Impacto de las Nuevas Tendencias Regulatorias en la Producción de Parenterales. Innovacion en Packaging Primario

Transcription

1 Impacto de las Nuevas Tendencias Regulatorias en la Producción de Parenterales Innovacion en Packaging Primario 1

2 Contents Company Highlight What s Changing in Pharma Pharma Trends Harmonisation New Requirements Impact of New Requirements 2

3 International Support Support in R&D Technology Transfer Business Process Re-engineering Feasibility Studies Qualification, Validation & Management Regulatory Affairs Engineering, Design & Construction Support Business Development & Alliance Quality in Outsourcing & Auditing IT in Compliance Training 3

4 References 4

5 What is changing in Pharmaceutical world Pharmaceutical International Tendences 5

6 Future & Trend Direction Vision

7 Tendences to 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, Internet marketing investment will exceed the investment in traditional media 3. American model of direct to consumer advertising will not be imported into Europe; 5. 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/ companypatient) 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 since 2013 will be worth more than a third of the global market 7

8 Pharmaceutical World is Changing 8

9 Tendences to 2020 Big Five 1. France 2. Germany 3. Italy 4. Spain 5. UK Growth Markets include: 1. China 2. Brazil 3. Russia 4. India 5. Mexico 6. Turkey 7. Poland 8. Venezuela 9. Argentina 10.Indonesia 11.South Africa 12.Thailand 13.Romania 14.Egypt 15.Ukraine 16.Pakistan 17.Vietnam Source: Business Monitor International 9

10 Tendences to 2020 In 2020, because of crisis Pharma s revenues will be lower in traditional GIIPS markets 10

11 Tendences to While will increase in growing market 11

12 Tendences to

13 and in the meantime. 13

14 Financial Penalties Increased number of penalties 14

15 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. 15

16 Increase of Regulatory Attention 16

17 Increase of Regulatory Attention 17

18 Increase of Regulatory Attention 18

19 Increase of Regulatory Attention GMP News 15/04/2016 New FDA Draft Guidance 'Data Integrity and Compliance with cgmp' published In recent years, the topic "data integrity" has become a priority for European and American inspectors. At the beginning of 2015, the British authority MHRA published a first paper on that topic - see our News "MHRA revises its Guideline on Data Integrity in the short Term". Another significant draft document on data integrity was published in 2015 too by the World Health Organisation WHO - please see our News "New WHO Draft on "Good Data and Record Management". Recently, the US American FDA has released the draft of a Guidance for Industry entitled "Data Integrity and Compliance with cgmp". Although the FDA describes the Guidance as a non-binding recommendation, one may assume that the document presents the current thinking of the FDA regarding the topic. The FDA criticises the fact that more and more cgmp deficiencies with regard to data integrity have been observed during inspections. Those deficiencies have led to a number of follow-up measures like Warning Letters or import alerts. For the FDA, the integrity of data is one of the main quality issues. In the Guidance, the corresponding reference points in parts 21 CFR 211 and 21 CFR 212 are listed in detail as well as the principles for electronic records laid down in 21 CFR Part

20 Increase of Regulatory Attention 20

21 Increase of Regulatory Attention GMP News 14/10/2015 Finally published: new Annex 16 on QP Certification and Batch Release The European Commission has published the final version of the revised EU-GMP Guideline Annex 16 "Certification by a Qualified Person and Batch Release". Deadline for coming into operation is 15 April As one important topic, it has been pointed out that the major task of a Qualified Person (QP) is the certification of a batch for its release. In this context, the QP must personally ensure the responsibilities listed in chapter 1.6 are fulfilled. In chapter 1.7 a lot of additional responsibilities are listed which need to be secured by the QP. The work can be delegated and the QP can rely on the respective Quality Management Systems. However "the QP should have on-going assurance that this reliance is well founded" Starting materials comply and the supply chain is secured, including GMP assessments by third parties The necessary audits have been performed and the audit reports are available Manufacturing and testing performance are compliant with the MA Manufacturing and testing processes are validated Changes have been evaluated and investigations completed It is important to mention in this context that "the ultimate responsibility for the performance of an authorised medicinal product over its lifetime; its safety, quality and efficacy lies with the marketing authorisation holder (MAH). However "the QP is responsible for ensuring that each individual batch has been manufactured and checked in compliance with laws in force ( ), in accordance with the requirements of the marketing authorisation (MA) 21

22 and what is changing in Terms of International Harmonised Regulatory Requirements?? HARMONISATION PRINCIPLES 22

23 Why new rules & harmonisation? The need to Harmonize 1. For a better and uniform control, and to establish common and references rules 2. To supply unique parameters for both, inspector, and producer, enforcing common understanding, product knowledge, process knowledge 3. To harmonize validation activities, registration &regulatory issues 4. To improve competition on quality 5. To demonstrate consistent ToT 6. For a better SAFETY 7. To Protect both, patient and LOCAL INDUSTRY 8. For a FASTER Analysis / check, to be done, where applicable in an environment of mutual support 9. Speaking the same language, requiring the same controls 10. Comparing supplier, processes, final product, report mode, managing SIMILAR submission 23

24 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; Annex 15: EudraLex - Volume 4 - EU Guidelines for Good Manufacturing Practice for Medicinal Produts for Human and Veterinary Use - Annex 15: Qualification and Validation; Annex 16: EudraLex Volume 4 - EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use - Annex 16: Certification by a Qualified Person and Batch Release 24

25 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 25

26 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 26

27 Process: Annex 15 & EMA Guide Line Data: Data Integrity New & Emerging Regulatory Requirements: Not only PROCESS but ORGANISATION 27

28 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 28

29 EMA Guide Line Process Validation Continuous Process Verification Hybrid Approach Design Space Verification Scale-Up Post Approval Change Control Standard v/s NON standard methods of Manufacture 29

30 ICH Q10 PQS Model 30

31 Impact Annex 15 Continuous Process Verification Quality by Design Approach QbD development - high degree of Product Quality Assurance Continuous Process Verification an alternative to Traditional Process Validation Continuous Process Verification: Process validation should NOT be viewed as a ONE-OFF event (Life Cycle Approach); Science Based Control Strategy Required Attributes for Incoming Materials ICH Q8R2 Process Design CQA, CPP PAT & Multivariate Statistic Product Realization In- Process Control On-Process Control At-Process Control EMA Guideline for Process Validation EU GMP Annex 15 Manufacturing Process Validation On-Going Process Verification 31

32 FDA Guidance for Data Integrity 32

33 MHRA Guidance for Data Integrity 33

34 WHO Guidance for Data Integrity 34

35 EMA Guidance for Data Integrity (Canada, Japan, Switzerland, Australia, New Zealand, Israel, USA, India ) GMP Guide: Chapter 1 (Quality Manufacturing Problems) GMP Guide: Chapter 4 (Data Integrity) GMP Guide : annex 1 (Water for Injection, Reverse osmosis, etc.) GMP Guide: annex 17 (parametric release) GMP Guide: annex 21 (New: Importation of medicinal products) GMP Guidance on Data Integrity 35

36 Common Data Integrity Requirements 1. What is data integrity 2. What is metadata 3. What is an audit trail 4. static and dynamic record formats 5. backup 6. to exclude CGMP data from decision making? 7. Does each workflow on our computer system need to be validated? 8. Access to CGMP computer systems be restricted? 9. Who should review audit trails? 10. Electronic Copies - used as accurate reproductions of paper or electronic records? retain paper printouts or static records instead of original electronic records from stand-alone computerized laboratory instruments, such as an FT-IR instrument? 12. When does electronic data become a CGMP record? 13. Labs: system suitability results from reprocessed laboratory chromatography? 14. Personnel trained in detecting data integrity issues as part of a routine CGMP training program? 36

37 Impact on Organisation The most impacted Quality Management System & Quality Document Management Product Life Cycle & Process Validation Data Integrity and Data Protection Batch Record and Product Release 37

38 Impact on Organisation ANNEX 15 Product & Process Knowledge, Continuos Monitoring Quality Target Product Profile Process Outline Prior Knowledge Process Dev. Process Design Space Control Strategy Continious Improvement Q7 (API) Q8 (Ph. Dev.) Q9 (QRM) QBD for Quality Engineering Deign Qualification PQLI QBD CQA CCP Technology Transfer (in QBD) QBD for Quality Engineering Deign Qualification Product & Process Knowledge, Continious Improvement QRM, PQS, Data Management (Audit Trail, Deviation Management, CAPA, Batch Records) 38

39 Organization Impact Quality Requirements: 1. Better Process Understanding 2. Better Process Document (CQA & CPP) 4. Accuracy in Clinical Data Reporting 5. Pharmacovigilance 6. Dossier Preparation 7. Documentation Management Operation Requirements: 1. Training 2. Production Document Accuracy 3. Process Accuracy & Validation 3. Better Process Control 4. Qualified & Controlled Strategy Supplier 5. Deviation Management 6. Periodical Audit 7. Batch Record Accuracy Data Management Requirements 1. Data Integrity Policy 2. Data Access restriction Based on need to do approach 3. Audit Trail Policy (Paper, Hybrid, Validated) 4. Data Storage Location and Control 5. Computer System Validation 6. Periodical Audit 39

40 Organization Improvement Organization Definition: 1. Department, Roles, Organization Chart 2. Responsibility 3. Site Master File & Site Master Policies 4. Roles Definition, Records, & Training Records 5. Internal Qualified Person according with Need to do Bases 6. Periodical Audit : o Layout, Controls, Technical Specs, Analytical Data, Production Batch Records Data Management Requirements 1. Process Workflows; 2. Definition of Data: 1. Master Data 2. Raw Data 3. Data Source 4. Data Location 5. Data Availability 6. Data Protection 7. Trainings 40

41 Gilberto Rossi Leandro Mbarak