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STABILITY TESTING FOR MEDICAL CANNABIS No34Issue 34 | Jun/Jul 2022Common and Typical GDP ViolationsHighlights of the 24th APIC ConferenceBioburden – Regulatory Expectations and Practical ExperiencesThe Present and Future of Remote Audits
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:Dr Andrea Kuehn-HebeckerDr Markus FunkAnne-Theresa GuensterDr. Sebastian ThoelkenSven M. DeutschmannWolfgang SchmittDr Gerhard Becker 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: 1290534329 Page 7: iStock, ID: 1295897671 Page 11: iStock, ID: 99615890 Page 13: iStock, ID: 609055166Page 19: iStock, ID: 654100004Page 22: iStock, ID: 1299800048 GMP range of topics continues to growLooking at the last 30 years, the GMP topic spectrum has grown more and more. GMP, i.e. Good Manufacturing Practice, used to focus on a narrowly defined range of topics within "classical" pharmaceutical manufacturing. Gradually, more and more areas were added. Today, GMP regulations also deal with active pharmaceuti-cal ingredients, biopharmaceutical production and the production of cannabis for medicinal use, among other things. In addition, GMP has initiated the development of the GDP regulations.In this issue, you will find a total of 6 articles on the above-mentioned topics, as well as on the current topics, remote audits and FDA warning letters.Enjoy reading!Oliver SchmidtEditoralContent44Cover story Stability testing for medical Cannabis – What needs to be consideredThis article explains the stability requirements that medical cannabis must fulfil.7Common and Typical GDP Violations An Evaluation of GDP Non-Compliance Reports since 201411Highlights of the 24th Active Pharmaceutical Ingredients Conference of APICA summary of the last APIC/Cefic Global GMP & Regulatory API Conference, which took place in October 2021.13Q&A from European GMP Conference: “Bioburden – Regulatory Expectations and Practical Experiences”In-depth Questions and Answers on Biopharmaceutical Manufacturing19The Present and Future of Remote AuditsHow will distant assessments be able to complement on-site audits?22The most Frequent GMP Deficiencies in Quality Control An analysis of the Warning Letters of the last 5 years711131922
3NEWS FROM OUR ASSOCIATION www.eca-foundation.orgEuropean QP AssociationAt its Board of Directors meeting in early December, the European QP Association (EQPA) had decided to concretise its requirements for membership in the Association. This was due to ambiguities in the previous requirements, changes in the political landscape and planned adjustments in PIC/S countries. The changes as available on the EQPA website apply to all new memberships. Existing mem-berships The EQPA Activity Plan 2022was finalised and agreed by the board. Amongst other things it outlines objectives, goals and board meetings planned in 2022. Code of Conduct for QPs Georg Göstl took the lead to develop a draft proposal for a Code of Conduct to QPs in the name of the EQPA. Background: Article 52 of Directive 2001/83/EC requires from member states to issue national Codes of Conducts for QPs. Alter-native approaches are also possible. According to a survey feedback, 21 years after coming into force this legal article did not result in any Code of Conduct in any cur-rent member state nor in EEA member states. All member states obviously claim to have alternative procedures developed or in place (usually without explaining to QPs which ones). The EQPA wants to fill this gap. EQPA board members were invited to comment this first draft. Benchmarks IMP QP Working Group For the QP Forum 2021, participants and members of the IMP Working Group had submitted a number of questions in advance via a “Call for Questions”. Many of them have already been addressed in the presentations and in the Q&A sessions. However, due to the numerous chat questions during the conference, the speakers were not able to present all the benchmarks that were prepared based on the submitted questions. Therefore, a survey was sent out. It was also asked for possible topics of interest for the next QP Forum’s IMP Pre-Conference. Contract QP Activities According to Article 48 of Directive 2001/83/EC each manufactur-er has to have at his disposal at least one Qualified Person. There are no details on the contractual arrangement for this “disposal of services”, though. As QPs in many member states offer their service as independent entrepreneurs and “contract QPs”, these states have developed rules and expectations posed on independent QPs usually without own MIA. Therefore, EQPA has sent out a survey to find out more about this area of QP activities, which is not harmonized within the EU. Results will be posted in the members’ area as soon as availa-ble. QP Forum 2022 The EQPA Board has decided to offer this year's QP Forum (01-02 December in Berlin, Germany) also as a Live Online Conference. Delegates can either attend on site in Berlin or at home/ in the office. All lectures and sessions of the main Forum will be held con-secutively. A lot of hot topics for QPs have been identified and will be dis-cussed in the various presentations, like: Revised EU-GMPs Electronic Data Risk Management Supply Chain Responsibilities Preceding the Forum, two parallel Pre-Conference Sessions on specific topics will run on 30 November: Investigational Medicinal Products and Quality Culture. To find out more please visit the QP Forum website.IWG meeting with Interested Parties on 10 March EQPA and ECA were taking part at the EMA’s inspector’s Working Group Meeting with Interested Parties on 10 March (online). The Interested Parties noted some actions during the meeting: 1. Covid-Lessons learned / GMP 2. GMP for importers (Annex 21) EFPIA with AESGP, ECA/EQPA, EIPG, MfE, VE 3. GMP for MAH with ECA/EQPA, EIPG, MfE, PDA 4. QP Training and operations ECA/EQPA with EFPIA, EIPG, PDA, MfE 5. EudraGMDP update and integration of OMS 6. IMP situation Ukraine Comments to planned revision of the ICH Q9 Guideline In December a draft of a planned revision of the ICH Q9 Guideline was published. The ECA Foundation together with its European QP Association set up an Expert Working Group to comment on the draft. This Expert Working Group was led by Yves Samson and with the members Britta AbellanFrançois Croizet, PQE France Jérôme Keldenich, Cenexi Philippe Lenglet, Laboratoires Servier Véronique Dagois, Capexpert Jean-Denis Mallet, Pharmaplan Éric Villain In the following you can find again what the ECA’s Interest and Working Groups have been working on in the first third of 2022.Dr Afshin Hosseiny (Chairman ECA Foundation)continued on back page
4IntroductionStability is defined as the extent to which a product retains, within specified limits, the same properties and characteristics that it possessed at the time of its manufacture and release throughout its period of storage and use (i.e., its shelf-life). All specification limits thus apply during stability studies and during the whole shelf life of the drug product until the end of the labeled expiry date (APIs: re-test period / retest date). Every pharmaceutical product on the market shall be so constituted that, if stored as directed, it will meet all applicable pharmacopoeial requirements and manu-facturer's specifications until its expiration date. But which param-eters need to be tested for medical cannabis during stability stud-ies? And which requirements apply? Useful information in relation to these questions is provided in the following sections. Stability Programme according to EU-GMP – What is required?The stability programme designed in accordance with the ICH Q1 Guidelineson Stability is required to establish the shelf life of a product and for receiving a marketing authorization. According to EU-GMP(Chapter 6), the manufacturer must have an ongoingstability programme to support the shelf life of the prod-uct. The programme shall meet ICH Q1 requirements. Bracketing and matrixing is possible according to ICH Q1 Guidelines (“Stability studies should be performed on each individual strength and container size of the drug product unless bracketing or matrixing is applied”). For multidose containers, in-use stability studies are required in princi-ple according to EMA´s NOTE FOR GUIDANCE ON IN-USE STABIL-ITY TESTING OF HUMAN MEDICINAL PRODUCTS. However, for example, stability testing is usually not required under GPP(e.g. Canada / NZ).The specific requirements for stability testing of herbal drugslike Cannabis, which is a narcotic substance, are sometimes challeng-ing. E.g. storage needs to be done in climate chambers in specifi-cally designed and secured facilities. In addition, specific rules have to be followed concerning import/export (e.g. need for special li-Stability testing for medical Cannabis – What needs to be consideredAbout the AuthorDr Andrea Kuehn-Hebeckeris Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the area packaging, herbal medicinal products, development and Lifecycle Management.
5censes), transport (e.g. GDP + additional security measures), sam-ple & waste handling and documentation.How do CBD and THC degrade?In an acidic milieu Cannabidiol(CBD) converts to Δ8- und Δ9-THC, whereas in an (highly) alkaline milieu, oxidation to a chinone due to reaction with oxygen occurs. During storage in presence of air, THC can be dehydrated to Cannabinol(CBN). CBN is also an oxidation product of Tetrahydrocannabinol(THC). Therefore, most of the national Pharmacopoeias set a limit of max. 1% for CBN (D, DK, CH) in flowers (D: in extracts max. 2.5%) and max. 1.5 % (Israela) as sta-bility indicator. The USP Cannabis Expert Panelbproposes for THC-dominant and THC/CBD intermediate types that CBN is max. 2% of the content of total THC.More information is provided in the article “Thermal Stability of cannabinoids in dried cannabis: a kinetic study”, from Juris Meija et al., published in Analytical and Bioanalytical Chemistryfrom January 2021. In addition, there is a free-of-charge simulator, based on the work of the same group – where it is possible to “play” with differ-ent initial cannabinoid values and temperatures and calculate the expected values after a certain time: Cannabis stability calculator (https://metrology.shinyapps.io/cannabis-calculator/).Which Guidelines / Pharmacopoeias provide use-ful information?General Applicable Guidelines from FDA and USP General Chapters• <1191> Stability Considerations in Dispensing Practice: The chapter covers aspects of drug product stability that are of pri-mary concern to the pharmacist in the dispensing of medica-tions.• <1079> Risks and Mitigation Strategies for the Storage and Transportation of Finished Drug Products • <1149> Guidelines for Assessing and Controlling the Physical Stability of Chemical and Biological Pharmaceutical Raw Ma-terials, Intermediates, and Dosage Forms (the original physi-cal properties, including appearance, palatability, uniformity, dissolution, and suspendability).• <1207.1> Package Integrity Testing in the Product Life Cycle—Test Method Selection and Validation• FDA Draft Guideline on Cannabis and Cannabis-Derived Com-pounds: Quality Considerations for Clinical ResearchSpecific EU Guidelines for Stability / Herbal DrugsFor herbal drugs, herbal drug preparationsand herbal medicinal prod-ucts, (HMPs) reference is made to the stability section of the EMA Guideline on quality of herbal medicinal products(EMA/HMPC/201116/2005).Further guidance is provided in:• Start of shelf-life of the finished dosage form (Annex to guid-ance on the manufacture of the finished dosage form) - CPMP/QWP/072/96. • Questions and answers on quality of herbal medicinal prod-ucts - EMA/HMPC/41500/2010. • Reflection paper on stability testing of herbal medicinal prod-ucts - EMA/HMPC/3626/2009• Guideline on stability testing for applications for variations to a marketing authorization - EMA/CHMP/CVMP/QWP/441071/2011.• Guideline on stability testing: stability testing of existing ac-tive substances and related finished products - CPMP/QWP/122/02.• Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products - EMA/HMPC/162241/2005.• Guideline on quality documentation for medicinal products when used with a medical device - EMA/CHMP/QWP/BWP/259165/2019Which parameters need to be tested during stability?The question often is: Which parameters should be tested during stability? And: Do all parameters for release testing need to be tested during stability? It is highly recommended to test the CBN content (degradation product) during stability studies (see above). In addition, Malta´s General Guidelineson the production of Can-nabis for medicinal and research purposes (Appendix I, Quality & Stability) proposes that stability tests must include, as a minimum, assays for THC & CBD, loss on drying (LOD), and microbiological contamination (see table 1). Where applicable, the tests and limits provided in the European Pharmacopoeia (Ph. Eur.) general chapters Herbal Drugs, Herbal Drug Preparationsand Herbal Drug Extractsmust be followed (USP <561> Articles of Botanical Origin/ <565> Botanical Extracts). In ad-dition, the provisions of the national monographs (e.g. Dc, DKd, CHe, NZf) need to be applied, as well. Regarding the use of analytical methods, see also Ph. Eur. chapter 5.26.Implementation of pharma-copoeial procedures(new) and 5.27. Comparability of alternative ana-lytical procedures(draft).In case of extraction solvents being used, Residual Solvents(Ph. Eur. 5.4, USP <467>) and Identification and Control of Residual Solvents(Ph. Eur. 2.4.24) have to be considered (CoA). For raw materials coming from an outside source, further tests (e.g. fumigant resi-dues, radioactivity) may be required. GMP for Herbal Medicinal Products (HMPs) + Post Conference on Qualification & Validation Aspects for CannabisLive Online Conference8/9 November 2022Learn more about this course:www.gmp-compliance.org
6Table 1: Proposed parameters for release and stability testing for Cannabis flowersCertificate of Analysis (CoA)STABILITY TESTINGCBNCBNContent THC*Content THC*Content CBD*Content CBD*LOD**LOD**Microbiological Contamina-tion***Microbiological Contamina-tion***Pesticides1Heavy Metals1Mycotoxins1Foreign Matter(Total Ash)****Identity *Assay limitsCannabis flowers: Usually, the total THC / CBD content must be 90 - 110 % of the labelled content. However, this might be different, e.g., if the flowers are considered to be an API. The USP Cannabis Expert Panel, for example, recommends 80 – 120 %. DAB Cannabis Extract: THC content: 1 - 25 %. Total THC / CBD: 90 to 110 % of the labeled content.Finished dosage form(e.g. Cannabis oil): Usually, the total THC / CBD content must be 95 - 105 % of the labelled content. **Usually max. 10-15 %. The USP Cannabis Expert Panel proposes to per-form water activity testing.*** Ph. Eur. 5.1.8. / 5.1.4. [USP <1111>] (depending on the dosage form / route of application), see also: Reflection paper on microbiological aspects of herbal medicinal products (EMA/HMPC/95714/2013). Starting material / herbal drugs used for the production of extracts: Usually criteria of Ph. Eur. 5.1.8, category A might be acceptable. In the case that it is demonstrated that these limits cannot be met, higher limits must be sufficiently justified.**** e.g., required in DK, NZ (usually max. 20 %)1 Skip testing might be possible, if justified and authorized, based on data and risk assessment.Terpenes: Where the amount of terpenes (or any other ingredient, includ-ing other cannabinoids) is specified and labelled, if intended as an as active ingredient, then the content needs also to be tested via an (validated) assay during stability studies.Where can I find information on reference substances?In 2008, EMA´s HMPC published a Reflection Paper on Markers used for Quantitative and Qualitative Analysis of HMPs(EMEA/HMPC/253629/2007). The HMPC recently announced to review Ph. Eur. definitions and HMPC monographs / assessment reports taking into account regulatory practice and different views on the role of active and analytical markers. A discussion paper will be drafted with proposals for better definitions considering existing Ph. Eur. defined extract types (particularly quantified extracts) [HMPC Work Plan 2022]. Further guidance (e.g. on characteriza-tion requirements for reference substances to be established as a primary standard) is provided in Ph. Eur. 5.12. Reference Standards.The German Pharmacopoeia(Deutsches Arzneibuch, DAB) cur-rently contains the two monographs Cannabis Flower and Cannabis Extract. Reference substances, such as cannabinol (CBN) and can-nabidiol (CBD), are required for assay and purity tests, as well as for identity tests (TLC), specified therein. A notice from the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arznei-mittel und Medizinprodukte, BfArM) dated from 9 February 2022 recommended the following revised reagent descriptions for inclu-sion in the DAB:Cannabinol RNCannabidiol RNCannabidiolsäure RN(Cannabidiolic acid)Delta-8-Tetrahydrocannabinol RNDelta-9-Tetrahydrocannabinol RNDelta-9-Tetrahydrocannabinol-Säure RN(Delta-9-Tetrahydrocan-nabinolic acid)The revision concerns the change that 13C-NMR data can be used alternatively (or in addition to 1H-NMR data) for identification. Pre-viously, substances must comply with 1H-NMR and13C-NMR tests.Ph. Eur. and USPIn the European Pharmacopoeia (Ph. Eur.), there are currently no Ph. Eur. reference substances for cannabis analysis provided (the Ph. Eur. Cannabis monographs for flowers and extracts are cur-rently under development). However, the USP includes mono-graphs for Dronabinol and CBD (draftg) and already offers several reference substances (see also USP's "Cannabis for medical use" website): Delta-9-Tetrahydrocannabinol Exo-Tetrahydrocannabinol Cannabinoid Acids Mixture Cannabinoids Mixture Cannabidiol Solution Cannabidiol Delta-8-tetrahydrocannabinol (Δ-8-THC) is described in the USP under "Reagents" ("Use a suitable grade, which may be a solid ma-terial or a solution in methanol"). Several supply sources for "suit-able grade" Δ-8-THC are also listed there.aIsrael Medical Cannabis (IMC) - GMP (SOP 152): Good Manufacturing Practice for Medical Cannabis Products.bCannabis Inflorescence for Medical Purposes: USP Considerations for Quality Attributes (J. Nat. Prod. 2020, 83, 1334-1351).cGerman Pharmacopoeia (DAB) Monographs Cannabis Flower and Cannabis Extract, StandardizeddDanish Monograph Cannabis Flower (Dansk monografi Cannabisblomst)eSwiss Pharmacopoeia (Ph. Helv.) Monograph Cannabis FlowerfNew Zealand Product Quality Standards Monograph (Appendix 2 of the Medicinal Cannabis Scheme)gUSP draft monograph Cannabidiol [Pharmacopeial Forum (PF) 48(1)]
7The wholesale distribution of medicinal products requires a Whole-sale Distribution Authorisation (WDA). Within the European Union, these authorisations are issued by the national competent author-ity of the member state in which the wholesale distributor oper-ates. The member states shall enter the certificates of good distri-bution practices which they issue in the EudraGMDP. This database is maintained and operated by the European Medicines Agency (EMA).1If an inspection shows that the wholesaler's GDP compli-ance cannot be confirmed, a so-called GDP non-compliance report is issued.The explanatory notes to the database state: “A certificate of Good Distribution Practice (GDP) is issued to a wholesale distributor by the national competent authority that carried out an inspection if the out-come of the inspection confirms that the wholesale distributor com-plies with Good Distribution Practice, as provided by European Union legislation. If the outcome of the inspection is that the wholesale dis-tributor does not comply a statement of non-compliance may be en-tered into EudraGMDP. GDP certificates and statements of non-compli-ance may be issued to wholesale distributors of medicinal products and distributors of active substances.”2Documents issued by UK authorities up to and including 31 Decem-ber 2020 remain available for consultation in EudraGMDP. How-ever, as of 01 January 2021, they are no longer included or updated, with the exception of documents relating to sites in Northern Ire-land.Number of ReportsThe number of GDP non-compliance reports entered into the Eu-draGMDP database is rather small. As of mid-April 2022, a total of 26 documents were listed, 25 of which are from the period covered in this article – between 2014 and 2021.The following table provides an overview of how the reports are spread over the various years. About the AuthorDr. Markus Funk joined CONCEPT HEIDELBERG in October 2019 as operational director and is in charge of the topics GDP and analytics.Common and Typical GDP ViolationsAn Evaluation of GDP Non-Compliance Reports since 2014
8The GDP Compliance ManagerLive Online Training on 11/12 October 2022gmp-compliance.orgYearNumber of GDP non- compliance reports2014120150201612017120184201962020620216Issuing AuthoritiesAs can be seen from the table below, most GDP non-compliance reports were issued by German authorities in the period from 2014 to 2021. The table also shows that many countries have not yet entered any GDP non-compliance reports into the database.CountryNumber of GDP non-compliance reports entered between 2014 and 2021Germany7Romania4Czechia3Slovakia2Portugal2United Kingdom2Cyprus1Spain1Austria1Denmark1Malta1Reasons for Issuing the ReportsThe table printed below provides an overview of the deficiencies that led to the issuing of the 25 GDP non-compliance reports from 2014 to 2021. In each case, an attempt has been made to assign the deficiency in question to one of the requirements from the EU GDP Guidelines.3Since the individual deficiencies are generally only de-scribed very briefly, certain imprecisions in the categorization can-not be excluded.The total number of violations is much higher than the number of reports, as most reports list several independent aspects. Typical-ly, therefore, it is not a single violation but rather a variety of devia-tions that led the respective authority to issue the GDP non-com-pliance report. However, the report itself often lists only the critical and major deficiencies, although there may have been other find-ings as well.AreaQuantityCHAPTER 1 — QUALITY MANAGEMENT1.2. Quality systemNo adequate documentation for acting according to the procedures5Deviations from established procedures not documented or investigated3No GDP-compliant quality assurance system in place2No appropriate quality risk management established2Inappropriate corrective and preventive actions (CAPA) 2It is not ensured that the product delivered maintains its quality and integrity and remains within the legal supply chain during storage and/or transportation3QA department understaffed1No change control system in place1Doubtful reliability of the CEO due to an ongoing criminal procedure1Other / general deficiencies (not further specified)41.3. Management of outsourced activitiesNo sufficient control and verification of the out-sourced activity1
91.4. Management review and monitoringNo assessment of performance indicators that can be used to monitor the effectiveness of processes within the quality system1CHAPTER 2 — PERSONNEL2.2. Responsible personServices / availability of a responsible person not ensured5Responsible person does not fulfil his/her obligations5Doubtful reliability due to an ongoing criminal procedure12.4. TrainingNo regular GDP training performed / no training documentation available 2CHAPTER 3 — PREMISES AND EQUIPMENT3.2. PremisesInadequate premises and storage facilities / storage facilities not qualified4No adequate access control system to prevent unauthorised access to the premises2Inappropriate cleaning1No pest control programme1No physical segregation of non-marketable medicinal products13.2.1. Temperature and environment controlNo or insufficient temperature and environment control43.3. EquipmentTemperature monitoring not performed by calibrated measuring instruments1Location of temperature measuring instruments not sufficient to meet the required purpose13.3.1. Computerised systemsThe computerised system has not been properly validated13.3.2. Qualification and validationMissing validation or qualification reports2CHAPTER 4 — DOCUMENTATION4.2. GeneralDocumentation not available or missing4CHAPTER 5 — OPERATIONS5.1. PrincipleNo measures implemented to minimise the risk of falsified medicinal products entering the legal supply chain.2General deficiencies (not further specified)15.2. Qualification of suppliersInappropriate qualification of suppliers9Failure to conduct due diligance before purchasing from a new supplier25.3. Qualification of customersNo qualification carried out / no system in place / qualification inadequate75.4. Receipt of medicinal productsInadequate receipt control (for counterfeit drugs)2Insufficient documentation1General deficiencies25.5. StorageNo temperature records available1General deficiencies (not further specified)25.8. SupplyDocumentation not available4CHAPTER 6 — COMPLAINTS, RETURNS, SUSPECTED FALSIFIED MEDICINAL PRODUCTS AND MEDICINAL PRODUCT RECALLS6.2. ComplaintsInappropriate handling of complaints16.3. Returned medicinal productsInadequate handling of returned medicinal products26.4. Falsified medicinal productsTrading in falsified medicinal products (not pur-chased from legal supply chain)5Missing connection to securepharm system16.5. Medicinal product recallsEffectiveness of the arrangements for product recalls not ensured3Responsibility not fulfilled1CHAPTER 7 — OUTSOURCED ACTIVITIES7.2. Contract giverUse of contracted entities without acceptable qualification1No audits carried out at contractor acceptor1CHAPTER 8 — SELF-INSPECTIONS8.2. Self-inspectionsNo regular self-inspections performed 2CHAPTER 9 — TRANSPORTATION9.2. TransportationNo temperature records available / no temperature monitoring performed2Temperature deviations not adequately investigated1OTHERSIncorrect and/or incomplete information given to inspectors / Failure to comply with the reporting requirements5EvaluationMany of the deficiencies documented in the GDP non-compliance reports are related to the duties of the responsible person. According to chapter 2.2 of the EU GDP Guidelines, the wholesale distributor must designate a person as responsible person, which should fulfil his or her responsibilities personally and should be continuously contactable.As can be seen from the overview table, in five cases the availabil-ity of a responsible person was not even ensured. In five other cases, a responsible person was available, but he or she did not
10fulfill his or her duties. In one case, there were doubts about the reliability of the person due to ongoing criminal proceedings.The responsibilities of the responsible person include the organiza-tion and control of the wholesale operation. In addition to logistical activities, the responsible person also has a lot of other duties, such as4: • Ensuring that initial and continuous training programmes are implemented and maintained;• Approving any subcontracted activities which may impact on GDP; • Ensuring that self-inspections are performed at appropriate regular intervals following a prearranged programme and nec-essary corrective measures are put in place; • Approving any returns to saleable stock;Thus, even most of the findings listed in the overview table can be linked, at least indirectly, to the fact that the responsible person in question did not perform his or her duties in compliance with the EU GDP Guidelines.One area of focus in this regard relates to falsified medicines. In addition to (intentional) trade in counterfeit drugs, insufficient checks and inadequate measures to minimize the risk of counter-feit medicines entering the legal supply chain were criticized on numerous times. The inadequate qualification of suppliers, which was mentioned in as many as nine GDP non-compliance reports, and the lack of due diligence mentioned in two cases should also be seen in this context. According to chapter 5.2 of the EU GDP Guidelines, appropriate qualification and approval of suppliers, should be performed prior to any procurement of medicinal prod-ucts. Before entering into a new contractual relationship with a new supplier, a wholesaler should carry out due diligence checks. The purpose of this is, among other things, to minimize the risk of counterfeit medicines entering the legal supply chain.Finally, the qualification of customers must also be mentioned. Ac-cording to chapter 5.3 of the EU GDP Guidelines, wholesale distrib-utors must ensure they supply medicinal products only to persons who are themselves in possession of a wholesale distribution au-thorisation or who are authorised or entitled to supply medicinal products to the public. In seven cases, companies did not comply with this requirement because either no qualification was carried out or the qualification was considered insufficient by the authority.1 A free read only access to the EudraGMDP database is available via http://eudragmdp.ema.europa.eu/.2http://eudragmdp.ema.europa.eu/inspections/selectLanguage.do; accessed 11 April, 2022.3Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use– 2013/C 343/01.4Cf. chapter 2.2 paragraph 5 numbers i to xii of the EU GDP Guidelines.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
11APIC's annual API Conference is the most important forum for API manufacturers and the pharmaceutical industry. In 2020, the con-ference took place as a live online event - as did the "24th APIC/CEFIC Global GMP & Regulatory API Conference" in 2021. The in-creased focus on the topics of global collaboration in the field of regulatory affairs and GMP-compliant manufacturing was yet again reflected in the selection of speakers: representatives from the in-dustry and from international authorities met online to receive first-hand information and to exchange views on current develop-ments.After the opening of the conference by APIC President Hilde Van-neste, one of APIC's representatives, Matt Moran, guided the par-ticipants and speakers through the first conference day. The first day of the conference featured presentations by Lyle Cani-da, US FDA, on the QMM (Quality Management Maturity) pro-gramme, Rita Purcell, HPRA Ireland, on Brexit and Andrzej Rys, Euro-pean Commission, on reshoring of production sites. In addition, Maggie Saykali, Cefic, presented the challenges and opportunities of European supply chains in the context of API production, espe-cially in times of the Covid-19 pandemic.As a special highlight of the first conference day, the presentation by Jennifer Sloan, Pfizer USA, must be mentioned. As was to be ex-pected in advance from the name of the presentation ("Covid Vac-cine - can the API Industry and Authorities learn from Speed from Concept to Patient Use?") it was very well received not only by the participants but also by the speakers and APIC representatives, which was evident in the large number of questions and com-ments.Jennifer Sloan's presentation highlighted the success story of Cov-id-19 vaccine production over the past months, which was charac-terised by the four key words "Courage", "Excellence", "Equity" and "Joy" (see also Figure 1). The fact that the point "Joy" also played a crucial role here and contributed significantly to the success be-came clear not only in the video shown by Jennifer Sloanon the About the AuthorAnne Günster joined CONCEPT HEIDELBERG in 2019 and organises and conducts courses and conferences on behalf of the ECA Academy in the areas API Manufacturing, Regulatory Affairs, Documentation and Laboratory Data Integrity.Highlights of the "24th APIC/CEFIC Global GMP & Regulatory API Conference"26-28 October 2021
12applied and newly established supply chains - which would prob-ably be impossible to establish under "normal circumstances".As in the previous year, the first day of the conference ended with a final Q&A session and closing remarks by APIC President Hilde Vanneste. The second conference day began with six parallel sessions, which were led by APIC representatives Rainer Fendtand Beate Miller. Par-ticipants were able to choose three topics from of the six practice-oriented sessions and change the online meeting rooms according to their fields of interest. As in previous years, these presentations were seen more as an exchange between speakers and participants and were peppered with surveys, in-depth questions and discus-sion rounds. The presentations on "Latest developments in nitros-amine impurities - impact on the API industry", "Regulatory hurdles and opportunities" and "China Drug Product regulatory process" attracted great interest, but the sessions on "Data Integrity: What's next", "Remote Audits - A concept for the future?" and "ICH Q13- Achieving regulatory harmonization for Continuous Manufactur-ing" were also well received.In the afternoon, Hélène Bruguera, EDQM, presented the activities and innovations regarding the CEP procedure and inspection pro-gramme of the EDQM. Special attention was given to the presentation "Update from AN-VISA" by Renan Araujo Gois, ANVISA Brazil (see also Figure 2). In his presentation, he explained the new Active Pharmaceutical Ingredi-ents (APIs) regulation (RDC 359/2020) of ANVISA and provided in-formation about the contents of the DIFA (Active Pharmaceutical Ingredient Dossier) as well as of the CADIFA (Letter of Suitability of the Active Pharmaceutical Ingredient). After a general overview, the administrative points of the registration of active pharmaceuti-cal ingredients in Brazil were listed and the challenges in this re-gard were pointed out. The transition periods until the mandatory use of the new registration process were explained in detail. Fi-nally, the presentation included information on the stability stud-ies required, GMP requirements and the handling of nitrosamine impurities.The last day of the conference started with the presentation "The Importance of Workplace Wellbeing in the post pandemic world" by Sophie Moran, Ibec Ireland, and was accompanied by APIC repre-sentative Danny de Scheemaecker.In addition to the topics "Digitalisation opportunities in API & GX-product development" and "Update on EAEU legislation", which were presented by Uros Klancer, San-doz, and Ekaterina Bobrysheva & Arkadiy Gorozhanin, Sandoz, Marieke van Dalen, Aspen Oss, presented the complexity of international API supply chains and the challenges involved. Following the final Q&A session, Luisa Paulo, APIC Vice President, concluded the 24th APIC/CEFIC Global GMP & Regulatory API Conference with her closing remarks.Once again, the exchange between rep-resentatives of industry and authorities formed the core of this conference. The dedicated Q&A sessions of the event provided a perfect frame-work for this.Note: The "25th APIC/CEFIC Global GMP & Regulatory API Conference" will take place in Amsterdam on 26-27 October 2022. On the occasion of the 30th anniversary of APIC, high-ranking representatives from international drug regulatory authorities and industry will report on the current quality and regulatory trends regarding active pharmaceutical in-gredients and discuss current issues with you. The ICH Q7 requirements and their implementation in the GMP environ-ment will also be explained in detail and discussed in depth during the pre-conference session "ICH Q7 How to do - Doc-ument Hot Topics from the revised APIC guidance" on 25 October 2022.CourageThink bigSpeak upBe decisiveExcellenceFocus on what mattersAgree who does whatMeasure outcomesEquityBe inclusiveAct with integrityReduce healthcare disparitiesJoyTake prideRecognize one anotherHave funFigure 1: Slide 3 of the presentation "Covid Vaccine - can the API Industry and Authorities learn from Speed from Concept to Patient Use?" by Jennifer Sloan, Pfizer USANew API Regulation - OverviewPublished in April 1st, 2020Into force in August 3rd, 2020 (transition period)Primarily intended for DIFA holderRDC 359/2020DIFA + CADIFARDC 361/2020ALTERING• Submission procedure• Variations• Suspension/WithdrawalFigure 2: Screenshot of slide 4 of the presentation "Update from ANVISA" by Renan Araujo Gois, ANVISA
13BackgroundWith the chapter <1115> "Bioburden Control of Nonsterile Drug Substances and Products", the USP brought the topic of bioburden into the focus of pharmaceutical manufacturers. The chapter puts the focus on• Increased focus on the control of microbial populations throughout the production cycle of excipients, active ingredi-ents and finished medicinal products.• Greater emphasis on the control of microbial populations at all stages of manufacture in the development of formulations and manufacturing processes.• Place greater emphasis on water activity as a control measure.• Greater emphasis on water for pharmaceutical use and clean-ing of process equipment.• Introduce content that raises awareness of housekeeping and disinfection as control measures.But "bioburden" is not just an issue for non-sterile products. Annex 1 of the European GMP Guide requires: "Bioburden should be moni-tored prior to sterilisation. There should be working limits for con-tamination immediately prior to sterilisation that relate to the ef-ficiency of the method to be used. The bioburden test should be performed for each batch, both for aseptically filled products and for terminally sterilised products."Last but not least, bioburden testing for medical devices manufac-tured or used in the US is regulated by Title 21 of the Code of Fed-eral Regulations and globally by ISO 11737.These recent developments prompted the ECA Academy to ad-dress this topic in a special workshop session to look at it from different angles and provide information on the regulatory back-ground as well as practical examples and strategies for bioburden control. Pharmacopoeia experts, representatives of pharmaceuti-cal quality control and testing laboratories compiled the most im-portant information and showed the challenges of bioburden con-Q&A from European GMP Conference: “Bioburden – Regulatory Expectations and Practical Experiences”Dr. Sebastian Thoelkenis Process Expert Microbiology, MS&T Steriles at Novartis Pharma Stein in Switzerland.About the AuthorsSven M. Deutschmannis Head of Global ASAT Adventitious Agents Testing & Alternative Microbiological Methods, Global Analytical Science & Technology at Roche Diagnostics in Ger-many.
14trol strategy and how to implement adequate control in companies. From the questions that arose during this workshop, the experts started to compile a Q&A document. The first section, "Biopharma-ceutical Manufacturing". compiled by the Chairman of the ECA Pharmaceutical Microbiology Working Group, Sven Deutschmann , Roche Diagnostics, and Sebastian Thoelken of Novartis Pharma Stein AG is now available.Q and A-Sessions: “Biopharmaceutical Manufacturing”Sven Deutschmann (Roche), and Sebastian Thoelken (Novartis Pharma Stein AG)This document lists all questions received during the “Bioburden”-Workshop after the following four presentations held by Sven Deutschmann (Roche) and Sebastian Thoelken (Novartis) on Biop-harmaceutical Manufacturing:• Bioburden Testing – Guidelines and Regulations(S. Deutschmann, Roche Diagnostics GmbH)• Microbial Control Strategy for Biopharmaceutical Manufac-turing(S. Deutschmann, Roche Diagnostics GmbH)• Bioburden for Sterile Operations(S. Thoelken, Novartis Phar-ma Stein AG)• Assessment of Bioburden Excursions in Non-Sterile Biolog-ics Manufacturing Processes(S. Deutschmann, Roche Diag-nostics GmbH)1. Microbial Control System• Questions: (i) “What is the lower specification for a bioburden? A bioburden with specification less than 1 is not realistic? (due to the environ-ment, consumables and equipment of the test)? So what should be the lower specification? Less than 3? Less than 5?” (ii) “Regarding bioburden limits: Samples from BDS production in Class D, C and B are taken aseptically and analyzed in a non-clas-sified microbiological laboratory. Occasionally, a couple of colo-nies can appear on plates from sampling or handling. Does it make sense to have a bioburden limit of <1 CFU/10 mL in this setting or what would you recommend?”Answer: A stepwise progression of limits is defined. Tighter limits are set closer to the end of the process with ≤ 10 CFU/10 mL if DS is frozen.• Questions:(i) “Did you perform a bioburden method suitability test for each defined sampling points? Or did you adopt an approach based on a worst case sample (probability of the intermediate / buffer to in-terferes with the test) to cover some other steps and reduce meth-od suitability test effort based on a risk assessment?”(ii) “Authorities and inspectors - to what extend do they expect monitoring the control of bioburden in the complete buffer/drug substance/drug product process, is this all risk based?”Answer: Yes, a Method Suitability Test is performed for each defined sampling point. A risk-based approach is used to de-fine the sampling points considering e.g. amongst others (i) configuration of process equipment, including the placement of bioburden reduction filters to avoid possible blind spots in detection of contaminants or (ii) open processing steps and surrounding environment or (iii) the potential impact of condi-tioning steps (e.g., extreme pH adjustments or solvent/deter-gent additions) for potential inactivation of putative biobur-den must be considered or (iv) the growth-promoting capability of the process pool.• Question: “Should buffers which are received sterile filtered be tested for bioburden before being used in manufacturing? We al-ready test for endotoxin.”Answer: There are no specifications that require this. If steril-ity of the buffer is mandatory, then this should also be verified by certificates or demonstrated by testing.• Questions: (i) “Should there be alert levels for all bioburden IPCs taken from aseptic production?”(ii) “For aseptic production in class C-D clean rooms, do you still recommend alert levels for all IPC steps? Or is alert levels for IPC steps only required when aseptic production in class A-B?”Answer: Yes.• Question: “Can processes of pH manipulation of the pool (like viral inactivation) mask the presence of bioburden or endotoxins in it? I mean, is possible BB being detected in the BB analysis in a sample of the pool prior to execute the viral inactivation and not after the viral inactivation is ended?”Answer: Yes - the potential impact of conditioning steps (e.g., extreme pH adjustments or solvent/detergent additions) for potential inactivation of putative bioburden must be consid-ered.• Question: “Do you always sample and test for endotoxins in par-allel to Bioburden? If not why?” (note: explicit question to the Novartis colleague)Answer: Not always but in most cases. Note: EMA GUIDELINE ON THE STERILISATION OF THE MEDICINAL PRODUCT, AC-TIVE SUBSTANCE, EXCIPIENT AND PRIMARY CONTAINER does not request to test for endotoxins prior to sterile filtra-tion. Only a bioburden control is requested.• Question: “If alert levels are required for all IPC steps does it then apply to all product phases (Phase I-III, PPQ and commercial)? And how do you establish alert levels for phase I-III and PPQ if only a small amount of batches have been produced?”Answer: Yes. Provisional limits are used during development until sufficient historical data has been generated. Alterna-tively, for products manufactured infrequently (e.g. in devel-opment) data from similar processes may be used.• Question: “As the Bioburden is sampled before sterilization by fil-tration the product is not yet sterile so some inspectors want us to apply all expectations that are rather applicable to biological DS. Is this relevant? What would you recommend?” Answer: The philosophy of stepwise progression of the limits should be applied for DP manufacturing as well. Hence, the limits applied for Drug Product manufacturing should not be less stringent as the limits defined for Drug Substance. Step-wise progression of limits. • Question: “What about the bioburden (and its by-products) im-pact on used production equipment. In case of microbial counts; there is any guideline/rationale to assess resins/UFDF mem-
15branes safety to be used again in the manufacturing process? If the event is TNTC and no calculations can be performed, there is any way (e.g. some kind of blank run study) to defend no impact due to this byproduct?”Answer: Cleaning and sanitizing operations should be strin-gent enough to remove contaminants and any by-products. The effectiveness of the cleaning and sanitizing measures must be proven in a cleaning validation and a monitoring of the cleaning and sanitizing measures must be established in the routine.• Question: “Regarding hold time limits for manufacturing, is it im-portant to define hold times for each process step? Or the overall hold time (all process steps until start of sterilization) is what mat-ters from a microbiological point of view?”Answer: Yes. A maximum hold time for each process step must be defined and validated.• Question: “You described controls to assess the risk of contami-nation for Pharmaceutical ingredients and API manufacturers. To your knowledge, is there a requirement for environmental moni-toring of facilities manufacturing API or raw material intended to be used for the manufacturing of non-sterile drug product (dry forms)?”Answer: If a hygiene zone is defined for the production in which the production is to take place, then the requirements for this hygiene zone must be fulfilled.2. Drug Substance Manufacturing• Question: “Is it bioburden anaerobic test required or FDA expect-ed in any of the manufacturing process steps, such us in cell cul-ture?”Answer: Yes, FDA requested to test for anaerobic bioburden at the end of the mammalian cell culture process.• Question: “Was the mammalian cell culture media used in the fi-nal bulk of the product?” Answer: No. In CHO-based expression systems, the product is released into the supernatant. The supernatant is purified. Hence, the cell culture medium is no longer in the final prod-uct.• Question: “What is the recommended method for pre-culture harvest samples in order to microbial detection, filtration method or liquid media as TSB?”Answer: It depends on the specification for the pre-harvest samples. If “absence of any microbial contaminations” is de-fined, a qualitative method such as the direct inoculation could be used. If a bioburden limit is defined – e.g. ≤ 10 CFU/10 mL – a quantitative method must be used. Due to the defined volume to be tested, only the membrane filtration method is applicable.• Question: “Referring pre-filtration samples of the column eluate. Elution phase is usual not constant during the whole phase, nor-mally a high peak of concentrated product is eluted in the first fraction of the elution while the concentration of product lowers as the end of the phase is nearing. Which moment should be sam-pled and how we can assure that is representative of the whole phase?” Answer: The bioburden in the relevant fraction used for fur-ther processing should be tested. 3. Drug Product / Final Product Manufacturing• Questions: (i) “EMA Guideline on the sterilization of the medicinal product, active substance, excipient and primary container (6 march 2019) states that “In most situations, a limit of NMT 10 CFU/100 ml (TAMC) would be acceptable for bioburden testing”. From your perspective, does therefore 100 ml represent the minimal volume to be filtered? And do you have experienced FDA expectation about minimal volume for product to be filtered?”(ii) ““What is a reasonable bioburden limit prior to sterilization of a small volume pharmaceutical solution? Guidelines suggest 100 cfu/100 ml, but if the whole batch is only one vial of 20 ml, this would mean 2 cfu per vial, almost sterile. 100 cfu/100 ml does not make sense, but what other limits may be justified?”(iii) “Is the specification/acceptance level 10 CFU/100 ml?” Answer: A sample volume of 100 mL is expected. Any devia-tion from this sample volume must be justified and accepted by the competent Health Authority. Generally, no “minimum” volume can be defined. It is always a case-by-case considera-tion.• Question: “For terminally sterilised products, for which the man-ufacturing process includes a bioburden reduction filtration step before sterilization, where in the process should IPC bioburden be sampled? Is it OK to test bioburden after filtration (but before sterilization)? Or bioburden should be tested on the bulk (before filtration and sterilization)?”Answer: Additional sampling points may be required if the Drug Product manufacturing process includes further process steps.• Questions:(i) “When analyzing a 10 ml sample (IPC or DS), do you express fi-nal result in CFU/10 ml or do you allow extrapolation to 100 ml to comply with EMA Guideline on the sterilization of the medicinal product, active substance, excipient and primary container (6 march 2019)?”(ii) “Spec < 10 CFU/100 ml ... if we have only 10 ml to be test, then I found not comfortable to have a specification < 1 CFU/10 mL : The bioburden test made under microbiological lab can't manage a specification of < 1 (equipment, environment of the test...)?”Environmental Monitoring - Trending, Analysis and Data ManagementLive Online Training9/10 November 2022A Special Training on Efficient Data Man-agement and InterpretationLearn more about this course:www.gmp-compliance.org
16(iii) “For small size batches you are ok to extrapolate a result ob-tained on a 10 ml (or 30 ml) sample to 100 ml. This is based on an assumption that micro contamination is homogeneous in a sam-ple. However, most of time, germ are clustered in a sample. There-fore how do you justify you approach?”(iv) “What is the considered a low batch size ? max 10 liters ? more?”Answer: Your internal test method must define the reporting. The final result could be reported in CFU/10 mL or after ex-trapolation in CFU/100 mL.• Questions:(i) “Did you demonstrate Mycoplasma retention capability of your 0.2 micron-filter when used for sterilization of products?”(ii) “Especially how did you manage USP<1229.17> chapter on my-coplasma sterilization? Or do you plan to go to a standard 0.1 mi-cron sterilization?”(iii) “Bioburden prior sterile filtration: do you check really absence of Mycoplasma?”Answer: Yes (for DS process) and No (for DP process). Typical-ly, the requirements for filter used for final sterile filtration provided in sub-section 4.1.5. “Sterile filtration” and the filter data to be provided in the quality dossier is summarized in Table 3. of the EMA guideline are used. Absence of Mollicutes will be demonstrated at the end of the cell culture / USP pro-cess and aseptic manufacturing conditions guarantee that no Mollicutes contaminations occur during the DSP process. (Note: USP chapters above 1000 are not binding but for infor-mation only).• Question: “Alert level = how is perform the identification? Always by 16S rDNA sequencing?”Answer: Yes• Question: “Annex 1: Terminally sterilisation stated as bioburden might be monitored. So not as mandatory. What is your experi-ence with inspections/authorisations regarding this topic? Was that the reason to go to batchwise testing, or was there another reason?”Answer: EMA GUIDELINE ON THE STERILISATION OF THE MEDICINAL PRODUCT, ACTIVE SUBSTANCE, EXCIPIENT AND PRIMARY CONTAINER Clearly requests monitoring of biobur-den prior to the final sterilization process.• Question: “If the last Bioburden sample should be missed (due to lab error or other reason), would this immediately mean a rejec-tion of batch, or could also then historical data save the batch? Or sterility testing of final product?”Answer: In principle, a missing bioburden result does not mean that the batch must be rejected. The company has the possibility to perform a risk assessment. If the bioburden re-sult of a late IPC sample is missing - or even the bioburden result prior to the sterile filtration step - then it will probably be very difficult to release the batch on the basis of a risk as-sessment. Ultimately, the QP decides in Europe and the QA unit in other countries.4. Risk Assessment• Question: “Is the risk assessment of MO recovered in an in-pro-cess bioburden for a sterile product an expectation?”Answer: During the batch release process, each contamina-tion event must be investigated as to whether it could have an impact on the product and/or patient safety and thus whether the batch concerned can be released or not on the basis of a risk assessment. • Question: “Do you consider that the risk assessment documenta-tion scope also include In-process control bioburden test on man-ufacturing intermediates or buffers (for biopharma drug sub-stance manufacturing)?”Answer: Yes• Questions:(i) “Could you share some steps for the non-bioburden procedure if test for bioburden is missed.”(ii) “When a bioburden result is missed do you handle this situation as a non conform bioburden result?”Answer: An Investigation of Missing Bioburden Result is a cross-functional activity including QC, QA and Production.• In a first step, the reason for the missing bioburden result must be identified and CAPAs must be defined. • The next step is to evaluate the ability of the manufactur-ing process to remove the contamination and/or possible byproducts. If available, the following data could be con-sidered:-Bioburden results for the process steps before and af-ter each sample type-Trend analysis and relevant bioburden results over the runs for the sample type in question-Endotoxin results for the first process step in which this test is performed after the sample type in question-Provide an assessment of environmental QC data for the production site and the Water used for process op-erations for the sample type in question.• Question:“Is patient safety and product quality assessment re-quired for in-process test pre-fitration bioburden of sterile prod-ucts?”Answer: No – the expectation is if the bioburden limit is ex-ceeded the batch should be rejected.• Question: “For ID of bioburden >alert level, to what level to you perform identification (always to species-level, or Gram-charac-terization)?”Answer: 16S rDNA sequencing is used as for the case-by-case assessment of bioburden excursion the contaminant must be identified to perform the next steps of the assessment.• Question: “PQI calculation. Is it taken into account the doubling time of the microorganism and the time from sampling until prod-uct pass through the filter to calculate the theoretical level of bioburden reached? And is this number use for the PQI calculation and not the bioburden count in the sample?”Answer: No, the bioburden count in the sample is the relevant value.• Question: “The critical components are analyzed in theory or re-ally practical measures (with external contractors)?”Answer: It is a combination of literature review, experimental study (proteomic study) but also clinical studies.
17• Question: “Which stability tests are recommended for justified there is not PQI?”Answer: Assays that analyze the integrity of the product.• Question: “For the assessment of Bioburden Excursions, bacterial DNA and cellular components could potentially be released from all bacteria. This means that for these components the number of microorganisms in the IPC is used to calculate the risk (microbial ID does not matter in this case)?”Answer: For the fraction of e.g. flagellin or bacterial DNA we use generic values. However, for e.g. cell wall components, it makes a difference whether the contaminant is a Gram-posi-tive or Gram-negative bacterium. Whether a contaminant pro-duces exotoxins, and if so, which ones, can only be evaluated if the contaminant has been identified.• Question: “What are the key literature sources/references for the patient safety assessment?”(note: explicit question to the Roche colleague)Answer: An important document is the Registry of Toxic Ef-fects of Chemical Substances (RTECS®), Comprehensive Guide to the RTECS, D. V. Sweet Ed., US Department of Health and Human Services, Public Health Service, 1997.• Question:“Literature search: do you find always the information about theoretical conc. of PAMPs?”Answer: Yes.• Question: “Proteases are evaluated during the PQI assessment right?”Answer: Yes.• Question: “If the result reported of the count is TNTC, is there any worst case to perform a PQI?”Answer: We do not use a generic assessment of bioburden ex-cursions. The test method must be able to quantitate ≥ 10-fold the action limit. But theoretically, you could also do a calcula-tion / an assessment assuming you have a contamination with 1000 CFU/mL or 10,000 CFU/mL of a worst-case microorgan-ism. The model also works with such assumptions.• Question: “There is literature of more potent exotoxins with re-gards B. cereus, how do you determine B. cereus to be the worst case?”Answer: To our knowledge, botulinum toxins (produced by Clostridium botulinum) are the most potent bacterial toxins. Followed by tetanospasmin and tetanolysin (both from Clostridium tetani).• Question: “If the reduction of the bacterial byproducts cannot be measured, we don´t know if the theoretical values calculated are reduce in the following process steps. Why is stability only recom-mended if there is not further reduction steps?”Answer: We know from process validation that cellular com-ponents (e.g. host cell DNA, host cell proteins, ...) are removed during the downstream process. However, we cannot define exactly what the purification rate is for specific microbiologi-cal components. Therefore, we only perform the stability study if in final purification process steps the bioburden value exceeds our pre-defined limits.• Question: “Is it safe to calculate the risk for each component separately? Maybe two components that both induce innate im-mune responses have synergistic effects? Or this is covered by the worst-worst-worst case aspect of the calculations?”Answer: For each component the calculation is a “worst-worst-worst”-case assumption. Hence, we negate synergistic effects. This is also accepted by the health authorities.5. Bioburden Testing• Question: “Regulatory expectations related to bioburden data in-tegrity. Second verifier analyst requirement for plate counting?” • Answer: (SD) In theory, yes. For some bioburden sampling points the contemporaneous verification could be waived based on a risk assessment. Guidance for such a risk assess-ment provides BioPhorum’s RISK ASSESSMENT OF TRADI-TIONAL CULTURE-BASED MICROBIOLOGICAL TESTS RE-QUIRING CONTEMPORANEOUS VERIFICATION. The current draft of the revision of USP <1117> follows this philosophy.• Questions: (i) “When the specification of the product has to be reported as combined TAMC and TYMC, should all colonies of each plate being counted, sum and reported regardless type of microorganism? I mean, - TAMC: 1 bacteria and 1 Mold - 2 CFU/10 mL- TYMC. 1 bacteria and 1 Mold - 2 CFU/10 mL- Final result: Combined TAMC+TYMC: 4 CFU/10 mL?”(ii) “What do you think about the sum of TYMC and TAMC results sometimes expected by EU inspectors?”(iii) “You has TYMC in the past. How did you manage the results? TAMC and TYMC separatly compared to 10 CFU/100 ml? Or you made the sum of both (as expected by some authorities)?”Answer: Neither Roche nor Novartis perform a TYMC count. Hence, this aspect is irrelevant for us.• Questions:(i) “Is SDA required for monitoring each steps of the in the drug manufacturing process? OR TYMC specification is just required for product release?”(ii) “Is TYMC really expected for in process bioburden testing for sterile products?”Answer: Health authorities have accepted that we test all IPC levels and the Drug Substance using TAMC only.GMP for Beginners in Sterile Manufacturing + Aseptic Process Simulation (APS) / Media FillsLive Online Training25-28 October 2022Learn more about this course:www.gmp-compliance.org
18• Questions:(i) “What are the studies to perform to prove that TAMC is suffi-cient to recover the most probable MO in our environment?”(ii) “Expose if they have develop tests to prove that most yeast and molds could be recovered on TSA in these incubation conditions?”(iii) “Never any expectation to prove that any mold or yeast would grow on TSA in your incubation conditions?”Answer: We did not perform any specific studies. Yeast and molds are included in our method suitability tests and these experiments and results were sufficient for the health author-ities that we could waive the TYMC.• Question: “To recover yeast and molds on TSA should we modify the incubations conditions?”Answer: No - we incubate at 30 - 35 °C. • Questions: (i) “Did you somewhere demonstrate that the 24 hours shelf life of bioburden sample has no impact on the representativeness of the sample?”(ii) “You said that the Bioburden Sample Hold Time of 24 hours was not always accepted. Could you share some examples?”Answer: No - a shelf life of 24 hours was accepted by the health authorities without supporting experimental data.• Questions:(i) “For suitability / validation of IPC bioburden = how many local isolates used on how many different batches?”(ii) “Which type and number of local strains do you add to the Growth Promotion Test?”Answer: Two in-house isolates must be involved in the biobur-den Method Suitability Test.• Question: “Specify the incubation conditions for TAMC: tempera-ture and duration?”Answer: 30-35°C for 3–5 days. Note: using a validated auto-mated colony counter the incubation time is only 36 hours.• Question: “For bioburden filtration method, if no growth is de-tected, how the result should be reported as 0 CFU/10 mL or <1 CFU/10 mL for a sample with specification of ≤10 CFU/10mL?”Answer: You can report either 0 CFU/10 mL or <1 CFU/10 mL. Your internal test method must define the reporting.• Question: “Temperature 5°C is more important than time for bioburden...so what about an holding time of 48h max but keep at 5°C and without data?” (note: explicit question to the Novartis colleague)Answer: The sample hold time was discussed with numerous authorities and a 24-hour hold time was finally agreed upon. This sample hold time is described in the dossiers and accept-ed by the authorities.• Question: “Do you have retest samples for bioburden and how use it?”Answer: If the defined and filed shelf-life of the bioburden sample is exceeded (note: 24 hours) we do not have a valid sample anymore.• Question: “Hold time for DP release when sterility and LAL testing apply? 24 hours is requirement from sampling to testing, but is there any hold time restriction between filling and testing?”Answer: Typically, no sample hold time is defined for sterility test samples. An “endotoxin recovery study” should be per-formed to assess whether any sample-specific endotoxin masking effects requires defining a sample shelf life for endo-toxin samples.• Question: “For phase III validation covering three batches (before commercial), can the IPC routine results be used for release when validation activities are ongoing? Or should the method validation covering all IPC steps be complete before routine IPC results can be used for release.”Answer: All validation efforts must be completed prior to the release of any material. • Question: “What is the rationale behind using In-house strains in Method Suitability Testing for Bioburden, which Sven (and others) mentioned?”(note: explicit question to the Roche colleague)Answer: The bioburden test method used should be able to detect microorganisms relevant for your manufacturing pro-cess and the respective facility / manufacturing environment. This will be demonstrated by including representative in-house isolates in your method suitability test.6. Raw material / Direct Material Testing• Question: “What about testing of raw materials that should be used for sterile prodcts, no testing of objectionable organisms is necessary for these raw materials?” Answer: For biopharmaceutical manufacturing processes no objectionable organisms are specified. Except for direct mate-rials where a monograph exists. These direct material must fulfill pharmacopeial requirements – and this could include the test for specified microorganisms.• Question: “For bioburden testing of primary packaging such as flexible bags, is it necessary to perform extraction efficiency test and to test the empty packaging for bioburden? Or you can reason that the microorganisms that gets extracted into the product is what matters and that they will be detected in the bioburden test-ing of the product (if you test bioburden pre-sterilisation on filled products)?” Answer: No testing of sterile single-use disposables is re-quired. The manufacturer can accept the vendor’s certificate (if all GMP-requirements are fulfilled, e.g. Qualitiy Agreement exists, audits were performed, …).• Question:“Regarding Method Suitability Testing for Microbial Enumeration Tests when applied to Starting Materials. Should the hold time between adding the microbial suspension to the product solution and the filtration of the solution be quantified as a part of the MST? Should it be subjected to a Worst Case scenario or to an upper limit?”Answer: The method suitability test should reflect the biobur-den testing under routine conditions. The method suitability test should be performed according to the relevant pharmaco-peial General Chapter without any pre-incubation step after the addition of the spike microorganisms.
19One of the tasks required under GMP regulations, but also as part of business continuity for marketing authorisation holders, manu-facturers and contract givers in the context of purchasing or out-sourcing, is to qualify suppliers and contractors. An important part of such a qualification process is the performance of on-site audits. However, due to the Covid 19 pandemic, an on-site audit may pose a potential risk to all parties involved or may not even be possible due to travel bans. This does not only affect auditors from compa-nies, but also inspectors from almost all global regulatory authori-ties. This in turn has an impact on the qualification programmes of companies, but also on ongoing and new authorisation applica-tions. What is important here is not only how to deal with the cur-rent situation, but also to look ahead; namely, to what extent dis-tant assessments may become part of qualification activities in the future. This important topic was therefore highlighted at the 16th QP Forum of the European Qualified Person Association (EQPA) in two contributions by three speakers. As in 2020, this forum again took place completely live online and attracted more than 300 par-ticipants over a total of three days in December 2021.First of all: Distant assessments will not be able to replace on-site audits. But they can be a valuable addition to both the inspection programmes of the authorities and the supplier qualification pro-grammes of the industry. Difficult namingRemote audit, distant assessment - which one is it? As there is no real uniform legal regulation so far, there are a number of different terms worldwide for the activities currently taking place. In addition to those mentioned above, there are also, for example, virtual in-spection, remote evaluation, remote assessment, remote inspec-tion, desktop inspection and desktop audit used by various authori-ties. In Europe, two are mainly used: Remote Inspection e.g. as "real-time remote GMP Inspection"(EDQM) and Distant Assessment (e.g. by the EU Commission and the EMA in their Questions and An-swers on regulatory expectations for medicinal products for human use during the Covid-19 pandemic1). In the following article, we will therefore use these terms as a guide, despite the title of this article.The Present and Future of Remote AuditsAbout 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.
20An ECA Foundation Interest GroupECAQPPRE-CONFERENCE SESSIONS | 30 November 2022Specific Requirements for IMPs (full day)Quality Culture (1/2 day)qp-forum.orgBERLIN, GERMANY & LIVE ONLINE01- 02 December 2022Real-Time Remote Inspections of the EDQMIn a first presentation titled "Conducting Remote GMP Inspections of API Manufacturers in Real Time", Dr Thomas Hecker, GMP Inspector at the EDQM, Council of Europe presented the EDQM programme. The EDQM, which monitors both compliance with Good Manufac-turing Practice (GMP) and the application for Certificates of Suita-bility for the monographs of the European Pharmacopoeia (CEP) at API manufacturers, also had to modify its inspection programme. For this purpose, the concept of "Real-Time Remote Inspections" (RTEMIS) was conceived and implemented. The aim was to find a way of obtaining better information and results than remote as-sessment procedures, which are carried out solely on the basis of documents. The aim was to use live real-time video connections between the inspectors and the inspected facilities. In doing so, the following technical challenges had to be taken into account, among others:• Data security• Suitable platforms for sharing documents• Secure web conferencing applications• Bandwidth via Wi-Fi or mobile networks (data transfer rate of more than 100 kilobytes/second)• Different time zonesIn September 2020, things got underway and the EDQM contacted production sites that had already been inspected by the EDQM and had good GMP compliance for a voluntary pilot phase. It quickly became apparent that this type of remote inspection requires more thorough preparation than an on-site inspection. Preparatory con-ference calls and connectivity tests are also important here. The secure exchange of confidential documents in real time re-quired some consideration. For this, the EDQM uses its own docu-ment sharing tool. Another important technical issue was what types of devices could be used to capture live images from poten-tially dangerous manufacturing areas. However, secured mobile phones are already available for this purpose and have been used for some time in other potentially explosive areas such as refiner-ies.The EDQM is satisfied with the results of the study. Even though the inspectors were not on site, a number of minor and major defi-ciencies were identified.Where do we go from here?Based on the principles of quality risk management, remote in-spections should become part of the EDQM inspection programme. These will be used in cases of travel restrictions or when the safety of the inspectors cannot be guaranteed. Real-time GMP remote in-spections should also be possible at companies with an appropri-ate GMP compliance history. Remote inspections will not be used, for example, to evaluate aseptic manufacturing processes or for companies that have not yet been inspected by the EDQM or have demonstrated poor GMP compliance in previous inspections.Real-time remote inspections thus provide the EDQM with another way to assess a site's GMP compliance. At the same time, however, it is emphasised that these remote inspections cannot replace on-site inspections in terms of value and effectiveness.
21The industry perspectiveIn a second contribution, both the industry's view and the GMP regulatory authorities' view were presented.Tor Gråberg, Head of External Advocacy, Global Quality, Operations at AstraZeneca and member of the EQPA Board of Directors, wel-comed the new opportunities that remote assessments present for industry. "Virtual inspections have the potential to save time and re-sources, while offering additional flexibility," said Tor Gråberg in his first slide. However, the industry is well aware of the disadvantag-es and challenges. For example, while remote audits and inspec-tions can be another tool in the qualification toolbox, there are limitations, as on-site audits simply allow for better interaction between auditor and auditee.However, experience within the industry and with legislation is constantly being expanded and developed to further optimise pro-cesses. Also, more advanced IT technologies will better support and facilitate distant assessments in the future.The GMP authority's viewDr. Rainer Gnibl, GMP inspector for the Bavarian government and the EMA and member of the Authority Advisory Board of the EQPA has an even more critical view. He observes that parts of the indus-try are striving for an equivalency of distant assessments to on-site inspections or audits. In addition to the direct intervention possi-bilities, sensory conditions such as feeling, smelling and the so im-portant gut feeling are missing during a distant assessment. Just like Dr. Thomas Hecker before him, he presented possible process-es within a distant assessment with the associated restrictions. He also had some very interesting examples of observations that could not have been made in a distant assessment. It is difficult to reliably assess the actual GMP compliance of a site on the basis of such remote assessments.There was complete agreement on the duration. Not only in terms of preparation, but also in terms of implementation, distant as-sessments sometimes take considerably longer than classic in-spections or audits - at least if one tries to do them properly and wants to delve comparably deeply into what is going on. This also puts a damper on the industry's hopes of saving resources.ConclusionBecause of its importance, the conclusion was already in the intro-ductory text: Distant assessments will not be able to replace on-site audits. The authorities will not accept this. But they will be a complement, both in the inspection programmes of the authorities and in the supplier qualification programmes of the industry. This can also be done in hybrid forms, where one part is inspected at one's own desk, but other parts are then inspected directly on site.Note: The Qualified Person Forum 2022 will take place from 01-02 December in Berlin and live online. This year, the EQPA will again address interesting and current topics at its Forum2, such as changed requirements for supply chain control due to the new An-nex 21, Brexit but also due to further developed technologies and their meta data.With the GMP WebApp from the ECA Foundation you get GMP NewsMajor GMP GuidelinesGMP Trainingsa comprehensive Search function GMP Guideline Manager (for ECA members only)on your smartphone or tablet PCAll GMP Information at Hand – anytime, anywhere!go toapp.gmp-compliance.org1 https://ec.europa.eu/health/sites/default/files/human-use/docs/guidance_regulatory_covid19_en.pdf 2https://www.qp-forum.org/ Qualified Person Education Course - Module AVienna, Austria19/20 October 2022Understand the Implications of becoming a QPLearn more about this course:www.gmp-compliance.org
22The quality control area is a particular focus of the inspectors dur-ing every FDA inspection. Here, violations of GMP regulations are found particularly frequently, as can be read in numerous warning letters.This article describes the type and frequency of GMP deficiencies in the quality control laboratories of the inspected companies on the basis of a systematic review of the Warning Letters citations. The data scope of this analysis includes the published Warning Letters of the fiscal years 2017 to 2021 (Oct. 2016 to Sept. 2021), which were addressed to manufacturers of finished medicinal products and contract laboratories. The citations examined refer to the fol-lowing sections of the Code of Federal Regulations (21 CFR):Subpart I – Laboratory Controls• 211.160 General requirements.• 211.165 Testing and release for distribution.• 211.166 Stability testing.Subpart J – Records and Reports• 211.194 Laboratory records.The paragraphs 211.167 Special testing requirements, 211.170 Re-serve samples, 211.173 Laboratory animals, 211.176 Penicillin contam-ination, which also belong to "Subpart I – Laboratory Controls", were not included in the analysis, as they are not or only occasion-ally cited in connection with GMP violations in the warning letters of the last 5 fiscal years.The analysis of the frequency of GMP deficiencies assigned to the respective CFR paragraphs, considered over the period of 5 fiscal years, is shown in the chart in the next page. According to this, the most frequent GMP deficiencies in the qual-ity control area concern the tests prior to release of the product as well as stability tests; the latter were cited particularly frequently in the last fiscal year (2021).The following describes the deviations from the requirements of the four CFR sections in the form of a summary of the GMP defi-ciencies as cited in the warning letters within the period under re-view.The most Frequent GMP Deficiencies in Quality ControlAn analysis of the Warning Letters of the last 5 yearsAbout the AuthorDr. Gerhard Becker is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in analytical and compliance topics.
23§211.160 General requirements. (Subpart I – Laboratory Controls)Your firm failed to establish laboratory controls that include scientifi-cally sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and pu-rity.The deficiencies described in the warning letters with reference to paragraph 211.160 concern the following issues:• Unsuitable or non-validated test methods without scientifi-cally supported significance are used, especially for microbio-logical controls.• Test specifications for incoming and final inspections are not available. Sampling plans are missing or unsuitable• Testing is done against unsuitable specifications.• Critical changes to electronic equipment in the QC laboratory are made in an uncontrolled manner. Uncontrolled manipula-tion of electronic data is possible.• Appropriate routine monitoring is lacking for the water sys-tem.§211.165 Testing and release for distribution. (Subpart I– Labora-tory Controls)Your firm does not have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifi-cations for the drug product, including the identity and strength of each active ingredient, prior to release.• Finished products are released for sale without testing for compliance with specifications. This is the most common violation of GMP rules cited in the Warning Letters with reference to 211.165. In isolated cases, this deficiency also affects active substances that are released for further processing without appropriate compliance test-ing.• Non-validated test methods are used.§211.166 Stability Testing. (Subpart I– Laboratory Controls)Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products, and to use results of such stability test-ing to determine appropriate storage conditions and expi-ration dates.• The test methods used in the studies do not dem- onstrate stability.• The stability studies do not include current con- tainer and closure systems.• Microbial stability or sterility of the products is not tested.• Only short-term stability studies are carried out; long-term studies to validate the declared shelf life are missing.• There is no analytical recording or quantitative measurement of impurities in the stability studies.• OOS results occur several times during the stability study, but are not further investigated; neverthe-less, the study data serve to validate the shelf life.• The analytical methods for the stability tests are not validated.• There is no on-going stability testing programme.• Data from older studies are used to justify the shelf life; stabil-ity studies involving the current supplier and the current pro-duction site do not exist.• Stability studies are completely missing.§211.194 Laboratory Records. (Subpart J – Records and Reports)Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with estab-lished specifications and standards.• Documentation is incomplete, missing -OOS results-Root cause analysis of OOS results-Data from failed tests-Re-test data, data on which the information on the certifi-cate of analysis is based-Data on microbiological tests as well as relevant informa-tion (e.g. incubation times, materials, etc.), data that should actually be documented according to the audit trail-Batch numbers-Data on shelf life of standards• Unofficial" records are used (uncontrolled Excel files or notes accessible to everyone, which are later destroyed).• Records are falsified, data is "invented"; audit trails are not se-cured against manipulation.The analysis of the warning letters shows that in many cases, the basic requirements for GMP-compliant work in the quality control laboratory as well as special requirements, e.g. for the perfor-mance of stability studies, are violated; the frequency of the latter has increased significantly in recent years. All in all, this kind of insight into the deficiency reports that repeat-edly appear in the warning letters and the scenarios described there, some of them in detail, can be useful for preparing for an upcoming FDA inspection.
24Comments and a comparison between the documents have been published on ECA’s website: https://www.eca-foundation.org/news/eca-foundation-comments-ich-q9-draft.html The collected comments for ICH Q9 were published by EMA on 20 April: https://www.ema.europa.eu/en/documents/comments/overview-comments-received-ich-guideline-q9-r1-quality-risk-management-ema/chmp/ich/24235/2006_en.pdf ECA/EQPA right at the beginning. www.qp-association.eu Validation Group The sub-groups started to update their chapters of the Group’s Good Practice Guide “Integrated Qualification and Validation Guide”. There is a big interest in the subgroup on electronic documentation. This group wants to exchange results with ECA´s Data Integrity and IT Compliance Group. The development of a version 3.0 is planned to be published at another „Launch“ Conference in November 2022. The Board meetings for 2022 are fixed, the the business plan is updated. www.validation-group.org European GDP Association • The next annual board meeting has been scheduled for June or July 2022. Like last year, the meeting will take place online via Webex. • The group has reserved a date for the next GMP&GDP Forum 2023 in the long term to be sure that the most important stakeholders can be present on the date. Content planning is supposed to begin in the summer of 2022.www.good-distribution-practice-group.orgPharmaceutical Microbiology Group• A board meeting was held in January, the next meeting has been scheduled for end of November. • An Annex on the group’s Microbiological Deviation Guide about microbial ID was written and reviewed by the board members. The comments are currently being incorporated by the authors. • Microbiological culture media are of high importance for qual-ity assurance and control in pharmaceutical and biopharma-ceutical manufacturing. Accordingly, the quality and suitabili-ty of the culture media must be ensured. Before a new batch can be used for microbiological testing, especially under phar-maceutical industry regulations, it must be properly tested for its ability to provide consistent and reliable results. Central to this is the growth promotion test (GPT). Both the USP and the EP promote this detection.• With a survey, the group wanted to collect some data on prac-tices with regard to the Growth Promotion Test – with a spe-cial focus on the local microflora strains selection and man-agement strategy. Answers are key for the assessment of current industry practices alignment and rationales. Results will be coordinated with the results from the surveys of other organisations.• A first Cooperation with BioPhorum started for the Joint ECA/APIC/BioPhorum conference on Biological Raw Materials. www.pharmaceutical-microbiology.orgVisual Inspection Group• Felix Krumbein (Körber) is new member of the ECA Visual In-spection Group. • The postponed Board meeting 2021 took place online in Janu-ary 2022. • The group has commented on and submitted the draft FDA Guideline on Visual Inspection in February.• No new updates planned until details from Annex I are pub-lished. • A survey within the group has taken place in February to iden-tify current topics for the annual conference. www.visual-inspection.orgATMP Group• The next Board Meeting has been scheduled for October.• The group commented on the USP draft guideline on Analyti-cal Procedures for mRNA Vaccine Quality. • An exchange with the Pharmaceutical Microbiology Group was initiated and first joint planning startedwww.atmp-group.orgData Integrity & IT Compliance Group• Schumacher sent a draft of version 3 of the Group’s Data In-tegrity Guide on 22 May 2022 to the reviewer team. Feedback on “Show stoppers” is due by 12 June. www.it-compliance-group.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 11, November 2018)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.