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PIC/S Asia Pacific Update
Presented by Bob Tribe 10th August 2015
Slide 2 © PharmOut 2015
Overview
• Asia Pacific becoming a major supplier of pharmaceuticals to the world.
• Problem areas in some Asia Pacific countries.
• Growing influence of PIC/S in Asia Pacific region.
• PIC/S GMP update & hot topic.
Slide 3 © PharmOut 2015
A changing world
• “The world has changed. The idea of a wholly domestically produced drug is a fast fading reality”
• “Nearly 40% of drug products consumed in USA are made outside USA”
• “Nearly 80% of APIs used in USA are made outside USA”
• “China & India are each expected to see a more that 400% increase in product exports between now and 2020, with China accounting for nearly 20% of all global product exports by that time”
Source: http://www.fda.gov/NewsEvents/Speeches/ucm388388.htm
Quotes from Dr Hamburg’s speech to MHRA – 6 March 2014
Slide 4 © PharmOut 2015
24 Asia Pacific countries
60% of the world’s population lives in the Asia Pacific region
Fastest growing region of the world
Slide 5 © PharmOut 2015
Typical problem areas in someAsia Pacific countries
• “Guanxi” in China; “old boy network” in India.(business connections/relationships; reciprocal favours)
• Companies operating “shadow factories”.(one as “showcase” factory; another operating at lower standard)
• Absence of deviations & complaints on record (even after 5 years)
• Data integrity (recent increase in recalls due to data integrity breaches)
• Site rules not observed (e.g. cellphones; smoking)
• Manufacture of counterfeit/falsified medicines. For EU, 31% of counterfeited medicines originate from India
& 20% originate from China. Almost 15% of medicines in global supply chain are counterfeit .
http://dgra.de/media/pdf/studium/masterthesis/master_strobl_seb.pdf http://www.cmpi.org/in-the-news/testimony/counterfeit-drugs-and-china-new/
Slide 6 © PharmOut 2015
Counterfeit: Lot: A041410 Authentic: Lot A052788
Counterfeited medicines manufactured in Asia Pacific(Source of slide: Mr Sia, Director of Audit & Licensing Division, HSA, Singapore)
Slide 7 © PharmOut 2015
Counterfeit Manufacturer
Slide 8 © PharmOut 2015
Counterfeited medicines manufactured in Pakistan
Counterfeit Authentic
http://www.pbs.org/wgbh/nova/next/body/uncovering-counterfeit-medicines/
Slide 9 © PharmOut 2015
Manufacturer of counterfeit Viagra tablets - located in China
http://www.pbs.org/wgbh/nova/next/body/uncovering-counterfeit-medicines/
Slide 10 © PharmOut 2015
Higher proportion of Critical & Major GMP deficiencies found in Asia
The relative number of Critical & Major GMP deficiencies raised per inspection by MHRA in 2013 was higher in Asia than other continents where MHRA inspections were carried out.
Source: http://www.mhra.gov.uk/home/groups/pl-a/documents/websiteresources/con464241.pdf
0
0.2
0.4
0.6
0.8
1
1.2
Asia(59 inspections)
UK(482 inspections)
N. America(57 inspections)
Ave. number of Critical & Major deficiencies per inspection for each continent
Ave. number of CRITICALS per inspection in that contienent
Ave. number of MAJORS per inspection in that continent
Slide 11 © PharmOut 2015
MHRA’s Top 5 Deficiencies in 2013
1Investigation of anomalies – deviationsRoot cause analysis, product impact assessment, etc.
2Quality ManagementSelf inspections, PQR’s, QRM, etc.
3Investigation of anomalies – CAPAPoor investigation, timeliness of investigation, etc.
4
Contamination, chemical/physical (or potential for)Dirty equipment/facilities, no justification for manufacturing different products in same granulation suite, etc.
5Supplier and contractor auditSerious errors in approved supplier listing, suppliers approved without audit, etc.
Future Focus: All above + Data integrity.
Source: http://www.mhra.gov.uk/home/groups/pl-a/documents/websiteresources/con464241.pdf
Slide 12 © PharmOut 2015
China – Getting Serious (Source: Dr Gerald Heddell, Director of Inspection & Enforcement, MHRA, UK)
Slide 13 © PharmOut 2015
API manufacture in India and China
• Most APIs in the global supply chain originate from India and China.
• History of poor GMP compliance at many sites.• Europe now requires APIs entering Europe to be
accompanied by a “written confirmation” of compliance to Q7 GMP requirements from the regulatory authority of country of origin*.
(under EU “Falsified Medicines Directive” 2011/62/EU -http://ec.europa.eu/health/human-use/falsified_medicines/index_en.htm )
* Switzerland, Israel, Australia, Brazil, Japan and USA are exempted from “written confirmation”.(In progress – South Korea, New Zealand, Singapore)
Slide 14 © PharmOut 2015
Influence of PIC/S* in Asia Pacific
• Currently, the biggest GMP change in Asia Pacific is the growing influence of PIC/S.
• Of the 24 countries in Asia Pacific, 18 countries are being influenced in some way by PIC/S.
• Only Asia Pacific counties not yet influenced by PIC/S are:– India– Pakistan– Sri Lanka– Bangladesh– Nepal– Papua New Guinea
* Pharmaceutical Inspection Cooperation Scheme
Slide 15 © PharmOut 2015
Summary of PIC/S Influence in Asia Pacific
PIC/S Members(at 1 July 2015)
PIC/S applicants being
assessed
Interested injoining PIC/S
Aiming to use the PIC/S GMP
Guide
Australia Philippines P.R. China CambodiaNew Zealand Thailand Brunei LaosSingapore Bhutan MyanmarMalaysia VietnamIndonesiaTaiwanJapanSouth KoreaHong Kong
Became member on 1 July’14
Will become member from 1 Jan’16
Became member on 1 July’14
Slide 16 © PharmOut 2015
Main features of PIC/S
Commenced operating in November 1995.Previously existed as “PIC” (Pharmaceutical Inspection Convention) from 1971 as a legal treaty between 10 countries.
PIC/S is an informal “Cooperative Arrangement” between GMP regulatory authorities; i.e. not a legal treaty.
•A forum for:• networking and confidence building• Exchange of information and experience on GMP• Focus on Quality Systems for Inspectorates• Focus on training of GMP inspectors• International harmonisation of GMP
No obligation for member authorities to accept inspection reports of other members.
Slide 17 © PharmOut 2015
‘PIC/S’ main advantage over a Mutual Recognition Agreement is that it is not legally binding, thus allowing Participating Authorities to co-operate and share information informally while keeping complete control over imported medicinal products.’
FDA observation on PIC/S
Geneva, 31 May, 2011
US FDA Commissioner, Dr. Margaret Hamburg, delivered a key-note address to the PIC/S 40th Anniversary Symposium said,
Slide 18 © PharmOut 2015
New Zealand
46 PIC/S member authorities (as of 1st July 2015)
IcelandCanada
USA
Argentina
South Africa
Australia
Malaysia
Taiwan
Switzerland
Norway
Indonesia
Ukraine
Singapore
Israel
Liechtenstein
EUROPEAN UNION Member States Agencies (28)
Japan
South Korea
4 Partners
EDQMEMA
UNICEFWHO
Slide 19 © PharmOut 2015
Brazil
Croatia
Iran
Phillipines
Hong Kong
Turkey
Mexico
Thailand
PIC/S applications being assessedAs of 1st July 2015 (up to 6 years allowed)
Will become 47th member of PIC/S from 1 Jan 2016
Slide 20 © PharmOut 2015
Chile
Belarus
Kazhakstan
Agencies that have applied to PIC/S for a “pre-accession” assessment (over a 2 year period)
Slide 21 © PharmOut 2015
Agencies showing an interest in joining PIC/S
The GMP Regulatory Authorities of:
• P.R. of China• Vietnam• Brunei Darussalam• Bhutan• Russia• Bulgaria• Nigeria • Saudi Arabia• Zimbabwe
Slide 22 © PharmOut 2015
PIC/S GMP Guide
PIC/S GMP Guide to GMP for Medicinal Products (PIC/S document PE 009-11, 1 March 2014).
• Similar to the EC GMP Guide:Main differences:− The term “authorised person” used instead of “Qualified Person” (QP).− No Annex 16 (QP) or Annex 18 (old API Annex) in PIC/S GMP Guide.
• Divided into 3 parts− Part I: PIC/S GMP Guide (general provisions).− Part II: GMP Guide for APIs (identical to ICH Q7).− Annexes 1 to 20.
(PIC/S GMP Guide available at www.picscheme.org)
Slide 23 © PharmOut 2015
Legal GMP requirements in different PIC/S member Agencies
PIC/S GMP Guide
(9 Agencies)
EU GMP Guide
(33 Agencies)
CanadaGMP
Guidelines
FDA GMP
Regulations
KoreaGMP
Standards
JapanGMP
Guidelines
ArgentinaAustraliaIndonesiaMalaysiaNZSingaporeSouth AfricaTaiwanUkraine
28 EU AgenciesIsraelIcelandLiechtensteinNorwaySwitzerland
Canada USA Korea Japan
Slide 24 © PharmOut 2015
GMP Requirements of Various Asia Pacific Countries
(current version of PIC/S Guide to GMP is PE 009-11, 1 March 2014)
Country GMP CommentsAustralia & NZ PIC/S Older (Jan’09) version applies (PE 009-8)ASEAN –PIC/S countries
PIC/S Current version applies (PE 009-11)
ASEAN –other countries
ASEAN or WHO
Under ASEAN Sectoral MRA, are obliged to migrate to PIC/S GMP
Taiwan PIC/S Current version applies (PE 009-11)Hong Kong WHO Current version to be apply from Oct’15South Korea KGMP Have filled gaps to be equivalent to PIC/SJapan JGMP Have filled gaps to be equivalent to PIC/SChina China GMP Based on EU, PIC/S & WHO GMPs
Singapore, Malaysia, Indonesia. Thailand, Philippines, Vietnam, Laos, Myanmar, Cambodia, Brunei.
Slide 25 © PharmOut 2015
PIC/S GMP Guide – pending changes(to mirror recent changes to the EU GMP Guide)
Guidance on the prevention of cross contamination (§. 3.6)
Chapter 3 (Premises & Equipment):
•Guidance on the prevention of cross contamination (§. 5.17 – 5.21)•Qualification of suppliers (§. 5.27 – 5.30).•Testing of starting materials (§. 5.35 – 5.36)•Product shortage due to manufacturing constraints (§. 5.71)
Chapter 5 (Production):
• Use of QRM to investigate quality defects & complaints.
Chapter 8 (Complaints & Product Recall):
•Modernised (after 14 years) to incorporate lifecycle approach.•Continuous process verification or hybrid approach.•Retrospective validation no longer acceptable.•Cleaning validation requirements clarified.•Entry into force on 1 October 2015 (already posted on PIC/S website).
Annex 15 (Qualification & Validation):
Slide 26 © PharmOut 2015
PIC/S Working Groups (an indication of future direction of PIC/S)
• Harmonisation of Classification of GMP Deficiencies (TGA = Chair)
• EMA-PIC/S Joint drafting Group on revision of Annex 1 (EMEA = Chair)
• Advance Therapy Medicinal Products (ATMPs)
• Steering Committee for the PIC/S Inspectors’ Academy (PIA) (HSA = Chair)
• Good Clinical Practices (GCP) and Good Pharmacovigilance Practices (GVP)
• Data Integrity (TGA & MHRA = joint Chair)
• Veterinary Medicinal Products
• Controlling Cross-contamination in Shared Facilities
Source: http://www.picscheme.org/bo/commun/upload/document/press-release-geneva-2015.pdf/
Slide 27 © PharmOut 2015
“Data Integrity” - a hot topic for many PIC/S Inspectorates
• Since mid-2013, data integrity has become a major focus of attention by many PIC/S Inspectorates.
• For example, from mid-2013 to February this year, 15 India manufacturers received warning letters from US FDA because of serious data integrity breaches. Supply of products to USA halted.
• Similar experiences by MHRA, TGA, ANMS, etc. in various parts of the world, including Asia & Europe.
• PIC/S Inspectorates share experiences on data integrity breaches.
• MHRA so concerned that they issued a “Data Integrity Definitions & Guidance for Industry” in January 2015 (updated in March 2015).
Sources: http://www.raps.org/Regulatory-Focus/News/2014/08/19/18980/Indias-Data-Integrity-Problems-Updated-17-June-2014/ https://www.gov.uk/government/publications/good-manufacturing-practice-data-integrity-definitions
Slide 28 © PharmOut 2015
New Initiative by PIC/S(Initiative of PIC/ S Sub-committee on Strategic Development )
• Maintain & share list of planned foreign inspections. To avoid duplication of inspections amongst PIC/S members. To encourage performance of joint inspections amongst PIC/S
members. To encourage reliance of inspection reports amongst PIC/S
members.
• Inform foreign regulatory authority of planned inspections in their jurisdiction. To provide opportunity to foreign inspectorate to observe PIC/S
inspections. To provide opportunity to foreign inspectorate to perform joint
inspections with PIC/S inspectors.
Source: http://www.picscheme.org/bo/commun/upload/document/press-release-geneva-2015.pdf/
Slide 29 © PharmOut 2015
Number of Foreign Inspections in 2013 undertaken by country
2013 Inspection Data
> 50 inspections
10 to 50 inspections
< 10 inspections
Australia
Slide 30 © PharmOut 2015
Regulators becoming more transparent
Publish establishment inspection reports, FD483s, warning letters, enforcement reports, etc.
US FDA
Publish manufacturer authorizations, GMP certificates, GMP inspection planning in 3rd countries, non-compliant & faulty manufacture.
EudraGMPdatabase
Publish inspection tracker (emerging issues identified through GMP inspections).
Health Canada
Many PIC/S authorities publish list of licensed manufacturers on their web site.
PIC/S member
authorities
Publish all “WHO Public Inspection reports” (WHOPIRs) on WHO web site.
WHO PQ
Slide 31 © PharmOut 2015
Version 1: • Manufacturing Authorisations• GMP Certificates
Search capabilitiesAlert on event capabilities
Version 3: Inspection plans in 3rd countries
• 1st release April 2007 (v1). v2 release July 2009.• Limited public access phased in from 2009-2011.• Access by MRA partners and other regulatory agencies in progress• Developed and maintained by EMA
Version 4: Information on “faulty Manufacture”
Links to other Community databases e.g. EudraCT
Version 2: GMP non-compliance
Opened since 1st February 2011 partially to the public, with information on compliant and non-compliant manufacturers
EudraGMDP DatabaseGood Manufacturing and Distribution Practice
Wholesale Authorisations and GDP Certificates
