Impacto de las Nuevas Tendencias Regulatorias en la Producción de Parenterales

Transcription

1 Impacto de las Nuevas Tendencias Regulatorias en la Producción de Parenterales Empaques Primarios y Tendencias Farmaceuticas para Inyectables 1

2 International Support Support in R&D Technology Transfer Business Process Re-engineering Feasibility Studies Momentum Life Science Regulatory Affairs Qualification, Validation & Management Engineering, Design & Construction Support Business Development & Alliance Quality in Outsourcing & Auditing IT in Compliance Training 2

3 References 3

4 What is changing in Pharmaceutical world Emerging Regulations Harmonisation Principle Quality by Design Impact of International Tendences in Business 4

5 Pharmaceutical World is Changing... Some generic tendences of the Global Market for 2010 to % of actual outsourcing activity will be directed towards countries such as China, India, Korea and other emerging countries (where available good quality of work & low production cost) 2. companies will invest in social media 10% of the marketing budget. 3. Internet marketing investment will exceed the investment in traditional media 4. American model of direct to consumer advertising will not be imported into Europe. 5

6 Pharmaceutical World is Changing... Some generic tendences of the Global Market for 2010 to Traditional selling model will become obsolete (informants visits = more = better relationships with doctors = more sales) 6. Smartphones applications will become the next big marketing opportunity (affecting business in doctor-patient/ company-patient) 7. Patient will become more informed and aware (patient active role ) 8. The adverse effects of the drugs will be reduced by more personalized therapies 9. Sales of drugs will remain stable in the USA and Europe but will grow in emerging markets, which in 2013 will be worth more than a third of the global market 6

7 Pharmaceutical World is Changing and more Credit Management, Globalisation, Demographic and epidemiological pressures, Advances in communication, Declining R&D productivity, Healthcare reforms, increments of global population aged 65+, change of f ocus on key mature markets v/s growth markets. 7

8 Pharmaceutical World is Changing 8

9 Pharmaceutical World is Changing Some impact of Changes. 9

10 Pharmaceutical World is Changing Some Numbers for South America GlobalData stated that «in recent years» investments in merger and acquisition strategies have soared in the continent to the record peak of 12.7 billion dollars With its constant growth, in Price s opinion, Brazil is poised to climb up to the fourth place worldwide among the fastestdeveloping healthcare markets, only outpaced by the United States, China and Japan. Also favored by its belonging to Nafta area Mexico is steadily growing too, with chances to generate a 20 billion dollars revenue by the end of this year; and the pharmaceutical business is also enlarging in Colombia and Argentina "Brazil is the largest medical device market in Latin America, followed by Mexico, Venezuela, Colombia and Argentina respectively." 10

11 and what is changing in International Regulatory Requirements?? HARMONISATION PRINCIPLES 11

12 Why new rules & harmonisation? Evaluation of Supply Chain s Risk (US Source) 12

13 Why new rules & harmonisation? 1. For a better and uniform control 2. To establish common and references rules 3. To supply univoque parameters for both, inspector, and producer 4. To enforce common understanding, product knowledge, process knowledge 5. To harmonize validation activities 6. To harmonize registration &regulatory issues 7. To improve competition on quality 8. To demonstrate consistent ToT 9.. The need to Hamonize 13

14 ICH International Council of Harmonisation,Regulatory harmonization offers many direct benefits to both regulatory authorities and the pharmaceutical industry with beneficial impact for the protection of public health. preventing duplication of clinical trials in humans.streamlining the regulatory assessment process for new drug applications.. reducing the development times and resources for drug development "Coming together is a beginning. Keeping together is progress. Working together is success." Henry Ford 14

15 Why new rules & harmonisation? The need to Harmonize Part of a long History Q8 Q9 Q10 Q11 Q12 Pharmaceutical Development Quality Risk Management Pharmaceutical Quality System Development and manufacture of drug substances Technical and Regulatory Consideration for PHARMACEUTICAL PRODUCT LIFECYCLE Annex 11: Good Manufacturing Practice Medicinal Products for Human and Veterinary Use Computerized System Using Risk Based Approach within Integrated QMS and Quality By Design for a general better Process Understanding, enforce modern concept of Business Quality & Risk based driven pharmaceutical product development and Manufacturing 15

16 Pharmaceutical World is Changing As of September 2013, 34,466 drug and device establishments around the world were registered with the FDA, pursuant to section 510 of the FD&C Act. Of these, 12,878 were based overseas, and 3,493 of those were drug establishments. To help ease the burden, the FDA should join forces with many other large-scale organizations in monitoring their registered locations Real-time monitoring, rather than annual inspections, would mean consistently higher qualities of both medical devices and drugs. 16

17 So, New Rules & Harmonisation.. The need to Cooperate, in a GLOBAL environment 1. For a better SAFETY 2. To Protect both, patient and LOCAL INDUSTRY 3. For a FASTER Analysis / check 4. For mutual support 5. Speaking the same language 6. Requiring same controls 7. Comparing supplier, processes, final product, report mode 8. For a SIMILAR submission

18 and what is changing in International Regulatory Requirements?? PQMS, PQLI, QUALITY BY DESIGN.. FDA and EMA protect and promote public and animal health, through evaluation and supervision of medicines for human and veterinary use. They want to expand the public s knowledge of medicines, medical devices, and cosmetics, so they have been closely collaborate in development of standards. Process validation is not ANYMORE as a one-off event. A lifecycle approach should be applied couple product and process development, validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production 18

19 PQLI Product Quality Lifecycle Implementation This Guide is the first in a series of ISPE Product Quality Lifecycle Implementation (PQLI ) Good Practice Guides (GPGs) that will describe enhanced, quality by design approaches to product realization, and is an introduction to and an overview of the Guides Series. Product realization is the achievement of a product with the quality attributes appropriate to meet the needs of patients, health care professionals, regulatory authorities (including compliance with marketing authorization), and internal customers This Overview Guide and the subsequent ISPE PQLI GPG Series address product and process development, transfer to, and establishment of, commercial manufacture using science- and risk-based approaches. Other Guides in the Series will cover: Critical Quality Attributes and Critical Process Parameters Design Space Control Strategy Illustrative Example using a Small Molecule Case Study The Guide uses ICH Guidelines Q8 (R2), Pharmaceutical Development, Q9, Quality Risk Management, and Q10, Pharmaceutical Quality System as a basis, together with other relevant ICH Guidelines. 19

20 Design in Quality by Design.. Quality cannot be tested into products; it should be built-in or should be by design (QBD) 20

21 PQLI & PAT Component Summary (an example of In & ON Process Control) Quality by Design: identifying Process Issues, CQA, CPP Design Space: identifying possible ranges, using DoE Risk Management: To better identifying Process & Controls Risks Continuous Improvement: establish how to analyze data and to improve efficiency of analysis Integrated System Approach: Using Process & Process Knowledge to establish Continiuos Monitoring Real Time Release: identifying Process Issues, CQA, CPP 21 21

22 PQLI Product Quality Lifecycle 22

23 Future & Trend Direction Vision

24 Impact on Regulatory Policies 24

25 Impact on Regulatory Policies 25

26 Parameters for Medicine Selection MEDICINE selection criteria Regulatory Agency & Government are introducing criteria to reduce public expenses respecting criteria's barriers 1. Quality (efficacy, accuracy, document control) 2. Availability of R&D, Process, Clinical, Analytical Price 3. (Best available price) 4. Documented production Consistency 5. Availability 26

27 Impact on Regulatory Policies Re-enforce control capability through specific evidence requirement on Process & Product Knowledge & Validation Improve AUDIT method & efficacy through Cooperation & interchange of Information Using Harmonized Standard Improve & harmonize regulatory requirements for submission & clinical evidence, even for generics Introducing generic regulation access policy into government program, re-enforcing principle of equivalence, efficacy, quality, documentation Speed up Regulatory Process using Harmonized Policy 27

28 Annex 15 (Highlights) EMA Guide Line for Process Validation 28

29 Annex 15 & EMA Validation Process Guideline EU Directive 2001/83 ANNEX 15 European Commission Health and Consumer Directorate-General (Eudra Lex, the rules governing medicinal products in the European Union, Volume 4, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use) Annex 15: Qualification and Validation...Principle of Qualification and Validation applicable to Facilities, Equipment, Utilities and Process used for manufacture of Medicinal Product... Guideline on process Validation for Finished Products (information and data to be provided in regulatory Submission) EMA European Medicine Agency - New Requirements and Guideline for Validation, introducing and re-enforcing Process Understanding, Process Control, Product Quality through RB Approach 29

30 EMA Guide Line on Process Validation Continuous Process Verification Hybrid Approach Design Space Verification Scale-Up Post Approval Change Control Standard v/s NON standard methods of Manufacture 30

31 Incremental Steps Changed Paradigm Pharmaceutical Development (Q8) Past: Present: Data transfer / Variable output Knowledge transfer / Science based / Consistent output Quality Risk Management (Q9) Past: Used, however poorly defined Present: Structured Process Thinking Pharmaceutical Quality Systems (Q10) Past: Present: GMP checklist Quality Systems across product life cycle 31

32 ICH Q10 PQS Model 32

33 Impact Annex 15 Basic Principles Control Operation through QUALIFICATION and Validation over PRODUCT & PROCESS LIFECYCLE.. Planned Changes.. For Facilities, Equipment, Utilities & Processes which may effect Product Quality should be documented- Impact Assessment REQUIRED COMPUTERIZED SYSTEM used for the manufacture of medicinal products should be validated according with EU Annex 11 ICH Q8, Q9, Q10, Q11 OR Other system.. Guaranteeing the same level of product quality & security should be used to support validation & qualification.. Data supporting qualification &/or validation studies obtained from external sources needs to be verified (Provider own Validation &/or in place data controls procedures) 33

34 Impact Annex 15 Organizing & Planning Validation Activities Planned Qualification & Validation Activities, taking into account Equipment, Process & Product Life Cycle ( Processes Impact Components) Approved Validation Procedures & Trained Personnel Precise Responsibility within the involved personnel ( NOT only QA &/or Validation Manager) VMP as a key element of the required Policy/Approach 34

35 VALIDATION MASTER PLAN Impact Annex 15 Organizing & Planning Validation Activities Design Qualification Factory /Site Acceptance Installation Qualification Operational Qualification Performance Qualification VMP has to contain: Validation Policy Organizational Structure of Validation Activity On site Facilities, System, Equipment, Processes summary & validation status Template for verification documents Planning Change Control and Deviation Management policy references Acceptance Criteria References to existing documents Assessment of required resources Validation Strategy (incl. Re-Validation & Re-Qualification) Statement on Materials, support, suppliers qualification level (appropriate) Complex Projects may require separate VMP Quality Risk Management use and QRM improvement life-cycle Policy 35

36 Impact Annex 15 Document Management Knowledge Management Good Document Practice PQMS will define Documents Life Cycle (including Doc. Role & responsibility) Inter-relationship document approach required (e.g.: Traceability matrix. Doc hierarchy) Validation protocols will includes CSA (Critical System Attributes) and Acceptance Criteria Harmonization and Alignment between Company Policy & Provider Verification Docs Protocol and Validation report Changes & Deviation and Conclusion have to be formally recorded and supported by scientific analysis and investigation (within Change Control Procedure) Validation Life Cycle: URS, DQ, FAT/SAT, IQ, OQ, PQ 36

37 Impact Annex 15 Process Validation All Pharmaceutical Dosage Form -EMA Guideline for Process Validation) N.B.: Life Cycle Approach to link Product & Process Dev Validation of Commercial manufacturing Process & Maintenance of Process State of control for routine production Traditional Approach OR Continuous verification Approach (processes robustness for consistent product quality) Proof of Process Robustness & Prospective Validation PRIOR to product marketing New Product Process Validation should cover all TARGET market strength Technology Transfer, Product Transfer, Product Updates should be documented in Marketing Authorization document (and its variation) Product Validation CQA and CPP to ensure Validation Status and Product Quality trough scientific basis and risk assessment Number of Validation Batches and size of validation Batches can be justified by Risk Assessment and Continuous Monitoring 37

38 Impact Annex 15 Organizing & Planning Validation Activities Facilities, Systems and Equipment used for Process Validation should be validated and test methods should be validated Process Knowledge from Development Studies should be accessible to manufacturing site.. And should be the basis for Validation activities (tech. transf.) Process Validation Batches must be done by Trained production Personnel Supplier should be qualified under Quality Risk management procedures prior Validation Batches (including packaging materials) Design Space Justification Mathematical (Statistical) Models used to confirm a state of control should be available Concurrent Validation ( incomplete validation for exceptional cases) justified in approved VMP and supported by sufficient (& consistent) data (uniformity, and comply defined acceptance criteria) may be acceptable (document should be available to the QP) 38

39 Impact Annex 15 Traditional Approach to Validation Nr. Of Batches under routine conditions required and based on Risk Management Principles The minimum of three batches could be changed in case of similar product or processes already used and validated into the same site/line Process Validation Protocol using defined CPP & CQA (Documented Product/Process Knowledge) Included into Validation Protocol: Short Process description CQA summary CCP and limits other justified NON critical attributes list of equipment and calibration status analytical (validated) methods In Process Control Additional testing Sampling plan Evaluating/recording methods Batch release certification process Function & responsibilities Timing 39

40 Impact Annex 15 Continuous Process Verification Quality by Design Approach QbD development allows routine process controls with high degree of Product Quality Assurance Continuous Process Verification used as an alternative to Traditional Process Validation Continuous Process Verification: Science Based Control Strategy CQA, CPP Required Attributes for Incoming Materials Product Realization PAT & Multivariate Statistic In- Process Control On-Process Control At-Process Control 40

41 Impact Annex 15 On-Going Process Verification Monitoring Product Quality showing life cycle state of control, analyzing process trends Verification change and improvement of Frequency and extension of Process Verification using increased Process Understanding On Going Process Verification Protocols (& Report) also supported by statistical tools (Variation & State of Control) PQR should be supported by On Going Process Verification On Going Process Verification monitoring incremental changes in Product Life Cycle 41

42 Guide Line on Process Validation Continuous Process Verification in line with ICH Q8, Q9, Q10 and the possibility to use Continuous Process Verification in addition to, or instead of, traditional process validation described into previous guideline has been added and is encouraged. dos NOT introduce new requirements on Med. Products.. But clarify how companies can take ADVANTAGE of the new possibility given when applying enhanced PROCESS UNDERSTANDING, COUPLED WITH Risk Management tools, under an Efficient QUALITY System Process validation as described into ICH Q7 Continuous Process Verification has been introduced to cover an alternative approach to Process Validation based on a CONTINUOUS MONITORING OF MANUFACTURING PERFORMANCES Approach based on Product & Process Development studies Knowledge &/or previous manufacturing experience. Applicable to both traditional & enhanced approach to Pharmaceutical Development 42

43 Guide Line on Process Validation Continuous Process Verification Process validation should NOT be viewed as a ONE-OFF event; have to incorporates a Life Cycle Approach, linking all phases of Product life cycle; Guidance on Process Validation Information and data to be Provided in Regulatory Submission (finished dosage form chemical medicinal product Human & Vet.), joint with ICH Q11 recommendation; Applicable also on Biological, with the appropriate approach due to the Bio Substances; Regulatory Submission information; ICH Q8R2 Process Design EMA Guideline for Process Validation EU GMP Annex 15 Manufacturing Process Validation On-Going Process Verification 43

44 Guide Line on Process Validation General Consideration Manufacturing Process Should be Validated prior Marketing.. Process Validation should confirm the adequate Control Strategy and the adequate Product Quality.. For all TARGET market strength, for all sites, for all product (to demonstrate the adequate site s control strategy) Continuous Process verification a risk-based real-time approach to verify and demonstrate that a process operate within pre-defined specific parameters (CQAs) and control strategy requirements (CPP); in-line, at-line, on-line, trends, PAT should be influenced by Prior Development & manufactory Knowledge Process understanding gained by manufacturin experience Product / Process Complexity Technology & Process Automation (legacy) process robustness, manufacturing history.. 44

45 Guide Line on Process Validation Other Consideration Hybrid Approach and Traditional approach have to be described into dossier, and have to be clear where (step) it is used one or the other;.. Design Space.. Traditional approach may requires Design Space verification Continuous Process Verification, allows validity of design space throughout the Product Life Cycle.. Scale Up scaling Up from laboratory though Pilot up to Industrial scale (Normal Operating Range)... Those part must be described into Dossier (3.2.P P.3).. Ranges of Batches Proposed justify that scaling up batches sizes NOT Alters Homogeneity of CQAs 45

46 ... Thanks for your attention! Leandro Mbarak Gilberto Rossi