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Ram Balani
CEO-Founder FDASmart Inc.
CPhI October 25th, 2011, Frankfurt, Germany
Presentation Agenda:
I. Recent GMP Compliance ‘Meltdowns’ or Disasters
» Heparin contamination deaths –China supplier –Changzou SPL source by Baxter from SPL Wisconsin » Ranbaxy US FDA “meltdown” - India – 30 drug exports to US banned plus One more (Sanofi/Shanta)
II. Leading up to a new distrust & guarded attitude from the West with API sourcing, manufacturing, etc
“Trust by Verify” Attitude now is the NORM in the West III. Defensive Steps to Fix Globalization problems The New US FDA & the Pharma Industry tries new things – more global vigilance, sharing, collaboration
US FDA - US FDA Globalization Pathway Taking new steps heretofore unheard of - pilot with shared inspections ! Industry - forming consortiums to collaborate (Rx-360) –how is this going? Private Sector-new services for sharing and collaboration
IV. Proactive Steps to Remedy – over there in India & China
V. Why we need help with managing GMP specially with emerging region – global GMP buries you with
DATA-DETAILS & DISTANCE ! VI. Some technologies that can assist – (A) Pre inspections – (B) During inspections (real time-really ) & (C) Post Inspections
-Assist with US FDA regulatory matters – GCP/GMP, NDAs, ANDAs, Electronic Drug registrations, SPL/XML etc. --Assist with US FDA mock inspections, CMC, etc (often with ex-US FDA experts) on-site or Remotely with collaboration tele-presence system -Assist SMEs sourcing with APIs from China/India -Establish New Markets in India and China, other emerging regions -- more at www.fdasmart.com
-Considered “GROUND ZERO” …….
now “EVERYTHING CHANGES !” (with the US FDA)
- 149 Deaths and hundreds of patients affected with allergic reactions
-Traced contaminated heparin from Baxter to SPL -Scientific Protein Labs in Madison-Wisconsin to-SPL owned Changzhou manufacturing plant
-US FDA under the “gun”
-Puts the US FDA under a huge microscope – re-examine import of drugs and APIs, etc.
-U S Senate HELP video - some revealing snippets
http://help.senate.gov/hearings/hearing/?id=3fe78bef-5056-9502-5da8-cf290af9c334
-Early 1980s, China introduced the GMP concept, and promulgated the Good Manufacturing Practice for Pharmaceutical Products in 1988, and began to handle applications for GMP certification in 1995
-SFDA (Beijing) is responsible for drug registrations and ultimately GMP
- Approximately 1600 inspectors covering 5000 sites
-Few understand GMP – little training
-Poor record of GMP inspections & other dubious practices kills an estimate 200,000 to 300,000 Chinese citizens every year
-Hurts China’s reputation overseas
- Now for the good news………………..
SFDA Progress
-March 2011 SFDA GMP Updates –what are they ?
▲Also this year- anti-corruption plan thru 2012 –
stringent policing of any abuse, negligence or
criminal act that leads to public harm
-Other positive things happening
▲Serious collaboration with the West, e.g. US FDA establishing offices in China
▲Serious training programs started for China’s GMP inspectors
▲SFDA serious about China compliance with PIC/S – Pharmaceutical Inspection Co-Operation Scheme http://www.picscheme.org/
News Flash………….SFDA hands cash to CMO whistleblowers !
India - GMP Meltdown I – Ranbaxy /Daiichi
● http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2008/ucm1048134.htm
● So what happened? “The inspection revealed significant deviations from U.S. current good manufacturing practice (CGMP) Regulations (Title 21, Code of Federal Regulations, Parts 210 and 211) in the manufacture of sterile and non-sterile finished products. In addition, violations of statutory requirements, Section 501(a)(2)(B) of the Act, were documented with respect to the manufacturing and control of active pharmaceutical ingredients (APIs). “
India - GMP Meltdown II – the “Sequel”
Sanofi Pasteur says it will recoup losses in India with new manufacturing plant
The company’s venture into Asia – a $784m (€575m) acquisition of Shantha Biotechnics – suffered a blow in April 2010 when the pre-qualification for Shan5 combination vaccine was cancelled by the World Health Organization (WHO) , due to manufacturing defects.
The cancellation of the Shantha-produced Shan5 vaccination for diphtheria, pertussis, tetanus, haemophilus influenza B and hepatitis B set Sanofi back hundreds of millions of dollars in sales.
India GMP
India GMP – Background on Regulatory Authorities
Central Authorities - CDSCO (Central Drugs Standard Control Organization)
(a) State Authorities –CDSCO branches - under the Drug and Cosmetics Act, the regulation of manufacture, sale and distribution of Drugs is primarily the concern of the State authorities
(b) Central Authorities DCGI) are responsible for approval of new Drugs, -Clinical Trials in the country - Laying down the standards for Drugs -Control over the quality of imported Drugs -Coordination of the activities of State Drug Control 0rganisations
Drug Controller General of India (DCGI) is akin to US FDA Commissioner in the US- is responsible for approval of licenses of specified categories of Drugs such as blood and blood products, I. V. Fluids, Vaccine and Sera.
- India has most number of US FDA cGMP approved manufacturing plants OUTSIDE of the United States ! India’s optimization of generics process gave us the head start!
India - New GMP Improvements-Progress
-New CDSCO API Registration Requirements for Indian API imports
- Drugs Controller General of India (DCGI ) will tighten its monitoring of bulk pharma imports - Indian authorities send inspectors to China, Korea, Vietnam, the UK, the US and other countries from where India sources bulk drugs ( Surinder Singh, drugs controller -general of India (DCGI)) -APIs and Bulk drugs imported in to India will need to be registered after passing GMP quality manufacturing certification/inspection by CDSCO -US FDA opens offices in Delhi, Mumbai – -USP opens branch in Hyderabad
“Out of sight-out of Mind” is dead- “Trust but Verify” is now the mantra! - Western pharma industry now highly suspicious of entire supply chain in Asia – expects much more from the APIs, CMOs, CRAMs, CROs, Pan European regulatory adherence
- The new US FDA after the “attitude adjustment” kicks in
- Global regulatory agencies – New levels of collaboration from US FDA, EMA, TGA (sharing inspections pilot )
New Attitude adjusment from GMP ‘melt-downs’ in emerging regions..
-MORE COOPERATION between US FDA and Foreign pharma regulatory agencies in Asia
- More FREQUENT INSPECTIONS OVERSEAS-numbers stepped up – local cooperation accelerated and foreign FDA counterparts co-training overseas – but US FDA resource challenged !
-GMP OVERSEAS is now mandatory JOB #1 if you want to do business with the US or elsewhere in EMERGING COUNTRIES !
- The US FDA may add product & violations specific searches to its public website database as part of its new transparency push
-Responsibility remains with you (* the API or Drug manufacturer *) for quality compliance – -“TRUST but Verify” – is the new mantra
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The 9 joint inspections performed were: Joint inspection team County of the inspected site Inspection date Europe (EDQM) / TGA India June 2009 Europe (EDQM) / TGA India June 2009 Europe (EDQM) / TGA India June 2009 Europe (UK) / TGA India June 2009 Europe (UK on behalf of EMA) / FDA Croatia June 2009 FDA / TGA Mexico November 2009 Europe (Italy on behalf of EMA) / TGA Japan June 2010 Europe (France on behalf of EMA) / FDA / TGA China September 2010 Europe (Slovenia on behalf of EMA) / FDA India October 2010
US FDA – required by law to inspect facilities every two years. ◦ ORA (Office of Regulatory Affairs does domestic inspections for CDER and
some from SBER). ◦ CDER performs foreign inspections ◦ CBER performs biologic inspections for some Biologic.
Scope: ◦ Ingredients (APIs + excipients) ◦ Finished dosage forms administered to humans/animals ◦ OTC, Rx products ◦ Biologics, veterinary drugs ◦ Drugs undergoing study (IND, etc) ◦ Manufacturers, test laboratories, packagers (including
pharmacies) ◦ http://www.fda.gov/cder/dmpq
Periodic (biennial) comprehensive cGMP
Pre-Approval Inspection (PAI) “For cause” Inspection may involve more than one assignment and will verify corrections
to previous inspections.
All inspections cover GMPs -New Risked-Based Approach to determine whether inspection will be
performed (biennial / PAI).
-Field Offices given greater flexibility on whether to perform PAI or biennial inspections.
API51%
Dosage27%
Intermediates10%
Control Lab2%
Both API and Dosage9% Micronizer
1%
Quality46%
Materials6%
Facilities & Equipment 17%
Packaging and Labeling1%
Production11%
Laboratory19%
The World Health Organization (WHO) version of GMP is used by pharmaceutical regulators and the pharmaceutical industry in over one hundred countries worldwide primarily in the developing world.
The European Union's GMP (EU-GMP) enforces more compliance requirements than the WHO GMP…
-Also more stringent compliance from the US FDA - Food and Drug Administration's version in the US.
-Then there’s PIC/S – yet another set if standards?
-Need to harmonize if we are to share inspections reports
cGMP is….. - Current Good Manufacturing Practice – a part of Quality Assurance.
-All Manufacturing process clearly defined -Manufacturing process is validated or proven
Elements to be addressed in cGMP: a-Appropriately qualified and trained personnel b-Adequate premises and space c-Suitable equipment and services d-Correct materials, containers and labels e -Storage and transport
-66% of foreign & 43% of U.S. audits by CDER - yielded 483s in FY '02:
Validation is No. 1 citation in warnings
-Study looked at -- 2,221 observations on all 483s Top 10 Ranking most-frequent citations on 483s: #10 Personnel Qualifications. #9 Testing and Approval or Rejection of components. #8 Laboratory Controls. #7 Production Record Review. #6 Responsibilities of the quality control unit. #5 Equipment cleaning and maintenance. #4 Batch production and control records. #3 Stability testing. #2 Testing and release for distribution. #1 Validation An example: “Failure to validate processes with a high degree of assurance and approved according to
established procedures.
The US FDA- GMP Inspections Revealing numbers….
All data and information in records submitted to FDA & supporting documents in the possession of the applicant MUST BE: ◦ Accurate & true representations of: Actual tests performed & the test results Actual manufacturing & quality control steps & procedures associated with
the development and manufacture of the submission batch (clinical/pilot or biobatch)
Any other actions and conditions associated with the application
What is the US FDA 483? Document lists observations made by the FDA representatives during the inspection of your facility.
The US FDA- GMP Inspections
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Prepare Internally- Inspection Management • Preparation: before the inspection • Escort: during the inspection • “Close-out meeting”: after the inspection Prepare Externally • When will the inspection take place (period/timeframe) ? • How many inspectors will be present ? • Inspectors’ competence • Generalist or Specialist ? • Will the inspectors work together or will they split up? • What regulatory principles apply? • Agree upon a common agenda in advance (if possible) • Notification of sub-suppliers and third-party contractors during the preliminary stages of the inspection
How To Prepare for GMP Inspections
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Preparing Internally • Preparation team: Audit Coordinator, Escort (Main escort, Note taker, “Runner”) • Discussion of the results of previous inspection(s) (has all corrective action agreed upon been implemented) • What documents will be sent to the auditors beforehand? • Working out an inspection “strategy“ for • Product audit: which batches have been produced, have there been deviations in the produced batches, OOS, have all deviations been implemented according to the relevant SOP ? • System audit: are all systems, change control, validation, training, etc. in order? Remark: Most audits will be a “mix” of product/system
How To Prepare for GMP Inspections
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Internally - con’t Main Escort Role • Ensures a pleasant inspection atmosphere and coordinates the general audit procedure (duty to supply information!) • Makes sure that the person interviewed responds (correctly) to a question • Negotiates GMP interpretations (where appropriate) • Lists what documents have to be provided during the absence of the notetakers and compiles a “shopping list” of the relevant topics/documents • Arranges organizational matters with other escort(s) • Summons meetings at short notice if required (“crisis meeting”) • Informs affected areas about the topics on the shopping
How To Prepare for GMP Inspections
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Notetaker Role • Makes a note of the items inspected and covered • Stamps the documents handed out with a “confidential” stamp • Records which documents have been looked at/handed out • Includes outstanding items/documents in the “shopping list” • Areas inspected and items discussed • Observations and other distinctive aspects
How To Prepare for GMP Inspections
How to Manage GMP Compliance
◦ Tools, technologies & resources can assist….. (A) Hire cGMP experts/consultants On-site – expensive
(B) Quality Management Systems Software – samples to follow – Master Control,
Trackwise – should be on going not just for inspection
(C ) Desktop collaboration software like web-conferencing, web presentation sharing, etc. for mock inspections or drills
(D) Hybrid – Technology Assisted Remote Experts, e.g. SmartInspect
(E) Do NOTHING! (feeling lucky ?)
Define quality activities, processes and workflows Plan using “point, click and drag” technology Manage all quality activities Analyze resources Record ongoing products, projects and studies Record activities associated with a project. Directly enter findings and attach supporting evidence Perform peer reviews and define approval processes Share as much, or as little, information as you desires Record, Track and manage CAPA observations and remediation steps
Trackwise® by Sparta Systems for Pharma & Biotech Industries Trackwise by Sparta Systems is quality management software that: -Supports centralized and consolidated tracking, -Workflow management and -Regulatory reporting for all critical business processes affecting pharmaceutical manufacturing operations -Trackwise software has been successfully enabling companies both big and small to streamline quality processes, consolidate redundant systems and reduce manual operations to improve top-line revenue generation. -Used by the top 20 pharma and biotech companies
Shared Inspection… a trend whose time has come?
IT technology can help ! ◦ Wearable Wireless for GMP –technology can help. Concept – site for GMP inspection and expert ARE AT 2 different places Technology uses Wifi (802.11b/g) or Cellular 3G networks Mobile and transmits REAL-TIME video/audio via the INTERNET!
-Web conferencing has facilitated meetings without need for travel post 9-11
-Tele-radiology – diagnosing X-rays where patient and radiologist are miles apart
- GPS mobile systems – who needs maps-remote and mobile access
SmartInspect System
►A real-time ,wearable, wireless, mobile Internet based conferencing system with “feet”, i.e. yours while
mobile
► Allows live video transmission while roaming and voice talking (like Skype) between two parties at remote sites,
e.g. South Korea and Syracuse or Peapack, NJ and China to collaborate
►Advance features allow snapshot
picture taking or entire video/audio session recording; Handheld 40X self-
focusing camera allows printed or written SOPs or labels to be read by
remote viewers
►Remote users use existing desktop or laptops for collaboration with unlimited
software download
►Encryption and VPN support for security within pharmaceutical
enterprise IT infrastructure
►Possible Applications: Technology transfer. Remote quality audits, 3rd
party manufacturing diagnostics, remote live training at pharmaceutical
manufacturing sites
What is it?
www.fdasmart.com/smartinspect
