Selling Your Pharmaceutical Products to USA, Europe and ASEAN Countries
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Ludwig HuberPhone: +49 7902 980582E-mail: [email protected]
Ludwig Huber, Ph.DChief Advisor, Global FDA Compliance
Regulations and Registrations
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OverviewRegulations 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
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Regulations and Quality Standards
Type Application Industry Controlled by
Good Laboratory Practice
Preclinical, toxicology studies
Pharma development
Healthcare Agencies
(+ Env. agencies)
Good Clinical Practice
Clinical trialsPharma
CROHealthcare Agencies
Good Manufacturing
Practice
ManufacturingQuality control
Pharma manufacturing,
quality control labs
Healthcare Agencies
ISO 17025Testing and Calibration
Food, environm, chemical
Private/public accreditation
bodies
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Value of ISO 17025
Country A
Product shipped from country A to B
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
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Preclinical Development
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Clinical Trials
Phase I, II, III
DrugDiscovery
Basic Research
Manufacturingincl. APIsQC Laboratories
GLPNot Regulated GCP
GLP = Good Laboratory Practices GMP = Good Manufacturing Practices
GCP = Good Clinical Practices
Submission & Review
IND BLA/NDAPost
MarketingSurveillance
Lead toDrug Target
GMP
GxP = GLP+GCP+GMP = Predicate RulesIND = Investigational New Drug ApplicationBLA = Biologic License Application NDA = New Drug Application
PreclinicalDevelopment
21 CFR 11 Electronic Records&Signatures
Safety, Quality, Efficacy
Submission & Review
Regulations Along the Drug Life
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Regulated BioEquivalency
Studies
Manufacturingincl. APIsQC Laboratories
BioEquivalency
GMP = Good Manufacturing Practices
Submission & Review
ANDAPost
MarketingSurveillance
GMP
GxP = GLP+GCP+GMP = Predicate RulesANDA = Abbreviated New Drug Application
21 CFR 11 Electronic Records&Signatures
Safety, Quality, Efficacy
FDA Regulations Along the Drug Life
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Key GLP RequirementsGeneral 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
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Key GCP RequirementsGeneral 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
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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
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Electronic Records & SignaturesFDA/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
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Organizations and Regulations
TGA/GMP (PICS)
EU Directive and Annex
US FDA Regulations
CanadaGMP
China GMP, SFDAPharmacopeia
USP
Pharmaceutical Inspection Convention Scheme (PIC/S)
(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
Japan-MHLWPharmacopeia
WHO, ICH, ISO
US FDA Inspection
Policy Guides
ANVISA
EMA EPPharmacopeia
ASEAN Harmonization
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United States Food and Drug Administration (FDA)
Member• United States GovernmentTasks• 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
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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 countriesImpact• 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 documentationWebsite• www.who.int
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International Conference for Harmonization (ICH)Members• Industry and government, • Industrial countries (US/Canada/EU/Japan)Tasks• Develops guidelines on selected topicsImpact• Guidelines signed into regulations in most member countries• Entered into the federal register in the US, but not in regulationExamples 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
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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)
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Pharmaceutical Inspection Convention Scheme (PIC/S)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
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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
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Good Automated Manufacturing Practice (GAMP) ForumMembers• 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
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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
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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
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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
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FDA Marketing AuthorizationBased 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
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FDA Form 356h
US Agent
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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
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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.
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Required Documentation
High level, strategic documentation(regulations, business, quality)
Process related documentation, approaches(SOPs)
TrainingMaintenance
Validation, Audits
Product test records, batch records, validation results,
training records, chromatograms
Test proceduresOperation manuals,
QC procedures
PolicyMaster Plan
Product/event related documentation(work instructions, also called SOPsor test scripts, protocols)
Compliance Records(batch/event related documentation)
Wri
tten
pro
cedu
res
Use the same set throughout the organization
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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
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483 Form Inspectional Observations
• Written during or after the inspection• Discussed with and handed out to the
user 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
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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)
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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 letters
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/
www.fdawarningletter.com
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