GDP Certification ProgrammeHighly qualified personnel is a crucial factor in the GMP-compliant manufacturing of APIs, drugs and medical devices. While your college and university education provides the scientific basis, the ECA GMP/GDP Certification Programme complements your professional training with a well-established certification. Certification OpportunitiesECA Certified Validation ManagerECA Certified Quality Assurance ManagerECA Certified API Production ManagerECA Certified Quality Control Manager ECA Certified Technical Operations ManagerECA Certified Computer Validation ManagerECA Certified Regulatory Affairs ManagerECA Certified Microbiological Laboratory ManagerECA Certified Sterile Production ManagerECA Certified Pharmaceutical Development ManagerECA Certified Biotech ManagerECA Certified GMP AuditorECA Certified GDP Compliance ManagerECA Certified Packaging ManagerECA Certified Data Integrity ManagerFor more information please seewww.gmp-certification.org
31In March 2022, ECA Academy conducted an online training on cleaning validation - during which participants had many ques-tions. Due to the large number of questions answered, we had split this post. Below you can find the second part of the questions an-swered by the speaker Robert G. Schwarz from FH Campus in Vi-enna. All answers reflect the opinion of the speaker and are based on his experience.41. Would a bracketing approach be appropriate for a biotech process?Generally spoken – yes, it could be an option.42. How to handle with cleaning validation for shared facilities (with pharmaceutical products and biological active additives)?First evaluation if shared facility is possible. Shared facility is not necessarily shared equipment, especially when we have closed processes and/or CIP cleaning it is less critical. Shared equipment is sometimes better than dedicated equipment cleaned in shared COP-washer – segregation issue in the washer itself – changeover cleaning with empty chamber required. For Multi-purpose equip-ment the cleaning process development and the lab scale studies is more difficult than the cleaning validation itself. A “hard” brack-eting could be performed including product and equipment brack-eting with a profound and traceable product-equipment-matrix. There the cleaning validation effort could be shrunk down signifi-cantly – one worst-case product with one worst case equipment covers “everything else”. Disadvantage is the lack of an optimized cleaning process for the different product equipment combina-tions. If this is the desired, way, less bracketing is possible because bracketing over different cleaning processes is only accepted in very rare cases by authorities. Additionally, if all products are mac-romolecules/proteins I’d highly recommend a degradation-strate-gy over using HBELs.Questions and Answers about Cleaning Validation - Part 2About the AuthorRobert G. Schwarzis a lecturer at the FH Campus in Vienna. He has 20 years of practical experience in aseptic processing, contamination control and cleanroom technology.
3243. Do we need to have full CFU count with identified microbes for non-steriles or is a general screen acceptable?The cfu count is needed, usually identification is not necessary be-cause objectionable microorganism are only relevant for product bioburden testing. In addition, I would recommend also performing endotoxin testing.44. How do you set bioburden limits - what rationale is used?Usually, the basis is the allowed bioburden in the product. It is cal-culated back to the surface from the absolute amount of microor-ganism allowed in the smallest batch. For rinse sample the volume of the finale rinse step and the sample volume needs to be taken into consideration. Additionally, if an open storage of equipment is possible a cross-check of the bioburden limit limits for the Clean-room Class (CRC) of the storage area for surfaces are needed.45. For excipient manufacturers it is difficult to judge what means "doesn’t harm the patient" as the application is mostly not exactly known. Do you have any recommendation?Limits are the requirements of customers, also internal, that use the excipients for final formulation of medicinal products. Those are usually defined in a quality agreement resulting in incoming goods specifications.46. EMA HBEL guideline instructs to calculate PDE with NOAEL and NOAEL is chosen based on available human and animal data. Why prefer NOEL over NOAEL?I suggest using NOEL, because a desired effect of product 1 with patient A could be an adverse effect for patient B using product 2.47. Regarding automatic cleaning: We want to implement a washbox with our cleaning validation - when we adapt the pro-grams later, do we have to repeat the CV with all 3 full runs?Depending on the extent of the adaption it can be risk assessment which identifies the adaption with minor impact and maybe only one verification run (to support this hypothesis with data) is need-ed or it could be a major impact where full revalidation is needed-48. Where is reliable toxicological study data available? Question also applicable for pharmacological data and study data?If you are a CMO you get the data from the license holder of the product you produce. It is part of clinical development to generate those data in the clinical phases for manufacturers of pharmaceuti-cal products. If you produce generics, you may get data from the patent holder.To my knowledge no freely available literature for HBEL are avail-able. Selection of suppliers for “common” small molecule APIs:https://www.freyrsolutions.com/permitted-daily-exposure-pde-calculationhttp://www.socosur.eu/PDEs/List.slshttps://kktechnolegal.com/toxicological-assessments/49. Typically, who should determine NOAEL, F1-F5 and calculate PDE?According to EMA “shared facilities Guideline” it is the task of toxi-cologist with requirements also mentioned in the Q&As to this Guideline also published by EMA:“Health-Based Exposure Limits should be determined by a person who has adequate expertise and experience in toxicology/pharmacology, familiarity with pharmaceuticals as well as experience in the determi-nation of health-based exposure limits such as Occupational Exposure Levels (OEL) or Permitted Daily Exposure (PDE).Where experts are contracted to provide the HBEL, contractual agree-ments in compliance with Chapter 7 requirements should be in place prior to work being conducted. It is not considered acceptable for man-ufacturers to ‘purchase’ HBEL assessments without recording an as-sessment of the suitability of the provider (including the specific techni-cal expert) as a qualified contractor.”50. Is there any possibility to calculate MACO only based on NOEL without therapeutic dosis?The only option I see would be that you assume that the therapeu-tic dose is the volume of the whole batch which usually leads to a very low MACO. Sometimes even under the LOQ of the analytical method for some acceptance limits.51. Volume rinsing solution - is this equal to sample volume?No, the rinsing solution volume is the whole volume used for the rinsing step where the rinse sample is drawn. For final rinse it is determined by the cleaning process for solvent rinse it should be a minimum volume to cover the whole product contact surface.52. Is concurrent validation acceptable?Yes, based on a profound risk assessment evaluating the specific circumstances it is acceptable.53. DEHT must be validated during initial validation but can be eliminated during cleaning monitoring? Is this true? Is it required to perform CEHT studies periodically?Usually, DEHT it is not part of the cleaning monitoring every time. For CEHT I would recommend performing a sampling after a main-tenance shutdown which should be part of the preventive mainte-nance program.Analytical Methods for Cleaning ValidationLive Online Training31 May - 2 June 2023Learn more about methods of cleaning validation and their application.Learn more about this course:www.gmp-compliance.org
3354. Does equipment sterilization fall under the cleaning valida-tion scope if it is a last step of "cleaning"?No, it only impacts the definition of CEHT.55. If after a sanitization process (CIP Chromatographic column) one/several parameters are OOL, is it mandatory to register it as deviation or could we execute a re-cleaning process until an ac-ceptable value?No, this would violate the validation of the cleaning process and it could be assumed that the process is not robust. Cleaning until the acceptance limits are met is comparable to testing into compli-ance.56. Which studies of NOAEL determination are preferred to use (human/dogs/ rats) while calculating PDE? If they all have differ-ent duration and values of NOAEL?Although I’m not a Toxicologist either the value for the species the medicinal product is applied is used or the “nearest” species, i.e., species with the most comparable physiology or, what I usually recommend, if I get the chance to discuss the tox assessment with its author, to calculate all the different PDEs and use the strictest value. Sometimes even it is necessary to re-evaluate HBELs based on data collected during clinical trial phase IV (pharmacovigilance) when the product is already on the market. This reflects the life cycle approach of every validation strategy.57. Cleaning monitoring when you’re not manufacturing using worst-case product. Do you need a risk assessment for that?Usually, it is not necessary to use the worst-case product for clean-ing monitoring. If there is no cleaning process being performed in the period where a cleaning monitoring needs to be performed, I’d recommend describing this scenario in the MVP or the cleaning monitoring SOP and perform the cleaning monitoring the first time the cleaning process is performed. Some colleagues even do this three times if the overdue of the monitoring frequency is signifi-cantly.58. Macromolecules/peptides: but could the remnants may serve as 'food' source for microorganisms?Yes, but this is covered via CHT.59. DEHT: is this some sort of plastic type? (e.g., dioctyl tereph-thalate - non-phthalate plasticizer)?No, it is the abbreviation for dirty equipment hold time, which is often used synonymously for DHT (dirty hold time)60. When no DHT is validated, is it ok to use 24h as a standard?No, DHT needs to be addressed in the cleaning validation accord-ing to Annex 15 of EU-GMP Guideline. You can’t justify 24h with data if you’d do so.61. Do you recommend cleaning the equipment before the pro-cess even if it is within the holding time of the previous process cleaning?Usually this is not necessary but depends on the storage condi-tions. I’d rather optimize those than perform a re-cleaning62. When equipment is dedicated, is it ok to stop testing after 3 conform CV runs (results and cleaning cycle ok), and the report is not finalized (e.g., very tight production schedule)?If the three runs are defined in the cleaning validation risk assess-ment/protocol as sufficient and only the report is missing from a formal point of view every produced batch needs to quarantined until the final report is approved, but the routine production can start.63. Is it possible to perform a cleaning validation and then take process control samples instead of validating long campaigns?You can always perform cleaning verification instead of cleaning validation, but if a sample is OOL you need to open a deviation and, in worst case, end the campaign immodestly. Additionally, you then need to sample to the full extent after every cleaning process.64. Do you have to perform inactivation studies with each manu-factured product?For macromolecules it should be performed for each substance where you don’t follow the HBEL/PDE-strategy.65. The rinse sample matrix in biotechnological processes should be taken in WFI? can it be taken in equilibration buffer? Can other buffers such as NaCl 0.9% be used?This is depending on the parameter to be measured and the ana-lytical method if the matrix components interfere with the analy-sis. Generally speaking, and from a regulatory perspective this is possible.66. How do you define the TOC limits if during cleaning your res-in releases the organic material coming from its own ligands?You need to assume that the organic carbon’s source is the most toxic substance in this production step and use the adequate limit. If this is not practically then another parameter, usually a compo-nent specific analytical method, needs to be established.67. What can you recommend establishing an acceptance limit for rinse samples from Chromatography columns if that equip-ment isn't in contact with PW? Is it possible to prove cleaning just from API/excipients not from solvents/eluent?This is no issue, because you can perform the rinsing sample with the eluation buffer if it is covered in the analytical method valida-tion.68. What can be simplified for CV (dedicated equipment)?No bracketing approach for products, DHT and CHT needed to be justified, no lab scale studies for cleanability. Also, maybe unspe-cific methods are needed. Limit is usually higher. Starting with a cleaning verification at the beginning to get data and stop after enough samples to show the process is validated is easier.
3469. Drug product manufacturing: Any experiences with HA (espe-cially LATAM (Brazil, Peru, ...) countries) if we have several bio products on the same equipment? And some products are mono-clonal antibodies, other protein molecules, mRNA, cleaning vali-dation is in place?Have a good risk assessment for DHT and CHT (incl. different sam-pling points for CHT), favor degradation-strategy HBEL-concept. Evaluate, if degradation products are potentially sensitizing and have a rational for that. Proper scientific risk assessment. Accord-ing to my experience ANVISA (HA of Brazil) is at a lot of topics com-parable stringent to US-FDA, especially when it comes to “num-bers” (e.g., ANVISA is the only HA in the world that specifies minimum recovery of contact plates with 50%). Justify why your recovery rates are acceptable for your purpose.70. For multi-purpose large molecules equipment: Is a worst-case concept still sufficient or should we have TOC method (with recovery for each product)?I’d consider a well-documented worst-case strategy with a risk-based approach is still state of the art. You have the TOC-limit spe-cific for every product anyway because it is based on the TOC-con-tent of your API-molecule.71. Is just the worst-case enough, or should we have to sample at least 1x after each substance?Depending on the reliability of the small-scale lab study for clean-ability it could be necessary to prove that lab scale is representa-tive for production scale that a verification run with one or more other products than the worst-case is reasonable. It is at least rec-ommended if small-scale lab study doesn’t identify one clear worst-case product (e.g., it is 50% harder to clean than the second product).72. When introducing a new product, is sampling at least 1x (or 3x) after manufacturing the new product sufficient and if every-thing is OK, can it go to the matrix and do only the worst-case?First it needs to be evaluated if the product could be produced on a multi-purpose equipment train based on its toxicity and cleanabil-ity. For cleanability lab scale studies are recommended. Addition-ally, it needs to be considered that every other product produced in between needs to be quarantined until the final CV report is ap-proved. Only after that it could go to the matrix being included in the OCV (cleaning monitoring).73. What tests are recommended to be performed in the manu-facture of biological products?Usually if you clean with inorganic cleaning agents like alkalis and acids unspecific methods like TOC are sufficient for product resi-dues especially when you could demonstrate full inactivation of active components. Cleaning residues are detected via conductivi-ty or pH. Bioburden and Endotoxins especially important in biotech production.74. Regarding sampling: Any guideline on how to consolidate dif-ferent plastic surface materials?No Guideline available for such a bracketing approach, Strategy should be the minimization of variety of plastic materials that are in direct product contact. Generally, a worst-case assumption is performed via different surface roughness, if no specific extracta-bles need to be considered. According to my experience chloro- or Bromo butyl-rubber materials without any coating are hardest to clean because of their porous surface structure. Besides that favor only PTFE (Teflon), Viton and silicone as materials for hoses or gas-kets that are not single use.75. If equipment is really hard to reach visual cleanliness but all other acceptance criteria are ok, what could we do?This is usually the case with CIP-systems and especially for piping. This is covered in a risk assessment. Some companies perform en-doscopic checks during preventive maintenance during production shutdowns.76. There are also hold times in between cleaning steps. Some-times they are very long. How do you validate that? (Sometimes it just hold in alkaline solution or something similar)If the equipment is covered in a cleaning solution, even if it is just PW or WFI this is to be considered as a cleaning step but with de-fined duration. It also needs to be addressed in the CV risk assess-ment if a worst-case cleaning cycle is, if this process step time var-ies, with the shortest (i.e., worst cleaning capability) or longest (potential impact on equipment and microbial proliferation) pro-cess step time.77. Is it possible to validate the CEHT only 2 times for 3 CV runs, because parts of the equipment train are needed for another pro-duction (tight production schedule)?Not based on the argumentation “tight production schedule” and I wouldn’t recommend arguing this in a risk assessment.78. Regarding campaigns: Do we need 3 CV runs with the full campaign length or is one full campaign length run and 2 shorter CV runs sufficient?No, if the parameters vary they are no three consecutive runs any-more. Could be argued in a risk-assessment. Based on my experi-ence I wouldn’t recommend that.79. When you decide not to manufacture the product anymore. do you have to perform cleaning monitoring with last manufac-tured product batch?I would recommend that. It goes align with concepts of calibrated instruments and should be part of a change control for GMP-com-pliant retirement.
35Validation Group The Board is still unchanged. The group met on-site mid of November.New Version of GuideThe version 2.2 of ECA´s Integrated Qualification and Validation Guide was published at the „Qualification and Validation Forum mid of November. 40 delegates from 12 countries welcomed the new version. The new version was discussed intensively, especially the chapter categorisation and electronic validation documenta-tion. Further, the wish for a simplified version, especially for suppli-ers, came up. For 2023 the plans are:Finalisation of the open chapters “Categorization” and “CARA”Collection of more practical examples to bring into the appen-dices (more content). Can later be transferred into small book-lets and videosRephrasing from “pharmaceutical manufacturers” to “regulat-ed firms” (or similar), ideally by the group members who are also dealing with food productsAddition of a small section about most important GEP activities / process flows being a prerequisite for successful qualificationSimplification of the guide for easy understanding by all Like the years before the ECA offers courses on “Process Valida-tion, Cleaning Validation, Process Understanding and about Ongo-ing/Continued Process Verification and a course about practical use of the Good Practice Guide Integrated Qualification and Valida-tion Guide online and on-site. The Qualification and Validation Forum in Nov 23, is also in planning. For all courses and confer-ences coming up, please see the current validation courses & con-ferences programmewww.validation-group.org European GDP Association The European GDP Association has finalised the programme for the GDP part of the GMP & GDP Forum 2023 (20-22 June 2023 in Bar-celona). The programme was published.Membership cards for the European GDP Association members were issued. Cards are valid for one calendar year (January to December 2023).www.good-distribution-practice-group.orgPharmaceutical Microbiology GroupOlivier Guenec is taking on new responsibilities at Sartorius and therefore announced to leave the Board in 2023. He will be suc-ceeded by Erric Clement Arakel from Sartorius. The Board Meeting took place at PharmaLab end of November in Neuss. In future there will be a face-to-face meeting before Phar-maLab and before/after the European Microbiology Conference and a virtual meeting in the other two quarters.New Annexes for GuidelineDuring the Board meeting, the two annexes (on microbial identifi-cation methods) to the Deviation Guide were approved by the Board. Cooperation with ATMP GroupIt was decided to invite Sabine Hauck, Chair of the ATMP Group, to the Board Meetings, as there is a lot of overlap, especially in the microbiological QC of ATMP.www.pharmaceutical-microbiology.orgATMP Group• Dr Ulrike Herbrand, CRL became a new member of the Board and attended the Board Meeting mid of October for the first time.• The Board Meeting took place online mid of October. During the meeting, the activity plan for 2023 was discussed as well as the content for the ATMP session at the PharmaCongress, and potential further topics were evaluated.• A two day ATMP Track was conducted during PharmaLab for the first time. The second day was organised in cooperation with the Microbiology Group. The track was very well attend-ed (seating in the room needed to be extended for day two).www.atmp-group.orgData Integrity & IT Compliance GroupNew Version of GuidelineVersion 3 of the ECA DI Guide was published in December 2022. The new version is available as a free copy for the members of the DI & IT Compliance Group.Comments on GuidelinesThe group prvided comments on the FDA draft guideline “CSA - Computer Software Assurance” in November 2022.Starting a discussion to comment the EU GMP Annex 11 concept paper. Deadline for the comments: 16 January 2023.www.it-compliance-group.orgVisual Inspection GroupThe Visual Inspection Guide as well as the CCIT Position Paper will not be changed due to the new Annex 1. The CCIT paper has been NEWS FROM OUR ASSOCIATION www.eca-foundation.org
ISSN 1867-7975GMP Handbooks • GMP RegulationsFDA cGMP GuideECA Good Practice Guide - GMP Matrix (Version 21 of May 2018)"FDA cGMP, EU GMP and ISO 9001 Matrix for a pharmaceutical Quality System - A GMP Roadmap"EU Guidelines to Good Manufacturing Practice Part 1, Part 2 and Part 3incl. Annexes 1-19 ICH Q7 GMP for Active Pharmaceutical Ingredientswith a Side-by-Side comparison and APIC‘s How-to-do Document (Version 16, July 2022)To order, please visit www.gmp-compliance.org/publications/gmp-publications.Important: ECA Members receive a discount of 35% for GMP publications. Check the ECA Members Area to find the ECA Promotion Code.updated to version 2.1 in October (editorial change in chapter 4.3: Stopper height of vials specified more precisely)Survey on Visual Inspection ConferenceFelix Krumbein develops a survey which will be used in the context of the next Visual Inspection Conference in order get some infor-mation of the audience.The group prvided comments on the FDA draft guideline “CSA - Computer Software Assurance” in November 2022.Starting a discussion to comment the EU GMP Annex 11 concept paper. Deadline for the comments: 16 January 2023.www.visual-inspection.org