GMPs for the 21st Century - The Indian Pharmaceutical ...ipapharma.org/events/reports/Anisfield-GMP.pdf · GMPs for the 21st Century ... Canada ... biological drug complex manufacturing

© Copyright Globepharm Consulting, 2008 1

GMPs for the 21st Century

(current international GMP developments)

Michael H. AnisfeldGlobepharm Consulting

COURSE SCHEDULE

GMP FundamentalsGMP FundamentalsIntroduction + Regulatory Environment

Drug GMPs World-WideKey GMP DriversWHO-PIC-EU-US GMPs: Similarities/Differences

Th F t f GMP

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The Future of GMPsGMP InspectionsWorldwide HarmonizationRisk Management


MICHAEL H. ANISFELD

Industrial PharmacistIndustrial Pharmacy Faculty – University of IllinoisHas trained FDA, MHRA, China, and India inspectorsPerform audits for UN agencies and governments

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Performs 25 – 35 full scale audits annuallyHas audited in 32 countriesGuides clients through FDA, MHRA, TGA inspections

Drug GMPs

WorldwideWorldwide


THE PRINCIPLES ARE THE SAME

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line thru initials signature date reason

THE DIFFERENCE IS THE NUANCE – NOT THE PRINCIPLE

1 >>> yes yes yes

1 yes <<< yes no

AUS

EU

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2 >>> yes yes no

1 either yes no

JPN

USA


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GMPs WORLD-WIDE

codesdirectivesguidelinesindustry practices

world-wide voluntary

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regulationsjapan united states korea (south)

compulsory


Know Your GMPs

World Health Organizationgwww.who.int/medicines/organization/qsm/activities/qualityassurance/gmp/gmpcover.html

Australiawww.tga.gov.au/docs/html/gmpcodau.htm

Canadawww.hc-sc.gc.ca/hpfbdgpsa/inspectorate/gmp_e.html

European Union

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European Unionpharmacos.eudra.org/F2/eudralex/vol-4/home.htm

Japanwww.yakuji.co.jp/e/publications/index.html

United States of Americawww.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm

The Drug GMP Web

ASEAN11 countries, mostly SE Asia

PIC/S28 countries + 11 candidates + 4 observers (UN agencies)

WHOOffi i l i 104 t i

ICH3 trade blocks – EU/JP/US

, y

EFTA/PICnon-club Europe

EECEuro-club – 6 countries

Official in 104 countries

+ Bilateral MRAs:USA - Australia, Canada, Sweden, SwitzerlandAustralia – NZ / EU- Canada , Switzerland

MERCOSUR [work in progress]Argentina-Brazil-Paraguay-Uruguay

EUEurope – 27 countries


Key GMP Drivers

United StatesUnited States

Canada

European Union

Pharmaceutical Inspection Convention /Scheme

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Convention /Scheme

EU +Australia, Canada, Malaysia, Switzerland, Singapore, South Africa

Key International GMP Documents

US GMPs and GuidelinesUS GMPs and GuidelinesExtensive Computer System + Computer Software Guidelines - CDRH

CanadaRisk Categorization of GMPsValidation Guidelines

EU GMPsAnnex on Role of the QPAnnex on Investigational Medicinal Products

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Annex on Investigational Medicinal ProductsAnnex on Sterile Medicinal Products

PIC GuidelinesRecommendation on Validation Master Plan, IQ, OQ, PQ, Cleaning (PI 006-2) Aide-Memoire - Inspection of Utilities (PI 009-2) PIC/S Guidance on Good Practices for Computerised Systems in Regulated "GXP" Environments (PI 011-2)


BUT THERE ARE SOME DIFFERENCES:

WHO/PICcontract giver/receiver requirements sampling must sample all drums of active chemicals

PIC/S + EUROPE qualified person responsibilityAUSTRALIA building must be air-conditionedFRANCE

pharmacists must be employed in production areas and in

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pharmacists must be employed in production areas and in laboratories (1 for 7 staff)

GERMANY steroids must be separatedINDIA

Production and laboratory supervisors must be pharmacistsProduction and laboratory supervisors must GMP Examination

INTERNATIONAL GMP INSPECTIONS

INSPECTIONAL SEVERITYNS E ON L SEVE YUNITED STATES [FDA]UNITED KINGDOM [MHRA]

AUSTRALIA [TGA]CANADA [HPFBI]

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EUROPEAN UNION /BalticJAPAN [JPMDA]

EUROPEAN UNION /MediterraneanBrazil, Saudi Arabia


Worldwide Harmonization

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International Conference on Harmonizationwww.ich.org

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International Conference on Harmonization (ICH)

Q1: Stability:Q1: Stability:Q1A(R2): Stability Testing of New Drugs and Products (Revised Guideline)Q1B: Photostability Testing Q1C: Stability Testing for New Dosage FormsQ1D Bracketing and Matrixing Designs for Stability Testing of Drug

Substances and Drug ProductsQ1E: Evaluation of Stability DataQ1F: Stability Data Package for Registration in Climatic Zones III and IV

Q2: Analytical Validation:Q2A: Text on Validation of Analytical Procedures

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Q2A: Text on Validation of Analytical ProceduresQ2B: Methodology

Q3: Impurities:Q3A(R): Impurities in New Drug Substances Revised Guideline) Q3B(R): Impurities in New Drug Products (Revised Guideline)Q3C: Impurities: Residual Solvents Q3C(M): Impurities: Residual Solvents - Procedures

International Conference on Harmonization (ICH)

Q4: Pharmacopoeial HarmonisationQ4: Pharmacopoeial HarmonisationQ5: Biotechnological Quality

Q5A: Viral Safety Evaluation Q5B: Genetic StabilityQ5C: Stability of ProductsQ5D: Cell Substrates

Q6: SpecificationsQ6A: Chemical Substances with its Decision TreesQ6B: Biotechnological Substances

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Q6B: Biotechnological Substances

Q7: GMPQ7A: GMP for Active Pharmaceutical Ingredients

Q8: Pharmaceutical Development – Quality by DesignQ9: Risk Management

document source - http://www.ich.org


Which GMPs Apply?

WHO EU PIC USAWHO EU PIC USA

Drugs TRS-908-anx4 2003/94/EC PE 009-2 21CFR211

Herbals Guideline Annex 7 --- ---

Devices --- ISO 13485 --- 21CFR820

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Cosmetics --- 2003/94/EC --- ---

APIs Guideline Annex 18(ICH-Q7A)

PE 007-2 ICH-Q7A

Steriles TRS-902-anx6 Annex 1 PI 007-2 Guideline

Where Do You Find the GMPs

WHOhttp://www.who.int/medicines/organization/qsm/activities/qualityassurance/gmp/gmpcover.html

European Unionhttp://pharmacos.eudra.org/F2/eudralex/vol-4/home.htmhttp://www.iso.org/iso/en/ISOOnline.frontpage

Pharmaceutical Inspection Scheme

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Pharmaceutical Inspection Schemehttp://www.picscheme.org/index.htm

United Stateshttp://www.gmp1st.com/drreg.htmhttp://www.gmp1st.com/mdreg.htm


GMPs: WORLD-WIDE PERCEPTIONS

JapanGOLF - MAHJONG – PACHINKO

GermanyGREAT MOUNTAINS OF PAPER

Singapore

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GIVES MAXIMUM PROFITS

ChinaGIVE MONEY - PASS

GOOD PRACTICES SOUP

GMP GCPGMP

GVPGLP

GSP

GCP

GAMP

GDP

GQCP

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GAPGIP

GAMP GQCP


ISO 9000

GMPs vs ISO 9000

FDA loathes ISO 9000FDA loathes ISO 9000Set your own standardsISO shopping

People who start with an ISO orientationfrequently fail GMPs

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People who start with a GMP orientationmake an easy transition to ISO


ISO 9000 vs. GMP

C id R d t C t lConsider Rodent Control:

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ISO 9000 ATTITUDE GMP ATTITUDE

X

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Future GMP PushFuture GMP Push

Risk ManagementRi k A tRisk AssessmentRisk Mitigation

GMP Observation Rating System: Canada

C iti l b tiCritical observation:Observation describing a situation that is likely to result in a non-compliant product or a situation that may result in an immediate or latent health risk and any observation that involves fraud, misrepresentation or falsification of products or data

Major observation:Observation that may result in the production of a drug not

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Observation that may result in the production of a drug not consistently meeting its marketing authorization.

Other observation:Observation that is neither critical nor major but is a departure from GMP principles.


Product – Patient Risk?

Critical productCritical productA critical product is one for which any of the following criteria may apply:

narrow therapeutic windowhigh toxicitysterile productbiological drugcomplex manufacturing process: process for which slight deviations in the control of parameters could result in a non-uniform product or a product not meeting its specifications. A l d i i l ti f l d lid f l

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As example, powder mixing or granulation for low dosage solid forms, long acting/delayed action products, sterile products.

High risk productsMeans products that may trigger a health risk even at low levels, following

cross-contamination. Those include but are not limited to penicillins, certain cytotoxic and biological products.

Canada: Critical ObservationPremises C.02.004

No air filtration system to eliminate airborne contaminants that are likely to be generated during fabrication or packaging.Generalized malfunctioning of the ventilation system(s) with evidence of widespread cross-contamination.Inadequate segregation of manufacturing or testing areas from other manufacturing areas for high risk products.

Equipment C 02 005

Quality Control Department C.02.013 C.02.014 C.02.015No person in charge of QC available on premises in Canada.QC department not a distinct and independent unit, lacking real decisional power, with evidence that QC decisions are often overruled by production department or management.

Finished Products Testing C.02.018 C.02.019Finished product not tested for compliance with applicable specifications by the importer / dist ib t b f l s f s l AND Equipment C.02.005

Equipment used for complex manufacturing operations of critical products not qualified and with evidence of malfunctioning.

Personnel C.02.006Individual in charge of Quality Control (QC) or production for a fabricator of critical/high risk products does not hold a university degree in a science related to the work being conducted and does not have sufficient practical experience in their responsibility area.

Sanitation C.02.007 C.02.008Evidence of widespread accumulation of residues / extraneous matter indicative of inadequate cleaning.Evidence of gross infestation.

distributor before release for sale AND no evidence is available that the products have been tested by the fabricator.Evidence of falsification or misrepresentation of testing results / forgery of Certificate of Analysis.

Records C.02.020 to C.02.024Evidence of falsification or misrepresentation of records.

Stability C.02.027 C.02.028No data available to establish the shelf-life of products.Evidence of falsification or misrepresentation of stability data / forgery of COA

Sterile Products C.02.029

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E f g f .Raw Material Testing C.02.009 C.02.010

Evidence of falsification or misrepresentation of analytical results.No evidence of testing (COA) available from the supplier/synthesizer AND no testing done by the Canadian fabricator.

Manufacturing Control C.02.011 C.02.012No written Master FormulaeMaster Formulae showing gross deviations or significant calculation errors.Evidence of falsification or misrepresentation of manufacturing and packaging orders.

Critical sterilization cycles based on Probability of Survival not validated.Water for Injection (WFI) systems not validated with evidence of problems such as microbial / endotoxin counts not within specifications.No media fill performed to demonstrate the validity of aseptic filling operations.

source: http://www.hc-sc.gc.ca/hpfb-dgpsa/inspectorate/gui_0023_risk_class_gmp_obs_entire_e.html


Questions ?

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STAY IN TOUCH

Mi h l H A i f ldMichael H. AnisfeldGlobepharm Consulting

[email protected]

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g p g


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