Selling Your Pharmaceutical Products to USA, Europe and ASEAN Countries

1. Selling Your Pharmaceutical Products to USA, Europe and ASEAN Countries Regulations and Registrations Ludwig Huber, Ph.D Chief Advisor, Global FDA Compliance Ludwig Huber Phone: +49 7902 980582 E-mail: Ludwig_Huber@Labcompliance.com Page 1

2. Overview Regulations and Guidelines: Overview • Regulations along the drug life • Good Laboratory Practices, Good Clinical Practices • Good Manufacturing Practices Organizations Overview: Roles and responsibilities • Local healthcare agencies: FDA, EMA • International healthcare: ICH, PIC/S, WHO • Pharmacopeias: EP, USP, JP, CP • Industry Organizations: ISPE, GAMP Registration Processes Required documentation

3. Regulations and Quality Standards

4. Value of ISO 17025 Product shipped from country A to B Country A Country B • Routine testing only tested in one accredited laboratory of country A • International comparability of test results through traceability to the same standard • Confidence in test results through validated methods and estimated and documented measurement uncertainty

5. Regulations Along the Drug Life Clinical Trials Phase I, II, III Manufacturingincl. APIsQC Laboratories Basic Research Drug Discovery PreclinicalDevelopment Preclinical Development GLP GCP Not Regulated GMP 21 CFR 11 Electronic Records&Signatures Lead toDrug Target BLA/NDA IND PostMarketingSurveillance Submission & Review Submission & Review Safety, Quality, Efficacy GxP = GLP+GCP+GMP = Predicate Rules IND = Investigational New Drug ApplicationBLA = Biologic License Application NDA = New Drug Application GLP = Good Laboratory Practices GMP = Good Manufacturing Practices GCP = Good Clinical Practices

6. FDA Regulations Along the Drug Life Manufacturingincl. APIsQC Laboratories Regulated BioEquivalency Studies Generic Drugs BioEquivalency GMP 21 CFR 11 Electronic Records&Signatures ANDA PostMarketingSurveillance Submission & Review Safety, Quality, Efficacy GMP = Good Manufacturing Practices GxP = GLP+GCP+GMP = Predicate Rules ANDA = Abbreviated New Drug Application

7. Key GLP Requirements General Quality System • Documentation • Personnel • Facilities • Equipment calibration and maintenance • Validation of procedures and methods Specific to GLP • Appointment of study director • Study plan and study protocol • Appointment of an archivist • Specific QAU responsibilities (e.g., approval of study) • Retention of samples and records

8. Key GCP Requirements General Quality System • Quality assurance system (equipment, validation of procedures) • Record keeping, Qualified personnel Specific to GCP • Primacy of subjects rights vs. ther interests of study • Scientifically sound protocol • Supporting data (from pre-clinical or clinical studies) • Investigational drugs manufactured under GMPs • Subject confidentiality • Informed consent obtained from subjects • Favorable risk benefit balance

9. Key GMP Requirements General Quality System • Quality Assurance System • Personnel, equipment, computer systems, documentation, subcontractors, self inspection, handling complaints, Out-of-specification results Specific to GMP • Raw materials • Process validation • Validation of methods and procedures • Cleaning validation • Dealing with OOS situations through failure investigations • Integrity, authenticity, availability of records

10. Electronic Records & Signatures FDA/EU Regulation • 21 CFR Part 11, EU Annex 11 to EU GMP Objective • Using e-records and signatures must be as trustworthy and reliable as using paper records and handwritten signatures Requirements • Validation of computerized systems, • Limited and authorized access to computer systems • Electronic audit trail, review of electronic audit trail • Accurate and complete copies of records, • Instant availability of e-records

11. China GMP, SFDA Pharmacopeia Japan-MHLWPharmacopeia USP ANVISA Organizations and Regulations EPPharmacopeia EMA EU Directive and Annex CanadaGMP US FDA Regulations US FDA Inspection Policy Guides ASEAN Harmonization TGA/GMP (PICS) Pharmaceutical Inspection Convention Scheme (PIC/S) WHO, ICH, ISO (Australian) Therapeutic Goods Administration, , ICH-International Conference for Harmonization, FDA = Food and Drug Administration, WHO = World Health Organization, USP – United States Pharmacopeia, EU = European Union, ASEAN = Association of 10 South East Asian Nations

12. United States Food and Drug Administration (FDA) • Member • United States Government • Tasks • Promulgates and enforces US regulations • Impact • By far the highest impact on pharmaceutical industry through toughest enforcement. Can stop manufacturing in the US or stop import. • Examples for documents • 21 Series Code of Regulations (CFR), e.g., Good Laboratory Practices, Good Manufacturing Practices for drugs and medical devices , Good Clinical Practices, Food Additives, Electronic records (Part 11), related guidance and inspection guides • Website • www.fda.gov Corresponding agencies in other countries

13. World Health Organization (WHO) • Member • All countries which are Members of the United Nations may become members of WHO by accepting its Constitution.In 2013 192 members • Tasks • Develops GMP guidelines and training material, contracts drugs and APIs mainly used by development countries • Impact • High impact on development countries. Guidelines use as source for local regulations.Drug and API contractors must comply and are audited by WHO • Examples for documents • GLMs, GLP Training documentation • Website • www.who.int

14. International Conference for Harmonization (ICH) • Members • Industry and government, • Industrial countries (US/Canada/EU/Japan) • Tasks • Develops guidelines on selected topics • Impact • Guidelines signed into regulations in most member countries • Entered into the federal register in the US, but not in regulation • Examples for documents • Active pharmaceutical ingredients (Q7 for GMPs of APIs). ICH Q2 for method validation, ICH Q10 for Quality Systems, ICH Q9 for risk assessment. M4 Series Common Technical Documents (and eCTDs) for drug registration • Website • www.ich.org

15. United States Pharmacopeia (USP) Offices • United States, Europe, India, China Tasks • Develops legally binding standards for FDA regulated industry; for techniques and methods Impact • Binding standards for FDA regulated industry Examples for documents • Chromatographic system suitability testing, Dissolution testing, Analytical Instrument Qualification, method change vs. adjustment Website • www.USP.org Corresponding organizations in EU (EP), China (ChP) and Japan (JP) EP/USP/JP Harmonizing procedures

16. Pharmaceutical Inspection Convention Scheme (PIC/S) July 2013, 43 Members Members • 43 Regulatory Agencies EU, Australia, Canada, Singapore, Malaysia, Argentina, South Africa, US FDA, Indonesia, Taiwan, New ZealandWaiting list: Thailand, Philippines • Tasks • Develops GMP type standards and guidelines for inspectors andGMP standards similar to EU, WHO Impact • Guidelines becoming regulations in Singapore, Australia, Switzerland • Guidelines seen as standard by industry in EU and SE Asia Examples for documents • GMP Guides, QC Lab training Guide, Good computer practices, validation master plan, API facilities inspection guide, Annex 11 Website • www.picscheme.org

17. International Society for Pharmaceutical Engineering (ISPE) Members • Industry, organizations in EU, America, Japan Tasks • On-line shop for GAMP products, provides trainings around the world, consulting agencies e.g., US FDA Impact • High influence on US FDA and EMA Examples for documents • Authored Part 11 white paper and influenced new FDA Part 11 Guide • ISPE Journal Website • www.ISPE.org

18. Good Automated Manufacturing Practice (GAMP) Forum Members • Industry from Europe, America Tasks • Develops guidelines on using automated systems in regulated industry Impact • Industry standard, referenced by Agencies, e.g, FDA, EU Examples for documents • GAMP 5 - Validation of computer systems • Electronic records, signatures, archiving • Network qualification Website • www.ispe.org

19. ASEAN Mutual Recognition Agreement • 10 member countries • Signed in April 2009 • Goal: Mutual recognition of GMP inspections • Likely to follow PIC/S GMPs • Will increase pressure on companies without recognized GMPs (e.g., PIC/S) through increased competitiveness • Officially came into force on Jan 1, 2011 • Procedure to get mutual recognition for GMP certificates and inspection reports established ASEAN - Association of Southeast Asian Nations Brunei Darussalam, Cambodia Indonesia, LAO PDR, Malaysia, Myanmar, Philippines, Singapore, Thailand, Vietnam

20. Procedure for Recognition of GMP Inspection Certificates in ASEAN Countries • ASEAN Joint Sectoral Committee (JSC) on GMP Inspection was set up in 2011 with Singapore as chair • ASEAN members submit applications for listing • ASEAM PIC/S members are listed without further assessment (Singapore, Malaysia, Indonesia) • Non-PIC/S-members must be assessed though a Panel of Experts formed by JSC • After assessment the Panel of Experts will submit the recommendation to JSC • Listed members can exchange GMP certificates and inspection reports

21. Registration in the United States • Small molecule chemical based generic and innovator drugs are registered through the Center for Drug Evaluation and Research (CDER). • Biological drugs and generic versions through the Center for Biologics Evaluation and Research • Main required documents: Investigtional New Drug Application (IND), New drug application (NDA), Biologic licence application (BLA) and for generics the Abbreviated New Drug Application (ANDA) Foreign Companies need an US based Agent as contact to FDA

22. FDA Marketing Authorization Based on quality, safety and efficacy data from • Pre-clinical studies – focus on safety • Clinical studies – focus on efficacy Can easily be 100 000 or more printed pages Relevant FDA Regulations • 21 CFR 314 (New drug application) • 21 CFR 601 (Biologic license application) Relevant Guidelines • Common (Electronic) Technical Documents (CTD), ICH M4, M4Q, M4S, M4E (accepted by FDA) FDA Form 356h and Instructions for filling out • Instructions for Filling out Form FDA 356h – Application To Market A New Or Abbreviated New Drug Or Biologic for Human Use

23. FDA Form 356h US Agent

24. Marketing Authorization Process • Applicant requests a pre-submission meeting with FDA • Applicant submits NDA to CDER or CBER (paper or electronic) • Preliminary technical screening and response within 60 days (e.g., completeness) • Review conducted by a team of technical specialists from different offices (chemists, physicians, statisticians, pharmacologists) • FDA informs applicants for easily correctable deficiencies • Applicant resubmits NDA • FDA prepares preliminary review report • FDA may conduct GMP inspections • Final review by appropriate Director (may consult advisory team) • Action letter issued within 180 days of the start of the review, unless extension agreed with applicant • Approval issued if submission acceptable

25. Registration in Europe • Through the European Medicines Agency (EMA) • Marketing authorization can be applied through • Centralied procedure (most common) • National procedure: only applied if registration is desired in a single country • Mutually recognized procedure: useful to extend single country application to all Europe • Biological drug applications are evaluated through the centralized procedured by EMA.

26. Required Documentation PolicyMaster Plan High level, strategic documentation(regulations, business, quality) Training Maintenance Validation, Audits Process related documentation, approaches(SOPs) Written procedures Product/event related documentation(work instructions, also called SOPs or test scripts, protocols) Test procedures Operation manuals, QC procedures Compliance Records(batch/event related documentation) Product test records, batch records, validation results, training records, chromatograms Check Regulations Use the same set throughout the organization

27. Inspections and DocumentationExample: US FDA • 483 Form Inspection Observation • only deviations listed • written for inspection exit meeting • Establishment Inspection Report (EIR) • very detailed • more like an inspection protocol • Warning Letter • Reviewed by FDA centers Look for examples on www.fdawarningletter.com

28. 483 Form Inspectional Observations • Written during or after the inspection • Discussed with and handed out to theuser firm in the inspection exit meeting • May reflect the view of single inspector • Major problem: inconsistency • Available to the public, including to competition, through FOI (Freedom of information) • Can have negative impact on company’s reputation • Can have other consequences: withholding product approvals • Compamies are advised to respond within 15 business

29. Establishment Inspection Reports (EIR) • Written when the inspector is back in the office • Very detailed inspection protocol, e.g., lists question/answers and positive and negative findings • Observations are classified as “No action indicated (NAI) ”, “Voluntary Action Indicated (VAI), or “Official action indicated (OAI)” • Reviewed by regional headquarter office • Most Helpful in preparation for FDA inspections • Available through FOI and private service providers(e.g., some are listed on www.fdawarningletter.com)

30. Warning Letters • Issued in case of severe deviations • Reviewed by higher level FDA officials in FDA centers • Frequently make reference to 483 inspection observations and to company responses because of inadequate response • Companies must respond within 15 days with corrective action plan • Typically follow inspection scheduled • The FDA publishes warning lettershttp://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ www.fdawarningletter.com