Law basics Flashcards

Question

EMA Updates:

Answer 1

Quality of Water for Pharmaceutical Use: Effective Feb 2021 Highly Purified Water category removed 4 water categories: Potable Purified WFI NEW: Water for Prep. Of Extracts (herbal products) Guidance on type of water req’d for different stages of product manufacture. Additional methods allowed to make WFI including RO with nanofiltration Detection & Notification of Shortages of Medicinal Products in EEA: (July 2019) Guidance issued to MAH about what classes as a shortage and actions to take in the event of drug shortage MAH must inform relevant NCA/EMA for CAPs Annex 1 of guidance provides template for NCA notification EMA/HMA task force set up – will implement a single point of contact network in EU Becoming global area of focus Reflection Paper on GMP Responsibilities for MAH: (Jan 2020) Clarify GMP responsibilities of MAH. Targeted at ‘virtual’ companies. MAH has ultimate responsibility and inspectors have power to inspect MAH Emphasises on responsibilities related to outsourcing and quality agreements Critical Medicines Shortage: EMA working group issued a public consultation on updated EU GMP Non-Compliance statement template Allowing the release of critical meds in Exceptional Circumstances Criteria must be met – with documented Risk Assessment List medicines that cannot be exported from UK

Answer 2

Safety features implemented 09Feb2019 – (GR/IT exempt until 2025) Safety Features GMDP Aide Memoir & Q&A documents to aid inspections and implementation

Answer 3

Implemented Jul 2019. Scope: Inspections and batch testing. Vet med/IMPs/Biologics not included in scope.

Answer 4

Nitrosamines: Probable human carcinogens and genotoxic – detected in several medicines since 2018 results in multiple product recalls (sartans (bp), rantidine (stomach acid), metformin (diabetes)). Caused by: Use of sodium nitrate in presence of secondary and tertiary amines in the manufacturing process  AMINE GROUPS Use of sodium nitrate/other nitrosating agents in combination with reagents, solvents and catalysts susceptible to degradation to secondary or tertiary amines Use of contaminated raw materials in API manufacturing process (solvents, reagents, catalysts, recovered/recycled materials, cross-contamination, degradation) Use of certain packaging materials  Blister packs with lidding foil containing nitrocellulose Series of guidance documents issued by EMA and CHMP including assessment report, lessons learned and Q&A docs. Action required by MAH: Risk evaluation of all APIs and finished products for possible presence of n/amines by Mar2021 (biologics – Jul 2021) and report findings to NCA. Risk identified  Perform confirmatory testing on products identified to be at risk of n/amine formation or cross contamination. Report confirmed presence ASAP. No. of batches tested risk based. If impurity level consistent test 10% of annual batches or 3 a year (whichever is highest). Fewer than 3 batches a year test all batches. N/amine present after Stage 2 testing  Limit to be included in finished product specification and product needs to comply if tested. Presence n/amine confirmed  File variations to update MA for any changes needed to address n/amine risk. Steps 2-3 must be completed by Sep2022 (biologics – Jul 2023). All new MAAs must have n/amines QRA included Maximum Daily Doses have been established (ng/day level) and limits need to be calculated based on MDDs. Testing difficult due to very low detection levels required – typically performed by specialist labs by GC-MS/MS or LC-MS/MS. EP general chapter (2.5.42) on testing n/amines in APIs adopted Dec 2020. Outlines 3 procedures (GC-MS, LC-MS/MS, GC-MS/MS). Validated for listed APIs, either as limit test with target conc. of 30ppb / a quantitative test. Can be applied to other APIs with appropriate validation. Covers 7 n/amine impurities. Will be published in Supplement 10.6 in Jul 2021 but available for download from EDQM website. Ref. std. available through EDQM. N/amine limits: Control at or below limit defined based on ICH M7 principles. Calculated using a lifetime daily exposure of the MDD. For multiple n/amines <1:100,000 risk level. Limits have been established for some specific n/amines and should be applied (ng/day level).

Answer 5

2 year standstill period for GB – Continue to follow EU guidance until 2023. NI effectively remains part of EU therefore changes only apply to GB (Scotland/England/Wales). CAPs remain valid in NI NI remain in EMVO Jan 2022: GB to NI need re-testing and re-QP cert Warehouses where product was imported from UK into EU now need MIA (previously WDA only). UK-EU Trade Agreement: Limited scope, mutual recognition of GMP inspections only. No access to EU databases MHRA Approved Countries – Import/Batch Testing/API Serialisation: GB no longer be part of EMVO. Therefore GB packs do not need to be serialised. If packs serialised & exported from EU to UK  don’t need to decommission on export until 31Dec2021. DR 2016/161 amended by DR 2021/457 in March 2021: exemption from obligation for wholesalers to decommission the UI of products exported to UK. Applies until 31Dec2021. English language packs can be supplied to ROI/NI/Malta/Cyprus. If packs were decommissioned and exported back into the EU new UIs would have been required. No importers in these countries licenced to apply new UI to packs. Therefore this amendment was required. After 31Dec2021 decommissioning UK packs on export req’d / new UIs req’d if packs exported back to EU Future NMVS proposed change in new UK Medicines and Medical Devices Act. PV Separate UK PV system for ICSRs and PSURs required, UK PSMF required. All PV data is submitted directly to MHRA. UK MAHs  provide MHRA with updated summary of PV systems by filing variation by Jun 2022. UK no longer have access to EudraVigilance. For EU ICSRs/PSURs relevant safety data from UK sources should be included as third country data in EudraVigilance. QPPV can reside in EU/UK. If in EU  UK contact person req’d with reporting line into QPPV. UK contact person responsible for establishment and maintenance of PV system for UK authorised products. 12 months to notify MHRA of contact person details.

Answer 6

Post Brexit GB MAs will be issued by MHRA, 4 routes: Existing 210 day UK procedure New national accelerated 150 day assessment for new & existing active substances and orphan drugs New rolling review for new APIs & biosimilars. Submitted in modules rather than a full final submission. For 2 years GB will adopt decisions by EC/NCAs on approval of new MAs. MAA must have PLGB number & submit eCTD/relevant data to MHRA. Excludes MAs granted via national procedure in EU MS. Typical timeframe: 67 days. Existing CAP MAs automatically converted to GB MAs & GB Product Licence (PLGB) issued. Baseline data must be sent to MHRA by 31Dec2021. In NI existing MAs remain valid. NI Unfettered Access: For MA approved in NI - NI companies can use Unfettered Access Procedure to allow GB approval of medicines with existing MA covering NI Apply for PLGB number to allow product to be supplied to GB. PLBG must be same product as in NI market MAH in NI must be a qualifying business GB wholesalers can only purchase from manufacturer in NI/GB Specific format PLBG xxx/yyy (UA) to differ from other PLGB routes to market Typical timeframe: 67 days.

Answer 7

List on MHRA website: Importation of medicines under a wholesaler dealers licence Batch testing of medicines Manufacturing of active substances with regulatory standards equiv. to UK Will be reviewed every 3 years

Answer 8

UK MRAs (signed): New Zealand Australia USA Japan (TA – replicates MRA) Israel (ACCA - trade agreement) Switzerland (TA – covers MRA) EU (TA – Annex TBT-2) In Negotiation: Canada (Signed but not fully in effect)

Answer 9

New role for importing of EU QP certified product from EU to GB. WDA holder: System to check EU product has been QP certified (Jan 21) Notify MHRA if importing QP certified product (Jun 21) Submit WDA variation, MHRA will update WDA RP-I named on the WDA (must be named on WDA by Jan 2023) RP-I will be responsible for: Implementing a system to confirm QP certification has taken place for products imported into the UK from EEA. Supply chain and GDP checks. One RPi can be responsible for multiple sites in company If importing product from other countries ordinary RP required. To be an RP-I: Degree or higher education certificate in pharmacy, chemistry, biology or related life science. Member of the one of the joint professional bodies. Minimum 2 years experience performing the function of an RP.

Answer 10

SI 2013/2033 UK Administration of vet meds: Veterinary Medicines Directorate (VMD) Similar structure to MHRA Part of DEFRA MAVIS: Medicines Act Veterinary Information Service Issue quarterly publication Licensing issues Yellow card system for ADRs QPPV can be located anywhere in world (post Brexit)

Answer 11

Legislation Continue to follow EU guidance until 01Jan2023 UK Medicines and Medical Devices Act 2021. CTR/UK NMVS/MDR to be included. UK will align with CTR where possible. NI Protocol Marketing Authorisations UK become 3rd country implications: Bulk product/API considerations. MHRA issuing written confirmations of compliance with EU GMP. Register available. Batch Testing and QP Certification: Import testing: UK will accept QP certified product from EU without import testing, Rpi check. EU will not accept QP certified product from UK. Licensing: UK local MA required, EU entity for EU MA MRAs: MRAs/TAs in place with pre Brexit countries (approved list on MHRA website) Reference and retention samples to be kept in EU. Northern Ireland extended transition period until Jan 2022. Access to EU systems inc. EudraGMDP and EMVS QPPV IMPs: UK sponsor requires legal entity in EU. UK will not have access to EudraCT or new CTIS Separate CTA required in UK for UK CTs. Sponsor may be in UK/EU. For IMPs imported into GB from EU need QP to verify EU QP certification and the QP can be resident in EU but must be named on UK MIA (IMP). QP to ensure valid QP certification in EU, valid GB CTA, IMP only shipped to trial sites in GB CTA and PSF/other documentation available to them. Safety reporting SUSAR reports to be sent to MHRA. UK will continue to recognise existing regulatory and ethics approval. VETs: Until Feb 2023 VMD will accept EU as location for MAH/QPs/QC/QP certification. From Jan 2021 adverse reports to be reported to VMD. Existing MAs for CAPs will automatically be transferred to GB MAs. Summarised dataset to be provided to VMD by Jun2021 with full baseline data submitted by Jan 2023 and variation to update packaging to reflect MA changes.

Answer 12

- IMP GMP Delegated Regulation 2017/1569 & Commercial GMP Directive 2017/1572 – repeals 2003/94/EC (same time as CTR) - Annex 13 will be replaced by ‘Detailed Commission Guideline on GMP for IMPs’ EMA have confirmed CTIS meets req’s, EC expected to publish notice in Official Journal of EU July 2021  CTR implementation Jan 2022 A streamlined application procedure for all clinical trials conducted in Europe via a single EU portal and database. A single authorisation procedure for all clinical trials. Content of CTA to be harmonised. Strengthened transparency for clinical trials data. One system for clinical trial submission, recording, reporting throughout EU, expected go-live Jan 2022. CTIS can be accessed by sponsors/authorities/public. CTIS newsletter now published twice a year by EMA with updates on system. Once go-live 3 year transition period. Yr 1: Use of CTIS optional. Yr 2 & 3: All new CTAs via CTIS and ongoing trials transferred to CTIS by end of Yr 3. Only QP legal duty specified is to ensure compliance with GMP – all other QP duties omitted. QP duties and authority inspection powers not all covered in CTR 536/2014 therefore included in IMP GMP DR 2017/1569. QP Duties – Article 12. IMP GMP includes a new section on Release of Batches which takes into account Annex 16 requirements.

Answer 13

There is an insufficient number and range of medicines to prevent and treat diseases in animals in the EU; Need to remove ‘red tape’. Simplify regulatory process. Centralised MAAs process that will allow companies to place and maintain a veterinary medicine on the entire EU market . Focus on how to reduce Antimicrobial Resistance (AMR) in animals and humans. Restrictions on use of antibiotics in food animals. QP duties generally similar to 2001/82 with one notable different - QP control report (rather than signing in a register). QP Duties – Article 97. Harmonised approach for Field trials (clinical trials) A separate GMP legislation for veterinary medicines expected to be implemented before Jan 2022.

Answer 14

Will amend 2001/83/EC and introduce new rules for drug-device combination products Establishment of an EU database on Medical Devices Integral devices need CE marking/conformity assessment issued by Notified Body in MAA. Non-integral devices need CE marking. Combination products - Integral/non-integral device classifications clarified based on their principal mode of action (Further EMA guidance issued) Person Responsible for Regulatory Compliance (PRRC) – Device QP equivalent Unique Device identification (UDI) Notified bodies changes and Unannounced audits of Notified bodies Post marketing Surveillance - Safety monitoring Integral: Forms single integral part of drug delivery – cannot be used alone (epi-pen) Non-Integral: Two or more components, not physically integrated but product & device combined for administration (re-usable syringe)

Answer 15

New system for classification: risk based New safety and performance req’s Clinical performance – increased attention Post Marketing Obligations – Surveillance No QP but RP

Answer 16

2nd Draft published, >2000 comments received. Delayed by Brexit/EMA move/Covid-19. Final version likely 2021 with phased implementation period 6 month implementation period for most aspects with expected 3 year implementation period for new technology aspects Embedding Quality Risk Management Embrace use of new technologies Much longer and more detailed than current version  removes ambiguity and give clearer instructions Requirement for a Contamination Control Strategy: Document reflecting the site-wide strategy for minimising contamination control. Holistic view of all potential contamination (micro, particulates, materials etc)., and cleaning and other controls in place to assess effectiveness of all control and monitoring measures in place. Requirement to perform Container Closure Integrity Testing: 100% leak test for fusion sealed units (e.g. BFS, ampules) and risk based for units sealed by other means. WFI by RO now permitted: As permitted by the Pharm Eur, Annex 1 updated to allow RO. Responsibility to keep up to date with Isolator technology: keep up to date with isolator technology / use of RABS. Shift to SUS – E&L considerations. Requirement to perform PUPSIT on filters: Perform Pre Use Post Sterilisation Integrity Testing on filters. Required for large volume products, risk assessed approach for small volume products Particulates Changes: Changes to room classification / qualification req’s. No longer requirement to perform 5um particle monitoring for all stages during classification and no micro contamination in Grade A during qual. (5um particulates not req’d for Grade A/B at rest & Grade A in operation. Finger dabs not req’d during qualification. Grade D ‘at rest’ limit provided.)

Answer 17

Detailed guidelines on IMP GMP to complement 2017/1569 published Expected implementation Jan 2022. May be updated Annex 13/Part V/moved to Chapter 10

Answer 18

Draft published for questions, consultation closed end Aug 2020. Draft v. short – 3 pages. Expected implementation TBC. Ensure integrity of supply chain and application of GxP requirements for importation of finished product into EU. Physical importation only. Nothing new.

Answer 19

Announced/Proposed updates to ICH: ICH Q2(R2) Analytical Method Validation (Step 1) – To include other non chromatographic techniques such as NIR ICH Q3C(R8) Impurities Residual Solvents (Step 4) – Recommended PDEs for 3 solvents ICH Q3D(R2) Elemental Impurities (Step 3) – Changes to PDEs for Gold/Silver/Nickel, new section on EI Limits for Cutaneous and Transcutaneous Routes added ICH Q3E Impurity (Step 1): Assessment and Control of Extractables and Leachables (New) ICH Q5A(R2) Viral Safety Evaluation of Biotech Products (Step 1) – Concept paper ICH Q9(R1) Quality risk Management (Step 1) – Provide clarity in identifying and assessing risk levels  more robust, integrated QRM ICH M4Q(R1) Common Technical Document: New Work Topic agreed, not yet started. ICH M7 Addendum on Genotoxic impurities that addresses nitrosamines to be included ICH M10 Bioanalytical Method Validation (Step 3) – Guidance on method validation expected for bioanalytical assays submitted in regulatory submissions ICH M12 Drug Interaction Studies ICH M13 Bioequivalence for immediate release OSD forms ICH E6(R3) Good Clinical Practice and ICH E8(R1) General Considerations for Clinical Trials (Step 1)

Answer 20

Q12 Product Lifecycle Management Stalled at stage 5 – In process of implementation, awaiting training material to be published and Inspectorate training to be conducted. Unable to be implemented in EU due to legal incompatibilities with EU law. Harmonise approaches to post approval changes using a risk based approach – aim to reduce number of variations Categorisation of Post-Approval CMC Changes, Established Conditions, Post-approval Change Management Protocol, Product Lifecycle Management Established Conditions – legally binding conditions to assure product quality, changing EC would require a variation Will add a focus on change management – PIC/S draft on effective change management supports this Q13 Continuous Manufacture At stage 1, adoption expected 2022 Capture key technical and regulatory considerations that promote harmonisation specific to CM Provide guidance on expectations for development, implementation and assessment of CM technologies Q14 Analytical Method Development At stage 1, adoption expected end 2021 May be combined into ICH Q2 To provide guidance with the aim of a more harmonised process, leading to less NCA comments while filing method development

Answer 21

New proposal for an EU Regulation to extend the role of EMA in crisis management, managing potential shortages of medicines and medical devices and to enable them to have a greater role in coordinating clinical trials. The proposed reg provides a framework for and the means to: Prepare for & manage the impact of major events and public health emergencies on medicinal products and medical devices. Establish a steering group on shortages and safety of medicinal products within the EMA. Single point of contact for sharing information on medicine shortages. Monitor and report on shortages of medicinal products for human use and medical devices. Provide advice on medicinal products with the potential to address public health emergencies. Provide support for medical device expert panels.

Answer 22

Aide Memoire Inspection of Health Based Exposure Limit (HBEL Assessments) and Use in QRM (ISSUED) Draft document on Effective Change Management How to Evaluate/Demonstrate the Effectiveness of a Pharmaceutical Quality System in relation to Risk Based Change Management Covers all steps of change management: Proposal  Assess  Implement  Review  Effectiveness Annex 1 Sterile Products draft (in conjunction with EU and WHO) Annex 2 Biological Products – New section 2A to include ATMPs (not split into separate Part as in EU) Draft document on Good Practice for Data Management and Integrity in GMP/GDP Environments

Answer 23

Points to Consider on Cleaning validation, including HBELs (DRAFT) Draft Guideline on GMP for Development Batches: Provides guidance on GMP to R&D and aims to strengthen GMP in R&D as from early research to final stages of development and formulation. Sliding scale of GMP dependant on risk at each stage of development. Draft Guideline on GMP for IMPs: Provides guidance on GMP for IMPs. Very similar to existing EU Guidance.

Answer 24

Centralised: Single MA for whole EU. Mandatory for specific therapeutic classes: Biotech products (vaccines), Orphan drugs, NCEs for AIDS, Cancer, ATMPs, Viral diseases and disease where wider reach is beneficial. EMA informed of proposal to submit a centralised MAA. EMA will appoint a Rapporteur and co-rapporteur, based on experience and knowledge of the disease states. MAA submitted to EMA/Rap/Co-Rap. Rap/Co-Rap review and send questions & report to CHMP. EMA sends these to the MAA. CHMP issues final opinion in 210 days. Member states have 22 days to forward opinion. If no objections or majority favourable, the decision is adopted. This should take place within 67 days of the opinion of CHMP. Decision is then notified to the MAA. - Accel. process available for products with major public need (covid vaccines) – approx. 6 months. - Conditional MA: Granted before Phase III trials finished, update when all data available and full MA granted - MAA under exceptional circumstances: MA where sufficient data cannot be obtained, not ethical to do CT National: 1 application in 1 country = 1 licence. National agency dictates timelines (typically 210 days). Labour intensive, but low risk. Mutual Recognition: Based on mutual recognition of a pre-existing national MA. May apply to more than one MS at the same time under mutual recognition procedure Applications submitted must be identical One MS becomes the Reference member state (RMS) and will evaluate the MAA. Assessment time: 210 days. The RMS will provide an Assessment Report (AR) with their final decision inc. granting of MA if positive outcome. Concerned Member States (CMS) have 90 days to recognise decision of RMS and grant National MA within 30 days. Repeat Use Procedure for further approvals in additional MS. Assessment time: 90 days + 30 days (granting national MA). Decentralised: MAA submitted simultaneously in several MS Product not previously authorised in any MS. Typically used for generics. MAA submitted to multiple MS at once. RMS (and at least 2 CMS) are chosen and evaluates MAA. RMS produces a report, which the CMS takes into account. Assessment time: 210 days + 30 days (national phase). Additional MS added by MRP.

Answer 25

New focus group to establish global approach to remote inspections for GxP

Answer 26

Guidelines for categories of variations 2013/c 223/001 Type 1A – Do and tell within 12 months Type 1AIN – Notify immediately (within 15 days) for continuous supervision of the medicinal product concerned Type 1B – Tell, wait 30 days, do (unless told otherwise) Type II – Prior approval Urgent Safety Restrictions – urgent changes to MA due to new safety information becoming available. Notify EMA/NCA of required restrictions and if no objections within 24 hours restrictions deemed accepted. Formal Type II variation must be submitted ASAP (within 15 days). Artwork changes – unless critical, usually have 6 months to implement change (9 months under Covid flexibilities). Artwork safety changes – 3 months.

Answer 27

MA ceases to be valid if medicinal product is not placed on market for 3 years following granting of MA or if medicinal product is removed from market for 3 consecutive years.

Answer 28

Type 1A: Name and/or address change Site deletion Batch size increase/decrease up to 10 fold Specification tightening Packaging/testing/certification site addition/deletion Type 1B Batch size increase >10 fold Addition/replacement of test as a result of S/Q issue Shelf life/retest period extension based on real time data Single excipient change with like-for-like excipient Addition of new manufacturing site (non-sterile) Type II Major changes to manufacturing process that may have sig. impact on S, Q, E Specification widening Shelf life/retest period extension based on ICH extrap. Formulation change Addition of new manufacturing site (sterile

Answer 29

Forms basis of info for HCPs on how to use the medicine safely and effectively. Should contain the same info as the PIL. Format is defined in EU legislation – Article 11 of 2001/83/EC Must be updated throughout the lifecycle of the product, as new safety & efficacy data becomes available. Found on MHRA SmPC & PIL website and electronic Medicines Compendium (eMC) website In Module 1 of MA

Answer 30

Biosimilars Generic and hybrid applications Orphan medicines Paediatric medicines Advanced therapy medicinal products Medicines for use outside EU (Article 58

Answer 31

For the UK, this is covered in 2012:1916 Initially valid for 5 years, if authorisation is renewed following this, MA granted for an unlimited period. Authority may decide that it is necessary to make a further application for 5 years, on the following grounds in the event there's not enough PV data

Answer 32

Modules: 1 – Admin (Regional info, SmPC, label mock ups) 2 – Summaries and Overviews of Q, S, E 3 – Quality 4 – Safety: Non-clinical study report 5 – Efficacy: Clinical study reports Module 3: 3.2.S (Drug Substance – 7 sections) 3.2.S.1 – General info 3.2.S.2 – Manufacture 3.2.S.3 – Characterisation 3.2.S.4 – Control of Drug Substance 3.2.S.5 – Reference standards and Materials 3.2.S.6 – Container closure 3.2.S.7 – Stability Module 3: 3.2.P (Drug Product – 8 sections) 3.2.P.1 – Description & Composition 3.2.P.2 – Product Development 3.2.P.3 – Manufacture 3.2.P.4 – Control of excipients 3.2.P.5 – Control of Drug Product 3.2.P.6 – Reference standards and materials 3.2.P.7 – Container Closure 3.2.P.8 – Stability (Summary & Conclusions/Post Approval Stability Protocol & Commitment/Stability Data)

Answer 33

MIA - human commercial product MIA (IMP) - clinical trials ManA - vet commercial product MS - specials (unlicensed – supply named patient basis) ManSA - veterinary specials WDA - wholesale distribution MaAT - preparation and administration of ATMPs Manufacturing licence = 2001/83/EC Art.40 MHRA will issue post Brexit for UK market

Answer 34

Section 1: Licence holder details Section 2: Variation history (updated each time licence is varied) Section 3: Details relating to each site (Multiple Annexes) Annex 1: Site Information – scope of licence Annex 5/6: Named Personnel Annex 8: Product Information (manufactured/imported) Storage and QC sites Typical Contents MIA Number Site name & address Scope of licence & dosage form: Products authorised to manufacture, package, import & release. QPs, Head of Production, Head of QC Storage sites Outsourced QC labs MIA issued following inspection - All FP manu/importers regularly inspected by EU NCA, unless MRA in place

Answer 35

Must have WDA. RPs listed on WDA. To sell or supply medicines to anyone other than the patient you need a WDA. Must comply with GDP and pass regular GDP inspections of your site. A pharmacy can be a wholesalers. Then must have a WDA. Persons operating from the UK require a WDA if there are: importing products from a non-EEA Member State for export to a non-EEA Member State exporting medicinal products to a non-EEA Member State. 2001/83 states WDA holder must have at least one RP. In the UK this requirement is set out in regulation 45 of 2012:1916. The RP should have appropriate competence and experience as well as knowledge of and training in GDP. RP responsible for ensuring PQS at wholesaler/distributor is effective. On EudraGDMP website – regular checks required to make sure licence still valid UK no longer have access, MHRA setting up UK GDMP for UK issued licences/certs

Answer 36

Must be registered with MHRA Must comply with GDP and pass regular GDP inspections of your site. A UK-based company that independently negotiates selling/buying medicines on behalf of another company must be registered as a broker. A broker does not: - own the products - physically handle the products - Distribute as a wholesaler Brokers must: -Have complaints & recall process -Have procedure for notification of competent authority for falsified medicines -Ensure brokered products have MA -Ensure suppliers have WDA or MIA -Have records of transactions of brokered products

Answer 37

Inspections, Enforcement and Standards – ensure compliance with GxPs related to manu & supply of product Inspectorate and process licensing GMP, GDP, GLP, GCP Process licencing- MIA, WDA, Broker registration. GMP/GDP/GLP certs. Enforcement Borderline Products, IAG & Reg advice DMRC Licencing – assess & approve MAAs and CTAs Vigilance and risk management – protects public health, conducts post-marketing surv., operates Yellow Card system Medical Devices – oversees Notified Bodies, support Advisory Group: Innovation

Answer 38

Regulates medicines within the UK – responsible for ensuring QSE Promoting international std & harmonisation Education on risks/benefits of medicines Influence regulatory framework Compliance Management Team (CMT): senior/expert inspectors, operations & unit managers. Main objective: protect public health, maintain supply of meds & try to avoid the need for reg action. Return company to state of compliance. Inspection Action Group (IAG): Multi-disciplinary team of medical and pharmaceutical assessors, legal advisors, enforcement reps and senior/expert inspectors. Can take action against QP. Enforcement powers of the MHRA : part 16 of 2012:1916 An inspector may at any reasonable time enter premises, but must produce identification upon request. The authority may apply for a warrant of entry from a magistrate to authorise entry without notice and by force if necessary.

Answer 39

4 types of post inspection letter: Type 1: routine Type 2: “warning” from inspector Type 3: Formal escalation to the CMT Type 4: Formal escalation to the IAG

Answer 40

Unit of the Inspection, Enforcement & Standards Division Recalls

Answer 41

Scope Raise a deviation Notification and escalation to SMT Recall Assessment team – Multi disciplinary, SMEs Initial Investigation Risk assess Decide if recall is require and type - proposal Discuss your proposal with the DMRC For CAP discuss with EMA Recall Notification to NCAs of other countries where product is marketed. Investigation Provide DMRC with a final report into recall Changes to MHRA Recall Classification Naming: Class 1: Now known as National Patient Safety Alert Class 2 or 3: Now known as Class 2/3 Medicines Recall Class 4: Now known as Class 4 Medicines Notification Company Led Medicines Recall/Notification – no alert

Answer 42

1. Procedure for receipt and handling of complaints 2. Must include process to access whether complaint presents genuine product quality risk, if there's likely to be other product / batches affected, if there's a risk of falsification, if complaint is justified / unjustified 3. Quarantine any stock still within your control while investigation ongoing 4. Batch documentation and retain sample review, with retesting if required 5. Review of other complaints for that product / batch / product manufactured from same suite / packing line etc. 6. Risk assessment to include medical and PV assessment, risk to patient safety, regulatory compliance, and GMP. 7. Clear timelines must be in place (based on nature of complaint), to ensure any quality defects that must be reported, are done so in a timely manner to the DMRC, MHRA and relevant in market competent authorities 8. Root cause and CAPA 9. Reconciliation of any recalled product

Answer 43

Reporter Details Product Details inc. batch details, MA information and presentation/packaging details Defect Details inc. defect description and category Investigation and actions details inc. consequences of proposed action on market

Answer 44

Monitoring effects of medicines after licenced for use. Identify & assess adverse effects / other medicine-related problem. SAFETY PROFILE of product in use. The EMA coordinates the EU PV system (EudraVigilance) and operates services and processes to support PV in the EU. After authorisation the medicine may be used in a large number of patients, for a long period of time and with other medicines. Certain side effects may emerge in such circumstances. Therefore essential that the safety of all medicines is monitored throughout their use. EU law requires each MAH, national competent authority and EMA to operate a PV system. An MAH should have a PSMF in place and a QPPV, QPPV responsible for: Establishing and maintaining PV system Preparing and providing PV reports inc. Periodic Safety Update Reports (PSURs) and Individual Case Safety Reports (ICSRs) PSUR: Routine reporting of trend and risk benefit, evaluating any changes to this balance to ensure ongoing suitability of products in market. The summary of the PV system should be provided in CTD Module 1.8.1

Answer 45

Eudralex volume 9 2010/84/EU (amended 2001/83/EC

Answer 46

responsible for assessing and monitoring the safety of human medicines. Made up of experts in medicines safety from reg auth. in MS, scientific experts and representatives of patients and healthcare professionals nominated by the EC. PRAC also monitor and provide recommendations / requirements to update safety info based on signals / events. The EMA is responsible for developing and maintaining EudraVigilance, a system for managing and analysing information on suspected adverse reactions to medicines authorised in the EEA. single repository for reports of suspected adverse reactions seen in healthcare practice and clinical trials. Post Brexit: UK system = SENTINEL

Answer 47

Requirement for new product being intensively monitored for PV data. Can be reintroduced if required. Safety update summary report after 18 months Can remove when safety of the drug is well established, must get approval from MHRA through submission of PV data. Typically 5 years.

Answer 48

Scope expanded to all GXPs Expectation to perform DI Risk Assessments Updated Definitions Raw data no longer refers to true copies Distinction between original records and true copies. Data governance – must be included in QTAs Primary record definition removed Audit trail, Data review & approval, Archive and Backup sections expanded Attributable Legible Contemporaneous Original Accurate + Complete, Consistent, Enduring, and Available Raw data: Must permit full reconstruction of the activities. Where this has been captured in a dynamic state and generated electronically, paper copies cannot be considered as ‘raw data’. Data Governance: The arrangements to ensure that data, irrespective of the format in which they are generated, are recorded, processed, retained and used to ensure the record throughout the data lifecycle. Key for Lab Original record: The first or source capture of data or information e.g. original paper record of manual observation or electronic raw data file from a computerised system, and all subsequent data required to fully reconstruct the conduct of the GXP activity. Original records can be Static or Dynamic. True Copy: A copy (irrespective of the type of media used) of the original record that has been verified (i.e. by a dated signature or by generation through a validated process) to have the same information, including data that describe the context, content, and structure, as the original.

Answer 49

PRINCIPLES OF QUALITY RISK MANAGEMENT * The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient; * The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk. * Underpins CONTROL STRATEGY – planned set of controls, based on product and process understanding, that assures process performance and product quality. GENERAL QUALITY RISK MANAGEMENT PROCESS QRM is a systematic process for the assessment, control, communication and review of risks to the quality of the product across the product lifecycle. Examples of where QRM used: Vendor oversight Cleaning Validation Environmental Monitoring Programmes Risk Register: Lists the known risks and the controls in place to mitigate them Risk Assessment, Control, Communication, Review ACCR EMA has issued guidance which contains examples of the tools that can be used: FMEA Process: Failure modes and Effects Analysis Risk Ranking: Fault Tree Analysis: HACCP : Hazard Analysis and Critical Control Points

Answer 50

Achieve product realisation: a system that allows for the delivery of products with the appropriate quality attributes to meet the needs of; Patients, Reg Authorities, doctors etc Establish & maintain a state of control: process performance & capability to assure quality & suitability. QRM Facilitate continual improvement

Answer 51

Enablers: QRM Knowledge Management

Answer 52

Management system to direct and control a pharma company wrt quality to ensure req’s of MA/CTA are met and the product is SQE. Responsibility of SMT. To achieve this quality objective a PQS incorporating GMP and QRM is req’d. Must be fully documented & effectiveness verified. All parts must be adequately resourced with trained personnel, suitable & sufficient premises, equipment & facilities. Covers product lifecycle: Development Tech Transfer Commercial Discontinuation QMS should cover full lifecycle of the product, From pharmaceutical development through to product discontinuation. Size and complexity of the company’s activities should be taken into consideration when developing or modifying a QMS. Design should incorporate appropriate ICHQ9 QRM principles including use of approp. tools. While some aspects of the system can be company-wide, the effectiveness of the system should be demonstrated at the site level. SMT are responsible for QMS, QP/Quality may be given task of managing the QMS but QP/Quality is not responsible to ensure an effective QMS is in place. QP must communicate concerns about QMS deficiencies to SMT.

Answer 53

Scope (human, vet, IMP, MDR) Start with quality vision & mission, then policies & procedures Define relevant policies & procedures: Chapters of EudraLex vol 4: PQS, personnel, premises & equipment, documentation, production, QC, outsourced activities, complaints & recalls, self inspection & batch release Quality review and improvement Requirement for SMT to own QMS, with regular management review, with formal process for monitoring of effectiveness of QMS and continual improvement KPIs that measure progress against quality objectives should be established, monitored, communicated regularly, and acted upon as appropriate as described. KPIs support batch disposition. Typical KPIs: Deviations, CAPAs, Change Control, RFT, Audits, PQRS, Complaints, Recalls, Regulatory Inspections, Scorecard Adequately resourced with competent personnel and suitable and sufficient premises, equipment and facilities. Interfaces between development/commercial, GCP/GMP/GDP etc. Quality culture NB, e.g. GEMBA walks, leading by example, no blame culture, visible metrics

Answer 54

High level overview of overall intentions and direction of org. Describes the standards the site will follow (GMP) and how (PQS). Culture that drives CI

Answer 55

Quality Manual: As defined by ICHQ10, describes the PQS on site. Includes; Quality policy Scope of the PQS Identifies the PQS system processes, ownership of processes, responsibilities of owners and maintenance of processes. Management responsibilities Defines framework of policies, directives and systems necessary to ensure products are manufactured, processed, packed & held in line with GMP, applicable laws, regulations & company expectations. List of SOPs of documents which ensure compliance with GMP Document Control Training Change Management Investigations Complaints & recalls Self Inspections Vendor management etc

Answer 56

Guidance notes in Eudralex vol.4 Part III Describes GMP related activities of the manufacturer General info on site (pics/diagrams of layout facilities) Site licences & authorised activities on site – Any other non pharma activities on site Then cover all chapters of Eudralex Vol 4 part I GMP Cert, MIA, Orgcharts, water system schematics etc

Answer 57

Batch documents: 1 year after expiry or at least 5 years after QP certification. Other documents: Based on QRA (typically 2/3 years): How critical is procedure? How established is procedure? (Established: longer, New: shorter) Separate system to ensure update if impacted by change?

Answer 58

Product quality reviews of all authorised products. Conducted at least annually. Can be grouped by product type. Part II/ICH Q7 also requires API PQR. Verify consistency of existing process, appropriateness of current specs (starting materials and FP), highlight any trends and identify any process improvements. Assess effectiveness of actions raised from PQR via self-inspection. Review of starting and packaging materials; in particular Review of API supply chain traceability Materials from new sources Review critical IPC and Finished Product Results Review all batches that failed spec & associated investigations. Review all significant deviations, related investigations, CAPAs, ECs. Review all changes made to processes or analytical methods. Review MA variations submitted, granted or refused. Review results of stability programme and any adverse trends Review quality related returns/complaints/recalls & associated investigations. Review adequacy of other previous product process or equipment CAPAs Review post-marketing commitments for new MAs and variations. Review qualification status of relevant equip and utilities (HVAC, water, etc) Review any QTAs and ensure they are up to date.

Answer 59

Contract QPs (Code of Practice): Must be named on MIA and have contract for services Readily available to company Has access to all relevant information inc. relevant sections of MA Kept updated with sig. deviations/changes/inspections and maintain oversight of PQS Regular contact, aware of quality metrics and confident effective PQS in place Before beginning certification allow sufficient time to become familiar with product and processes  training programme as per company QP training

Answer 60

Any activity that is outsourced should be defined, agreed and controlled. There must be a written contract between Contract Giver & Contract Acceptor and should be signed by those responsible for quality. The QTA outlines the R&R for each party and varies depending on the service outsourced. Before outsourcing activities the CG must audit the CA. Ongoing performance should be monitored and reviewed. QTA periodically reviewed and updated.

Answer 61

-Summary of info on quality, manufacture and control of any IMP (including comparators and placebo), and data from non-clinical and clinical studies. -Can use the structure of a CTD (Module 3). 2.1.S – Drug substance 2.1.P – Drug product

Answer 62

- Describes the CT - Approved by regulator before use - Change only by written amendment

Answer 63

Signed cover Letter Signed CTA form IMPD Investigator Brochure (IB) Study Protocol Labelling details MIA (IMP) QP Declaration on GMP for each site PIP Ethics Committee Approval Non-IMPD Proof of Payment

Answer 64

Ethics Committee Approval NCA Approval (for each country where CT will be run) Sponsor/representative based within EU EudraCT number

Answer 65

Compilation of all clinical & nonclinical data on the IMP relevant to study of the IMP in humans. Summarises all information available on the IMP. Provides investigator and others involved in CT (HCPs) with background info about the IMP to help them to work in line with the protocol. Provides all info necessary to assess appropriateness of trial, including risk-benefit ratio. Insight to clinical management of study conduct/subjects throughout CT. Key aspects and safety measures, such as: - Dose (of the study drug) - Frequency of dosing interval - Methods of administration - Safety monitoring procedures Provide the investigator with a clear understanding of the possible risks/adverse reactions, and of the specific tests, observations, and precautions. Guidance on the recognition/treatment of possible overdose/adverse drug reactions, based on previous human experience & on pharmacology of the IMP. Sponsor is responsible for keeping IB up-to-date. Reviewed annually and must be updated when any new and important information becomes available, such as when a drug has been approved for use commercially.

Answer 66

Guidance on requirements in Annex 13. - Typically include contact details/dosage form/batch details/patient ID/directions for use/storage conditions/shelf life/statement to say for CT use only/warning symbols

Answer 67

All information needed to prepare written instructions on processing, packaging, testing, batch release and shipping an IMP. Basis for certification and release. QP must have access. Continually updated. Updates managed via change management. Includes: Specs and analytical methods Manufacturing methods In-process testing and methods Approved label copy Relevant CT protocols and randomisation codes Relevant technical agreements Stability data Storage and shipment conditions.

Answer 68

Manufacturing: Over-encapsulation, Packaging: Bottling, Blister Packaging, Walleting

Answer 69

PSF (QP bible): Not part of CTA. CTA: Clinical Trial Authorisation. Authorisation by competent authority to conduct CT. IMPD: Quality, manufacturing and control of IMP. Part of CTA. (Like Module 3 in CTD). IB: Investigators Brochure: Info for management of study conduct and study subjects. Protocol: Describes the Clinical Trial and is approved by regulator before use. Order: Instruction from Sponsor to process, package or ship IMP. Not part of CTA.

Answer 70

1: First time in healthy volunteers, determine safety profile & identify safe dose, small numbers (20-80) 2: Checking safety and efficacy in patients on small scale, 100-300 participants 3: Confirming safety and efficacy in patients on large scale, confirm effective dosing levels, compare against existing treatments, 1000-3000 participants, basis of MAA 4: Post market surveillance of approved product, drug-drug interactions, dosage optimisation

Answer 71

Legislation and Guidance - Scale of manufacture (g vs kg). Multi/single use equipment. - Sliding scale of GMP, limited validation (sterile – full GMP) - Volume of data available to QP - Packaging processes more complex and typically a manual process. Typically contracted out. - Packaging processes more high risk for IMPs as potentially packing active and placebo at the same time or into the same kit. Potential for mix-up. - Constant changes (change management critical) - Blinding considerations for IMPs, packaging must be identical across different CT supplies. Also the blinding method must not impact on the product. - 2 stage release (QP & Sponsor) - Labelling considerations - Cleaning verification rather than validation - Absolute reconciliation - API GMP for IMPs not a legal requirement in EU, EudraLex Vol 4 Part II Section 19 applies - Ethics approval alongside regulatory approval - Use of comparators and comparator sourcing, EU if poss - IMP QP GMP Declaration that manu site complies with GMP - Reconstitution of IMP allowed w/out MIA (IMP) If done by healthcare setting auth to do such processes & IMP will be used in the facility (Annex 13 & 2005/27)

Answer 72

Open: Treatment type known Single Blind: Doctor knows treatment type Double Blind: Treatment type unknown Parallel: Stay on 1 treatment for entire study Crossover: Swap treatments during study

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