Current Regulatory Developments REG800. 1

Transcription

1 Current Regulatory Developments REG800. 1

2 Current Regulatory Developments EU Initiatives Directives and Regulations GMP Guidelines UK Initiatives MLX 345 MLX 357 ICH Initiatives ICHQ8(R1), Q10 and Q11 US FDA Initiatives Phase 1 clinical supplies Process validation REG800.2

3 EU Initiatives REG800. 3

4 EU Initiatives Directives and Regulations REG800.4

5 EU Initiatives New Variations Proposals REG800.5

6 New Variations Proposals 2007 Consultation Paper A three step process to change the Variations regulations, as follows: H REG800.6

7 New Variations Process: Co-decision Proposal for a Directive to amend the Variations sections of Directives 2001/82/EC and 2001/83/EC ALL authorisations to be handled by a single system including national authorisations BUT Possibility for Member States to continue applying national rules on variations to products fulfilling certain conditions. REG800.7

8 New Variations Process: Comitology 24 Nov 2008 : Regulation 1234/2008 Introduces Do and Tell for Type 1A variations Do not require any prior approval and can be implemented anytime before notifying the competent authorities Type 1A: submit annual report of changes made Type 1A(IN): notify immediately after implementation REG800.8

9 New Variations Regulation Regulation 1234/2008 Variations to be Type 1B by default; rather than Type II as at present Some Type 1B variations to be reclassified as Type 1A REG800.9

10 New Variations Regulation Regulation 1234/2008 Other changes: A new process for the classification of variations Lists of Type 1A and II Variations to be published as Guidelines Can ask agency for a recommendation on the classification for unforeseen variations The ability to group variations Effective 1 January 2010 REG800.10

11 New Variations Guidelines Draft Guideline on classification of variations issued 20 March 2009 Annex contains a list of variations that should be classified as Type IA or Type II on the basis of definitions and specific examples Some guidance on the scientific conditions to be fulfilled and the supporting documentation required regarding certain variations REG800.11

12 EU Initiatives Anti- Counterfeiting Proposals REG800.12

13 Anti-counterfeiting Proposals Proposed revision of Directive 2001/83/EC : 10 December 2008 Obligations for brokers Safety-features (eg serialisation number or seal) on packaging obligatory New legal duty for Qualified Persons: Confirm that the safety features have been affixed on the packaging REG800.13

14 Anti-counterfeiting Proposals No manipulation (i.e. removing, tampering with, or over-labelling) of safety features on the packaging by persons in-between the original manufacturer and the last actor in distribution chain Safety features may be removed by Manufacturing Authorisation holders if Check authenticity of product before doing so Replace the safety feature with a safety feature which is equivalent as regards the possibility to ascertain identification, authenticity and uninterrupted traceability of the medicinal product without opening the immediate packaging (Allows parallel importing to continue) REG800.14

15 Anti-counterfeiting Proposals Obligatory audits of supplying wholesale distributors of medicinal products Where product is traded between wholesalers holders of the WDA must verify compliance with GDP of the supplying wholesale distributor themselves through a body accredited for that purpose by a Member State competent authority REG800.15

16 Anti-counterfeiting Proposals WDA holders to verify that the manufacturer or importer holds a manufacturing authorisation NOTE: March 2009 EMEA Concept Paper on proposed revisions to replace the Guideline on Good Distribution Practice (94/C 63/03) REG800.16

17 Anti-counterfeiting Proposals Active substances used as starting material shall only be imported if Manufactured to standards at least equivalent to EU GMP Accompanied by written confirmation from the exporting third country that Standards of GMP applicable to the manufacturing plant are at least equivalent to those in the EU Plant is subject to control and enforcement ensuring that GMP cannot be circumvented BUT This requirement shall not apply if the exporting country is listed in accordance with Article 111b REG800.17

18 Anti-counterfeiting Proposals Article 111b: The Commission shall, following a request from a third country, list that country by way of a Decision if for APIs its regulatory framework and control/enforcement are comparable to those in the EU. Particular account shall be taken of: The country s rules for GMP The regularity of inspections of GMP The efficacy of enforcement of GMP The regularity and rapidity of information supplied relating to non-compliant producers REG800.18

19 Anti-counterfeiting Proposals Audits of manufacturers of API required MA holder Accredited body Increased use of EudraGMP database to improve transparency Provisions to be phased in between 18 and 48 months from date of publication of final amendment REG800.19

20 Anti-counterfeiting Proposals EFPIA response: Proposals will not fully secure patient safety. Anti-counterfeiting measures be based upon ensuring the integrity of original packs throughout the supply chain. Achieved by: Use of tamper-evident packaging or tamper-resistant closures Use of overt, covert and forensic authentication features Strengthening product identification at individual pack level through a harmonised coding standard (a 2D barcode). For measures to be effective - ban on re-packaging REG800.20

21 EU Initiatives EU GMP Guidelines REG800.21

22 EU Initiatives Part 2 Quality Risk Management REG800.22

23 EU GMP Guide Part 2 Draft for comment published April 2008 Comments were due by 31 October 2008 Incorporates principles of Quality Risk Management as per ICH Q9 New section on Quality Risk Management introduced as section 2.2. As per Part 1, Chapter 1 Remaining sections of CH.2 renumbered REG800.23

24 EU Initiatives Part 1 Chapter 5 REG800.24

25 EU GMP Guide Revision of Chapter 5 New requirements expected to include need for: Knowledge of the suppliers of APIs and high risk excipients Only purchase from approved suppliers Audit of suppliers of APIs and high risk excipients Formal agreements with suppliers, to include the distribution conditions Checks (integrity and seal) on each container Full analysis on at least 3 lots before instigating reduced testing Periodic full-testing for on-going monitoring REG800.25

26 EU GMP Guide Revision of Chapter 5 Whole issue of API supply chain management is receiving considerable attention following the issues with Heparin REG800.26

27 Heparin Contamination Issue Early serious injuries and deaths associated with heparin containing AIP from China Contaminant - oversulfated chondroitin sulphate FDA - contamination deliberate April FDA discover Show and Shadow factories for heparin manufacture REG800.27

28 Heparin Contamination Extent of contaminated heparin (shown in red) REG800.28

29 Heparin Contamination Political response US Congress: Voted to greatly increase the FDAs budget Serious questioning of the pharmaceutical industry s increasing move to outsourcing Greater emphasis on manufacturers taking responsibility for the supply chain for APIs and excipients More inspection of API suppliers International inspection cooperation REG800.29

30 Heparin Contamination Other Consequences Test for oversulfated chondroitin sulphate added to heparin monograph in most pharmacopeias FDA offices set up in China and India International inspection cooperation Focus on company supplier audits The Rx-360 Consortium REG800.30

31 The Rx-360 Consortium International non-profit organization including pharmaceutical manufacturers supplier companies trade organizations (as observers) Mission to create and monitor a global quality system that meets the expectations of industry and regulators assures patient safety by enhancing product quality and authenticity throughout the supply chain REG800.31

32 The Rx-360 Consortium Four distinct functions: 1. Standard Setting 2. Technology Development 3. Market Surveillance 4. Shared Supplier Audits REG800.32

33 EU Initiatives Annex 3 Radiopharmaceuticals REG800.33

34 Revised EU GMP Annex 3 Radiopharmaceuticals Effective 1 March 2009 Provides guidance for some relatively new technology, in particular Positron Emission Tomography (PET) short shelf life radionuclides active ingredient synthesis, dosage form preparation, patient administered in less than one day REG800.34

35 Revised EU GMP Annex 3 Guidance is given as to the GMP and non- GMP parts of the process; e.g. Cyclotron and Reactor steps : non-gmp GMP starts as soon as the chemical synthesis starts REG800.35

36 Revised EU GMP Annex 3 Parametric release is (still) seen as necessary with systems to follow up in the event of failed result when all testing has been completed Sterile products - two stage QP release process: 1. Release for administration 2. Final release after sterility testing REG800.36

37 Revised EU GMP Annex 3 Other changes New sections Introduction QA Documentation Glossary GMP requirements for the API - in line with EU GMP Part II Guidelines apply to clinical supplies Risk assessment strongly emphasised REG800.37

38 Revised EU GMP Annex 3 New requirements on environmental control during manufacture Section 27 closed (aseptic?) processes - Grade C acceptable aseptic (open?) processes - Grade A required REG800.38

39 EU Initiatives Annex 13 Investigational Medicinal Products REG800.39

40 Annex 13 IMPs Draft revision published in April 2008 Comments were due by 31 October 2008 Proposed changes Minor change to section 3 to reinforce independence between production and QC functions Reference to Annex 19 for guidance for reference and retention samples Rewording to enhance understanding of the two-step release procedure Change control process for the PSF defined in Technical Agreement between the QP and the Sponsor REG800.40

41 EU Initiatives Annex 14 Human Blood and Plasma Products REG800.41

42 Annex 14 Human Blood and Plasma Products Draft revision published January 2009 Comments due by 31 July 2009 Incorporates references to The Blood Directive 2002/98/EC The extensions 2005/61 EC 2005/62/EC REG800.42

43 Annex 14 Human Blood and Plasma Products Introduces key definitions Blood Establishment Body responsible for collecting blood or plasma Plasma Master File A stand-alone document setting out the characteristics of plasma used Responsible Person Blood establishment equivalent of the QP REG800.43

44 Annex 14 Human Blood and Plasma Products Clarifies responsibilities of the blood establishment RP and the fractionation plant QP Requirement for a contract of supply and for blood establishment audit by the QP EU Competent authority to approve non- EU blood establishments supplying plasma into the EU REG800.44

45 Annex 14 Human Blood and Plasma Products Standards for premises and manufacturing more detailed Persists in requiring Annex 1 standards be applied to all processing downstream of plasma stripping and thawing Does not require acceptance limits for environmental monitoring as per Annex 1 REG800.45

46 UK Developments REG800.46

47 Consolidation & Review of Legislation REG800.47

48 Consolidation & Review of UK Medicines Legislation Concept Paper published by MHRA January 2009 Current situation is very complex and fragmented Huge number of Statutory Instruments (SIs) Project with two strands: 1. Consolidation of existing legislation Using a Legislative Reform Order (LRO) 2. Simplification REG800.48

49 Present and Future Structure of UK Medicines Legislation REG800.49

50 Consolidation & Review of UK Medicines Legislation Consolidation MHRA hope to have draft Order by Spring 2010 Simplification Consultation will continue well into 2010 REG800.50

51 MLX 345 Risk-Based Inspections REG800.51

52 MHRA Risk-based Inspections MLX345 - Risk-based Inspection Programme for Good Practice Inspections : October 2007 Covers all GxP, i.e. GMP, GDP, GCP, GLP & GPvP Companies to regularly submit: corporate compliance statement self assessment report Review of company s profile to be performed by Inspectorate to determine Frequency Duration scope and breadth of any future inspection REG800.52

53 MHRA Risk-Based Inspection Model Intelligence Financial Compliance Company Regulatory Inspectorate Corporate compliance statement Self Assessment Risk assessment process Inspection Output Organisational behaviour change Inspection planning Inspection Company Risk Assessor Inspectorate REG800.53

54 Risk-based Inspections Two key elements: Corporate Compliance Element Organisation s willingness to comply with GxP How effectively an organisation monitors its compliance MHRA would request annually from the Chief Executive information concerning corporate compliance with relevant regulations how they will ensure that their organisation will meet these The Chief Executive will be held accountable for the accuracy and completeness of this information REG800.54

55 Risk-based Inspections Self Assessment element Regular self assessment report to be submitted to MHRA Report content and detail to vary according to the needs of the different GxPs REG800.55

56 Risk Factors MLX345 gives examples of specific risk factors to be considered for each GxP Risk factors for GMP Compliance history Recent changes at site Type of manufacture Medical need Specific triggers REG800.56

57 MHRA Risk-Based Inspections GMP Self-Inspection form published Guideline for Completion and Submission available from MHRA website Risk-based process applied for UK inspections from 1 April 2009 Risk profiling will determine the frequency, duration scope and breadth of future inspections Outcome of risk-ranking assessment Annex to inspection report REG800.57

58 Contract Laboratories Guidance REG800.58

59 Contract Laboratories Guidance Guidance for UK Manufacturer s Licence and Manufacturer s Authorisation Holders on the use of stand alone contract laboratories Published January 2008 When contract laboratories have to be named on Manufacturing or Marketing Authorisations and when they don t REG800.59

60 Contract Laboratories Guidance The contract labs named should be aware that they are named and may be subject to inspection by MHRA. Using a written contract/technical agreement the licence holders must ensure that the labs are aware and are in agreement with what is expected of them Licence holders must have assessed the laboratory as being fit for their purposes Contract labs involved in QC testing of medicinal products must do so in accordance with the marketing authorisation, PSF and EU GMP REG800.60

61 MLX 357 Supply Chain & Counterfeit Measures REG800.61

62 MLX 357 Supply Chain and Counterfeit Medicines Published in December 2008 Main proposals Applicant for a Wholesale Dealer s licence to demonstrate that he/she is a fit and proper person to undertake such a role minimum requirements to be set out in guidance Applicants to disclose criminal records Empower MHRA empowered to decline a Wholesale Dealer s licence if an applicant discloses a relevant criminal conviction Payment in advance for licence and inspection REG800.62

63 MLX 357 Supply Chain and Counterfeit Medicines Due Diligence obligation to notify MHRA of suspicious events Each body corporate at a Wholesale Dealer s site must have its own Wholesale Dealer s licence which cannot be transferred to another part of the business Clarifies MHRA powers to refuse to grant, suspend, revoke Wholesale Dealers licences if fees are not paid Removes the 35,000 turnover concession regarding reduced fees Comments were due by 13 March 2009 REG800.63

64 ICH Initiatives REG

65 Q8 Quality Risk Management REG800.65

66 Q8 (R1) Annex to Q8 Step 4 approval : November 2008 Published in EU as CHMP NfG : February 2009 Effective June 2009 Provides guidance how concepts and tools in Q8 can be put into practice REG800.66

67 Q8 (R1) Annex to Q8 Elaborates elements of pharmaceutical development as: Target Product Profile Critical Quality Attributes (CQA) Linking material attributes and process parameters to CQAs by risk assessment Design Space Control Strategy Product lifecycle management and continual improvement REG800.67

68 Q8 (R1) Design Space Provides guidance on: Selection of variables Defining and describing a design space in a submission Unit operation design space(s) Relationship of Design Space to scale and equipment Design Space versus proven acceptable ranges Design Space and edge of failure REG800.68

69 Q10 Pharmaceutical Quality Systems REG800.69

70 ICH Q10 Pharmaceutical Quality Systems Received Step 4 approval in June 2008 Expected to be implemented in EU as Annex to the EU GMP Guide REG800.70

71 Q10 - Principles Complements/facilitates implementation of Q8 Pharmaceutical Development and Q9 Quality Risk Management NOT intended to create any new expectations beyond current regulatory requirements Any content that is additional to current GMP requirements is optional REG800.71

72 Q10 Enablers The means for science- and risk-based decisions related to product quality Knowledge Management Manage knowledge from development through commercialisation to discontinuation Quality Risk Management (Q9) Proactive approach to managing risks to quality REG800.72

73 Q11 API Development REG800.73

74 Q11 API Development New expert working group started in June 2008 to write guideline Drug Substance Development API equivalent of Q8 Detail for the 3.2.S.2 section of CTD REG800.74

75 Q8, 9 & 10 Implementation Working Group REG800.75

76 Implementation Working Group (IWG) To cover implementation issues for Q8, 9 & 10 Technical Issues & Related Documentation Technical examples and case studies Level of detail to include in dossier Common understanding of terminology Inter-relationship between Q8, Q9, Q10 Application to both review and inspection Communication and Training Updating of existing ICH guidelines REG800.76

77 Implementation Working Group (IWG) Formal Question and Answer document published in April 2009 covering Quality By Design: Design Space Real Time Release Testing Control Strategy Pharmaceutical Quality System Impact On GMP Inspection Practices Knowledge Management Software Solutions REG800.77

78 REG FDA Initiatives

79 GMP for Phase 1 Clinical Supplies REG800.79

80 FDA GMP for Phase 1 IMPs Final rule to exempt investigational drugs in Phase I testing from certain GMP regulations Published in US Federal Register in July Took effect Sept Will apply to small-molecule drugs and biologics Inc. vaccines and gene therapy products Excludes products from human tissue or cells REG800.80

81 FDA GMP for Phase 1 IMPs Guidance for Industry: cgmp for Phase 1 Investigational Drugs Includes standards for: facilities and equipment, control of components, testing, stability, packaging, labelling, distribution, and recordkeeping REG800.81

82 Draft Guidance on Process Validation REG800.82

83 Draft FDA Guidance on Process Validation (PV) Published November Major step forward in approach to process validation Brings the industry into the 21st Century? REG800.83

84 Scope of Draft PV Guideline What s in? Human drugs Animal drugs Biological products APIs Drug constituent of a combination What s out? Type A medicated articles Medical devices Dietary supplements Human tissues for transplantation REG800.84

85 What s New in draft PV Guide? Aligns process validation with product lifecycle Takes on board Q8,Q9, Q10 Strongly endorses the QbD approach Product and process understanding is a fundamental requirement Emphasis on statistical approach Sound science based regardless No IQ, OQ No worst case No three validation batches No revalidation REG800.85

86 Product Lifecycle & PV Aligns process validation with the product lifecycle Continuous process verification Research Development Commercial Processing Release Distribution Process Validation Starts with product and process development Justifies commercial processing and release Extends to continuous process verification REG800.86

87 Definition of Process Validation The collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products. REG800.87

88 Process Validation The Stages Stage 1- Process Design Defines the commercial process based on knowledge gained through development and scale-up Stage 2- Process Qualification Confirms the process design as being capable of reproducible commercial manufacturing Stage 3- Continued Process Verification Ongoing assurance that during routine production the process remains in a state of control REG800.88

89 Process Validation and Product Release Before release for use by consumers the manufacturer should have gained a high degree of assurance in the performance of the manufacturing process such that it will consistently produce APIs, and drug products meeting those attributes relating to identity, strength, quality, purity and potency. REG800.89

90 Process Understanding and Process Validation Knowledge from product and process development Establish an approach to control Understand the sources of variation Detect the presence and degree of variation Understand the impact of variation on the process and product attributes Control the variation commensurate with risk to the process and product REG800.90

91 How much Process Understanding do I need Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree of assurance in its manufacturing process to justify commercial distribution of the product batches really is dead! REG800.91

92 REG Conclusion

93 Conclusion The rules keep changing! The rate of change is currently at an unprecedented level QPs, in particular, must keep up with these changes Take the time It is a GMP expectation REG800.93

94 Thank you David Begg Associates REG800.94