Regulatory Updates

Regulations, Guidelines & Other Documents

A select list of recently updated regulations, guidelines and other documents compiled by the ISPE Regulatory Quality Harmonization Committee (RQHC)’s Europe-Middle East-Africa Regional Focus Group

April/May 2020 Update

EU – MDR delay official – industry calls to push back IVDR
EU – MDCG offers new MDR implementation plan and significant change guidance
EU – Medical Device Coordination Group issues more details on clinical evidence and performance evaluation and Class 1 translational provision
- MDCG 2020-1 Guidance on Clinical Evaluation (MDR) / Performance Evaluation (IVDR) of Medical Device Software
- MDCG 2020-2 Class I Transitional provisions under Article 120 (3 and 4) – (MDR)
EU – Draft GMP annex on Importation
EU – Update to EMA publication on Nitrosamine expectations
EU – Publishes on ICH Q12 product lifecycle management
EU – Guidance for accelerated procedures for Covid-19 treatments and vaccines
EU – Update on management of clinical trials during Covid -19
EU – Covid19 Q&A - reg expectations for med. products during pandemic (‘regulatory flexibilities’)
EU – Update on actions to support medicine availability during COVID crisis
EU – Devices – new guidance on Notified Body Audits during the pandemic
EU – EMA to issue electronic certificates for medicines
WHO – FAQs on manufacturing, trials and testing during Covid-19
- There are MANY other Covid crisis management publications, from MHRA and others
ICH – Q3C solvents guideline updates
- PDEs drafted for 2MeTHF, cyclopentyl methyl ether and t-butanol
- And recorrected PDE for ethylene glycol
ICH – Implementation of ICH guidelines
ICH – Q1 stability training module
WHO – Technical Reports
- Annex 1 – procedure for development of monographs for inclusion in Int. Pharm.
- Annex 2 – GMP for radiopharmaceuticals
- Annex 3 – Production of WFI by means other than distillation
- Annex 4 – good chromatography practices
- Annex 5 – Quality management systems requirements (national inspectorates)
- Annex 6 – PtC for environmental aspects of manufacturing practices for prevention of antimicrobial resistance
- Annex 7 – Good storage and distribution practices
- Annex 8 – PtC setting remaining shelf-life of products
- Annex 12 – Biowaiver list
- Annex 13 – Implementation of QMS for national regulatory authorities

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March 2020 Update
- EU – New GMP Annex 1 – targeted consultation
- EU – Falsified Medicines – Q&A version 17 on Safety Features
- EU – European Commission issues new guidance on EUDAMED Medical Device database nomenclature
- UK – MHRA releases updated guidance on clinical device investigations
- US – Shortage Report
- Africa – South African Development Community BIOSIMILAR Guidances
- WHO – Revision of GMP for Sterile Products
- PIC/S – Saudi Arabia applies for PIC/S membership (February)
February 2020 Update
- EU – Draft Reflection Paper on GMP for MAHs
- EU – Pilot of simultaneous National Scientific Advice
- EU – Electronic Product Information
- EU – New guidance for Medical Devices and IVD Cybersecurity Under MDR and IVDR
- ICH – Recommended Adoption of ICH Guidelines in CHINA
  - ICH Q8; Q8,9,10 Q&A; Q10; Q11; Q11 Q&A recommended for adoption
  - Coming into force January 2020 – Q2; Q3AA, Q3B, Q3C, Q3D; Q5A, Q5B, Q5C, Q5E; Q6A; M7
- PIC/S Meetings in Toyama
- PIC/S Pilot on Inspection of Manufacturers of Steriles
January 2020 Update
- EMA – Midyear Report 2019
- EU – Nitrosamine Impurity Q&As UPDATED
- EU – Rolling overview link on Nitrosamines
- EU – Commissioner for Health states Medical Device Regulation deadline on May 26th 2020 will not change
- EU – Updated Guideline on Package Leaflet information for ETHANOL
- EU – Falsified Medicines Directive – Aide Memoire for GDP inspection
- EU – Genetically-Modified Organism requirements for in vivo gene therapy products
- ICH – Q12 CMC Product Lifecycle guideline completed
- WHO – Evaluating and designating regulatory authorities as WHO LISTED Authorities
- WHO- signs memo of understanding with IGBM (generic and biosimilar association) to promote access
- PIC/S – New recommendation on how to gauge the effectiveness of a PQS with risk-based change management
- ASTM – Ballot on draft standards
  - on Microbial Ingress testing for Single-Use systems
  - on Stability of Early Phase Protein Products
  - on Removal of Retrovirus by filtration
November 2019 Update
- EU – Nitrosamine Impurity Assessment Templates
- EU – Benefit Risk assessment for Phthalates in Medical devices
- EU – Process for Requesting EMA Certificates (Nov to Jan 2020 interim process)
- EU – Q&A on Implementation of MDR and IVDR
- EU – New guidance for manufacture of implantable devices
- EU – Commission announces (2y) delay for Eudamed Device database
- EU- China Dialogue on Medicines Regulation
- ICH Q3C Correction – PDE for ethylene glycol reinstated to previous value …
- WHO – Guidelines on Data Integrity
October 2019 Update
- EU – Proposed document on requirements for Regulatory Authority recognition of conformity assessment bodies conducting Medical Device regulatory reviews
- EU – Commission explains new MDR, IVDR rules on Expert Device Panels
- EU – Revised guidance on FMD Safety Features
- MHRA – Update on strategy for pharmacopoeial public quality standards for biological medicines
- EU – Requirements on N-nitrosamines in APIs / Products
- Two documents released –
  - Information on Nitrosamines for MAHs - Request to evaluate the risk of the presence on nitrosamine impurities in human medicinal products containing chemically synthesised active pharmaceutical ingredients (EMA/189634/2019)
    - 6M period (from publication date) to assess all synthetic APIs/derived medicinal products
    - 3y (2y in Canada) to verify with analytical testing
      At present, biological products stated to be out of scope
  - Questions and Answers on ‘ Information for MAHs’ (EMA/428592/2019)
- Call to clarify these publications 29th October
- EMA meeting on Sartans Learnings (TA invitees, HCPs, patient reps) in Amsterdam, 4th November
- Webex on topic by end year
August/September 2019 Update
- EU – US – Mutual Recognition Agreement fully in place (24th July)
- EU – Information on batch testing in context of Brexit
- EU – Limits for nitrosamines
- EU – Quality of peptone used in API manufacture
- EC – Additional guidance clarifying medical device vigilance requirements
- France – Draft Medical Device Cybersecurity Recommendations
- EU – 2 new guidelines on DP shortage notification
  - Detecting drug shortages and notifying regulators of shortages
  - Good practice guidance for communication to the public on medicines’ availability issues
- EMA submits comments to FDA on Biosimilars draft guidance
- EU – Ombudsman report on EMA pre-submission assessment activities
- EU-US – Meeting report from Workshop on Quality / CMC acceleration for early access approaches (Breakthrough and PRIME)
- EU – Guidance on Categorisation of Extension Applications and Variation applications
- EC – New guidances on Medical Device and In Vitro Diagnostic Regulations
  - Guidance on Article 15 of the Medical Device Regulation and in vitro Diagnostic Device Regulation
  - Guidance document Implant Card relating to the application of Article 18 Regulation
- EU – Q&A on use of Out of Specification batches of Advanced Therapy products
- EU – updated Q&A on FMD Safety Features
- WHO – Guideline (rev1) on Good Storage and Distribution Practices
- WHO – Guideline (rev1) on Production of WFI by means other than distillation
- WHO – Policy (rev1) on Remaining Shelflife of medicinal products
- WHO – Guideline on Good Chromatography Practices
July 2019 Update
- EU – Uptick in EMA Activities
- EU – US Mutual Recognition
  - Germany now recognised
    - Only Slovakia remains
- EU – 2 new guidelines on DP Shortage Notification and Communication
  - “a shortage occurs when supply does not meet demand at a national level”
  - Guidance on detection and notification of shortages of medicinal products for Marketing Authorisation Holders (MAHs) in the Union (EEA)
  - Good practice guidance for communication to the public on medicines’ availability issues
  - And from French Health Ministry (Buzyn) – New Roadmap to Fight Against Product Shortages
- EU – Update of the EMA Q&A Guidance on GMP
  - Create a new section on GMP for ATMPs AND
- EU – Q&A on Use of OOS batches of advanced therapy products
- TGA – guidance for sponsors seeking to obtain GMP clearance for an overseas manufacturing site of a medicine or API intended for supply in Australia.
  - GMP clearance guidance
- WHO – Guideline on Import Procedures for Medical Products
- WHO – Expert Committee on Biological Standardisation
June 2019 Update
- EU – Draft Guideline on the Quality Requirements for Drug-Device combination products (integral and co-packaged)
- EU – Information in Clinical Trial (adult and paeds trials) database that will be made public
- EDQM – Inspection Report on Inspections and trends of deficiencies (2006-2018)
- UK – Consultation on the application of Analytical QbD principles to pharmacopoeial standards for medicines
- UK – MHRA Blogs on
  - 2018 GMP Symposium
  - 2018 GDP Symposium
- RSA – Released a set of guidances for comment
  - eCTD; eSubmission; new registration validation templates (eCTD and esub)
  - VARIATIONS addendum for orthodox medicines
  - https://www.sahpra.org.za/Home/FullArticle/3bd90341-0e1a-417a-9676-d48513506e0a
- US – Development of Therapeutic Protein Biosimilars – DRAFT guidance on Comparative Analytical Assessment and other Quality-related considerations
- EU-US Mutual Recognition
  - Netherlands and Luxembourg now recognised
    - Only Germany and Slovakia remain
- EU – Recognise Korean-manufactured APIs as in line with EU standards
  - Adding to Australia, Brazil, Israel, Japan and USA
- WHO – Guidelines for Implementation
  - WHO Technical Report Series 1019 has the outcomes of the 53rd WHO Expert Committee
- Guidances on
  - Procedure for the development of WHO medicines quality assurance guidelines
  - Heating, ventilation and air-conditioning systems fir non-sterile pharmaceutical products - HVAC
  - GMPs on Validation – HVAC for non-sterile products; water systems; cleaning; analytical procedures; computerised systems; qualification; non-sterile process validation
  - Procedure on conduct of equilibrium solubility determination for BCS classification
  - Good practice for NRAs in implementing collaborative registration
  - Example of a NRA reliance model
  - Acknowledgement / approval of variations of products registered through the WHO collaborative procedure
- WHO – draft guidance on Quality Systems for Pharmaceutical inspectorates
- WHO – A framework for evaluating and designating WHO Listed Authorities
- Headline topics from most recent meeting of PIC/S Committee and Executive Bureau
  - PICS Inspection Reliance Initiative – examples
  - Updates on future revisions to PIC/S GMP Guide
    - Steriles
    - Biologicals and ATMPs
    - IMP
    - Certification and batch release
  - Plan to develop an Aide-memoire on Tissue and Cell Therapy Product Inspections (excluding ATMPs)
  - Completion of pre-accession of Saudi Arabia and application from Bangladesh
  - Next Seminar on QA of Sterile Medicinal Products
May 2019 Update
- EU - Variations Guidance Updates with CMC / GMP significance
- EU - EC launches portal to ease transition to new regulations on Medical Devices and In vitro Diagnostic Devices
- EU - Medical Device database to adopt Italy’s CND codes for Eudamed Device Database nomenclature
- EU - Draft corrigendum to Medical Devices Regulation
- EU - Medical Device Coordination Group Issues EUDAMED guidance
- FDA - confirms Bulgaria and Cyprus for Mutual Recognition
- Variations Guidance Updates with CMC / GMP significance: A series of updates to variation management approaches are issued by the EMA. These cover:
  - Submission of changes to AUDIT DATES to verify GMP compliance for API manufacture
  - Introduction of NEW MANUFACTURING SITE for DS or DP and what changes can be submitted under a single Type II Variation (changes to process, batch size, IPCs to adapt to new site settings - other changes should be submitted as a separate variations)
  - Submission of change to Module 3.2.S or the update of an ASMF
  - Submission of an updated CERTIFICATE OF SUITABILITY
  - What is considered to be a 'non-significant IPC or specification parameter (does not include downgrade of CPP to non-CPP)
  - What is considered to be within / outside range when applying for a NEW PACK SIZE
  - Submission of NEW WORKING CELL BANK
  - Submission of a new REFERENCE STANDARD FOR A BIOLOGICAL PRODUCT
  - What changes in MANUFACTURING SITES, building, rooms and EQUIPMENT are covered by company quality system and GMP
  - What is needed if there are changes to a MEDICAL DEVICE?
  - How should one submit TRANSFER OF TEST METHODS for testing of BIOS products to a new or already authorised testing site; submission of editorial changes
  - What is considered a NEW or MODIFIED THERAPEUTIC INDICATION.
Feburary 2019 Update
- EU - GMP Annex 2 Updated
- EU - Draft Guideline on Quality and Equivalence of Topical Products
- EU - EDQM survey on Dissolution Test attribute in Ph.Eur.
- EU - Collated comments on ICH Q12
- EU - Q&A on safety features
- EU - Regulator’s Template for FMD Safety Features
- EU - Electronic product information for human medicines
- EU - EDQM guide for the elaboration and use of monographs on vaccines and immunosera
January 2019 Update
- EU – Consultation on EMA Regulatory Science Plans to 2025
- EU – Mobile Scanning for Labelling and Product Leaflet
- EU – Draft revised BSE / TSE Guideline
- EU – Medicinal Products containing Genetically-Modified Organisms
- EU – Revision of Environmental Risk Assessment of Human Medicines
- EU –US Mutual Recognition Agreement
- PIC/S - DRAFT guidance on Good Practices for Data Integrity released
- ICH met in Charlotte NC, US in November
  - Q12 – CMC Lifecycle management - EWG did not meet in Charlotte - public comment phase nearing completion. Comments now being collated. EWG will have an interim meet to consolidate comments in Japan in February
  - M9 – BCS Based Biowaivers – EWG did not meet in Charlotte – public comment phase nearing completion. Comments now being collated.
  - M7 – Mutagenic Impurities – EWG reconvened to deliver clarification Q&As to the M7 guidance
  - Q13 – Continuous Manufacturing – EWG met for first time (FDA rapporteur) – concept paper finalised and constituents now engaged in providing ‘outline’ content of desired guidance
  - Q14 / Q2 – Analytical Development and Validation – early stages
  - Quality Discussion Group – Re-established to determine next wave of potential Quality topics
    - At present topics such as Extractables / leachables (proposed by PhRMA) are pre- any agreement to establish working group
November 2018 Update
- EU – Workshop on Accelerating CMC for PRIME / Breakthrough programs
- EU – Reflection Paper on Impurity Qualification Approaches
- EU – Draft guideline on Quality of Water
- EU – Updates on Excipient Packaging and Labelling Expectations
- EU – Update on EU / US MRA
- EU – Overview of comments received for guideline on quality aspects included in the product information for Vaccines
- EU – Guideline on requirements for Quality documentation for biological investigational medicinal products
- EU – Guideline on equivalence studies for locally-acting products in the GI tract
- EU – Revised guideline on BSE
- EU – Workshop on Product Shortage
- EU – Reflection Paper on (animal) tests used for product quality
- EU – EMA Workshop on Advancing Regulatory Science
- EU – EC letter on FMD Safety features implementation
- EU – Consultations on medicines for children and rare diseases
- EU – EC new guidance documents on Unique Device Identification System
- UK – MHRA Update on health-based exposure limits
- Swiss – Guidance document on Variations and Extensions
- ICH – Update to Q3C residual solvents
- PIC/S – New guidance on classification of GMP deficiencies
October 2018 Update
- EU – Dossier requirements for ancillary medicinal substances in a medical device
- EU – Updated Q&A on Safety Features – wholesaler and parallel importers / distributors
- EU – Concept paper for Neonate product development
- EU – New website for EMA
- EU – US Mutual Recognition – Portugal now recognised (15th country)
- Ireland – HPRA – Medicines Shortage Framework
- Russia – Draft Guideline on Data Integrity
- ICH – EWG presentation materials on ICH M9 BCS-based biowaivers
- WHO – Guidelines on Validation of Computerised Systems
- WHO – Appendix 6 Validation – Qualification
- WHO – Guideline on Analytical Validation
- PIC/S – Bulgaria applies for membership
- ISTM – Revision of E2891 Multi-variant data analysis standard
- FDA – Release of draft guidance on post-approval changes for drug substances
September 2018 Update
- EU – Medicines Supply Task Force – Workplan and Workshop
- EU – Update on EDQM’s actions on valsartan impurity management
- EU – Quality of Herbal Medicinal Products
- EU – Draft guideline on Quality, Safety and Efficacy of Medicines containing Genetically-Modified Organisms
- EU - Outcome of consultation on Health-based exposure limits Q&As
- PIC/S – Bulgaria applies to PIC/S and Jordan applies for pre-accession
- WHO – Guidelines on Import Procedures for Medical Products
- Saudi Arabia – Difficulties with acceptance of German manufactured products into Saudi Arabia
  - Various news reports. And also reports of EFPIA / PhRMA letter to Saudi Arabia on the topic.
August 2018 Update
- EMA – Updated application form for certificate of medicinal product
- EU – Revised (final) GMP Annex 2 on Manufacture of Biologicals
- EU – Revised (final) Annex 17 on Real Time Release Testing and Parametric release
- EU – Final GMO requirements for Investigational Products
- EU – Final guideline on the Quality, Preclinical and Clinical aspects of Gene Therapy Products
- EU – Updated Q&A guidance on Safety Features
- EU – Update on impurity-driven recall (valsartan)
- EMA - Annual Report 2017
- EU – Annual Report of the Inspectors Working Group
- EU - EMA Action plan on Advanced Therapy Medicinal Products
- EU / US Mutual Recognition Update – Lithuania and Ireland added
- EU / Japan – Updated Mutual Recognition agreement
- EU / US - Reinforced collaboration on medicines
- EU – Commission meeting on Medicines shortages
- MHRA (UK) – Updates GDMP and preparation for inspection guide
- ICH – revision of ICH Q3D (elemental impurities) – updated PDE for cadmium (3ug/day from 2ug/day)
- ICH – Release of ICH M9 draft guidance on BCS-based biowaivers for public comment
- PIC/S – Revision of PIC/S GMP guide
- PIC/S – New guidance documents (essentially based on EU guidance on these topics)
  - Cross-contamination in shared facilities
  - Health-based limits
  - Risk assessment for GMP for excipients
  - Good Distribution Practices
  - Inspection reliance
- WHO Q&As – Similar Biotherapeutic products
- WHO – Protocol for solubility measurements (draft)
- WHO – Drugs on essential medicines list eligible for biowaivers (draft)
- WHO – Proposal for revision of the WHO Certification Scheme
- WHO - Technical Report series 1010
  - Including Annex 3 – final guideline on procedures and data requirements for changes to approved biotherapeutic products
  - Annex 5 – Final guideline on testing of suspect falsified medicines
  - Annex 8 – Final Guidance on HVAC systems for non-sterile pharmaceutical products
  - Annex 9 – final guidance on good practice for desk assessment of compliance with GMPs
  - Annex 10 – Stability Testing of APIs and FPs
  - Annex 11 – National registration of pharmaceutical products and vaccines approved by stringent regulatory authorities
  - Appendix 5 - Validation of Computerised systems (draft)
May 2018 Update
- EMA – 2017 Annual Report
- EMA – Report on Prior Knowledge Workshop
- EMA – Final Q&As on Health-based exposure limits
- EMA – Requirements for Quality Documentation for Biological investigational products
- EMA – Revision of template for Serious GMP non-compliance
- EMA – Variation classifications
- EMA – Certificates of Medicinal Products issued by the EMA
- EC – Q&As on Clinical Trials regulation (largely administrative)
- MHRA – Updated Out-Of-Specification Guidance
- WHO – Proposed revision of the WHO Certification Scheme
- WHO – Guidelines on Import Procedures
- Australia – Consultation on adoption of EU guidelines
- EU GMP guide annexes: Supplementary requirements: Annex 16 (Updated May 2018)
  1. Can a site have more than one QP performing certification of batches?
  2. Can there be more than one QP involved in the certification of a given batch?
  3. In the context of handling unexpected deviations, what is included in the scope of registered specifications for medicinal products?
  4. What is an ‘unexpected’ deviation?
  5. Does Annex 16 permit QP certification of more than one batch affected by the same unexpected deviation?
- ANSM – Guidelines of follow-up actions after an inspection
April 2018 Update
- EU – Excipients in the labelling and package leaflet of medicinal products
- EU – Updated Q&A on Falsified Medicines Directive Safety Features
- MHRA – GXP data integrity
- WHO – Guideline on Validation
- WHO – Revised draft guidance on HVAC for Non-sterile products (part 2)
- WHO – Report on substandard and falsified medicines
- WHO – Production of Water for Injections
- Qatar – Guidelines for Variations
March 2018 Update
- EU – Guidance on safety and efficacy follow-up for Advanced Therapy Medicinal Products
- EU – Certificate of Suitability – TSE Risk assessment
- EU – Q/A on Flu Vaccine Preparations
- EU – Quality Aspects in Product Information for Vaccines
- EU – Q/As on BSE and Vaccines
- EU – Vaccines testing and reduction of animal tests
- EU – EMA Workshop on Paediatric Regulatory Framework
- US – FDA Publication on the Quality Overall Summary
February 2018 Update
- EU – In Use Shelf-life Studies – solid oral dosage forms
- EDQM – Revised guidance and application forms for electronic submissions of CEPs
- EU – Workplan for the Biosimilar Working Party
- EU – New monograph for Infliximab solution
- Australia – Implementation of PIC/S GMP guide
- ICH – New member and observer countries
- UAE – Registration of Innovative Medicines
January 2018 Update
- EU – Issue of revision of Annex 1 – GMP for Sterile Manufacture
- EU – Working Parties – 2018 Workplans (Quality, Biologicals, Vaccines, Safety)
- EU – Annual Report of the GMP-GDP Inspectors Working group
- EU – Final revised guidance on Clinical Trial Products
- EU / ICH – Publication of Step 2 draft of ICH Q12 – CMC Lifecycle Management
- EU – Variations expectations
  - Changes to API manufacturing site and DP packaging 1
  - Changes to API manufacturing site and DP packaging 2
- EU – Recommendations on improvements to package leaflets
- WHO – Q&A on Biosimilars
- Ethiopia – Guidelines for registration of biotherapeutics, vaccines and similar biologic products

Brexit

A list of select Brexit updates compiled by the ISPE Regulatory Quality Harmonization Committee (RQHC)’s Europe-Middle East-Africa Regional Focus Group.