Selling Your Pharmaceutical Products to USA, Europe and ASEAN Countries Page 1 Ludwig Huber Phone: +49 7902 980582 E-mail: [email protected]

Selling Your Pharmaceutical Products to USA, Europe and ASEAN Countries

Page 1

Ludwig HuberPhone: +49 7902 980582E-mail: [email protected]

Ludwig Huber, Ph.DChief Advisor, Global FDA Compliance

Regulations and Registrations

© Copyright Ludwig Huber - LabCompliance Slide 2

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


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


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

© Copyright Ludwig Huber - LabCompliance

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


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


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


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


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


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


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


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


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)


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


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


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


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


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


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


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


FDA Form 356h

US Agent


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


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.


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


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


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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