Regulatory Compliance for Global Pharma Market
Dr Rajiv A. Desai
President – Quality
Dishman Pharmaceuticals and Chemicals Ltd
Ahmedabad , INDIA
Workshop Organised by
Ahmedabad, Gujarat
18th December 2012
Basics of Business
What is the main aim of doing a business ?
Earn Profit !
When customer is ready to pay a good price,
What is expected ?
• Consistency
• Quality
• Value for money
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Pharma share around the world
2% 2% 1% 1%
6% China
7% Latin America
33% USA
18% Japan
30% Europe
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
US
Europe
Japan
Latin America
China
Middle East
Australia
Canada
Africa
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Generic Pharmaceutical Industry
Generic Drug substances and drug products allowed after patent expiration
A big business opportunity within the Pharmaceutical Industry
Cost of Generic drugs significantly lower than the Innovators
Generic Pharmaceutical companies look for opportunities targeting the
patent expiration dates
Around the world , various countries and geographies provide lucrative
markets in the pharmaceutical space
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Patent expiration of drugs (year wise )
Year
2010
2011
2012
2013
2014
2015
2016
2017
2018
2019
2020
2021
Patent expiry of Drugs
14
8
21
7
14
6
1
4
2
1
1
1
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Opportunities in the US Market
US Pharma market size is approx USD 320 billion
Generic substitution approximately 75 %
One of the largest and most matured market, globally
Reforms initiated by the US Government to reduce health care spending
Many Indian companies have ANDA filings, in-line with patent expiration
Para IV / FTF have formed a major share for many Indian Pharma companies
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Opportunities in the Europe Market
European Generics market is diverse
Regulations and Generics penetration varies across
Countries
Several governments have implemented measures at reducing healthcare
spending
70
60
50
40
30
20
10
61
55
50
32
25
0
17
Generic Penetration in Europe
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Opportunities in the Japanese Market
Reforms on reducing health care spending by
Japanese Government is opening up
new opportunities for Generics
Consumer mindset strongly towards brands
Generics market was around 23% at the beginning of 2012
This has gone up to ~ 30% by end of 2012
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Opportunities in the Emerging Market
Emerging Market represent the fastest growing
segment of the Global Pharma Industry
Total spending on health care likely to grow
from approx USD 150 Billion to USD 300 Billion by 2015
Russia, South Africa, Latin America (Brazil, Mexico )
and South East Asia are fast growing regions
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Increase in DMF submissions with the US FDA
900
Number of DMF submissions
800
700
600
500
400
300
200
100
0
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
Reference : US FDA presentation on GDUFA
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Increase in ANDA submissions with the US FDA
1000
900
Number of ANDA submissions
800
700
600
500
400
300
200
100
0
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
Year 2011 saw the highest number of submissions
Reference : US FDA presentation on GDUFA
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Backlog of ANDAs
3000
2500
2000
1500
1000
500
0
2006
2007
2008
2009
2010
2011
Reference : US FDA presentation on GDUFA
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Reference : US FDA presentation on GDUFA
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Reference : US FDA presentation on GDUFA
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
US FDA outside USA
Why ?
Many overseas manufacturing facilities
Large quantum of Outsourcing of manufacturing and clinical trials
Imports coming from countries with less well developed regulatory systems
Inspections should not be done at the borders of USA
Borders must be placed at the point of manufacturing
Engage more effectively aboard in order to be more effective at home
( Beyond the Borders )
India Office operational since January 2009
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Reference : US FDA presentation on GDUFA
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
US DMF filings from India
India has more than 2600 DMFs filed with the US FDA,
highest number in the world !!
More than 300 facilities have been inspected and accepted
for manufacturing in India
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
ANDA filings from India
During the year 2007 to 2011
2244 ANDA were approved from
around the world
Contribution from India
694 ANDAs
During the year 2011
431 ANDAs approved
Contribution from India
144 ANDAs
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
US FDA will now charge fees !
Generic Drug User Fee Act (GDUFA)
Fees for DMF
$ 21,340
(Drug Master file)
based on expected 700 DMFs to be filed
Fees for ANDA ( Abbreviated New drug Application)
$ 51,520
based on expected 850 ANDA to be filed
Fees for PAS ( Prior Approval Supplement )
$ 25,760
based on expected 576 PAS submissions
 Assumption of number of submissions based on previous year’s data
 Fees calculations , updated by US FDA on 25th Oct 2012
 The rates will be effective till Sept 2013
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Why facility audits are required ?
Driven by National Health Services for cheap medicines, market for Generic API
has increased.
70% of all APIs consumed in Europe are imported from China and India
Aggressive competition amongst the manufacturers for lowering the price has
led to cases of compromising Quality of the APIs.
Unknown impurities are a major concern for provoking side effects and
adverse reactions.
“Chinese Heparin” which caused more than 100 death in USA was attributed
to adulteration to bring down price and shortage of actual source of Heparin.
Cases of use of uncertified outsourcing increasing
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Recent European Union Directive
European Parliament and Council of European Union published a
Directive 2011/62/EU on 8th June 2011 on Falsification of Medicinal products
Local drug Regulatory authorities must certify the products exported by
manufacturers maintain Quality and follow cGMP as prescribed by
EU drug regulations
Such certificate should be in place even after the manufacturing facility
and products get all regulatory clearances from EU drug regulatory authorities
The directive promoted with the aim of protecting EU patients from
falsified medicines
This certification should be in place by 2nd July 2013, applicable for
drug substance intended for human consumption
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Initiative by the CDSCO on the EU directive
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Mutual Recognition Agreement awaited …
The European Fine Chemicals Group (EFCG) is proposing a global
harmonisation of the rules and regulations governing the manufacture of
active pharmaceutical ingredients (APIs)
Expected to provide consistency of Quality of APIs and Medicines will meet
the high standards as recognized by ICH
This should be achieved by mandatory inspections of all global API
manufacturers by a Mutual Recognition Agreement (MRA) and managed
by a National Regulatory authorities to share limited inspection resources
and avoid duplication
Reference : EFCG news release dated 12th Nov 2012
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Opportunities
Big opportunities bring big profits
High Quality standards expected
Big Opportunities also brings in fierce competition
Cost cutting / Cost saving
Problems with compromised Quality
Risk to patients
Government responsibility increases to ensure safe medicines
Regulatory audits and inspections become strict
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Why is an audit done ?
1 Protect Consumers ( Patients )
2 Collect evidence
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Why an audit is required ?
Physical inspections of the manufacturing facility
Check operations in the manufacturing area
Verify written procedures v/s actual practice
Check capability of people
Check controls on material management
Check the Process development activities
Check packaging and logistics
Ensure quality products to patients
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Importance of an audit
– Site inspections are one of the primary means by which the
regulatory authorities interface with companies
– Systematic preparation for an audit will have a positive
inspection
– A favorable inspection also helps build confidence and
credibility with the regulatory agency including
• Product Approval
• Customer Loyalty
• Business Impact
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Audit methodologies
1
Walk though the material flow within the site
2
Check for the SOPs being used at the site by various departments
3
Review the activities of the site and compare the SOP for compliance
This is a slow and tedious process !!
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
New approach of auditing
It’s a known fact that nobody is perfect, problems will be faced,
lets see how the problems are handled ….
1
2
3
4
5
6
7
Deviations / Non-conformance
Change controls
OOS
Reprocess / Rework
Rejections
Complaints
Preventive maintenance
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Auditor’s wish list
What will satisfy an auditor ?




List of various deviations and OOS
Full documented evidence of Investigation reports
Identification of possible root cause
Corrective and preventive actions
What will make the auditor uncomfortable ?
 No documented evidence of any incidences
 Improper investigations
 Investigations not based on Scientific rationale
It is difficult to predict what a specific auditor would want to see
But, its possible to prepare well !
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Audit preparation
 Be on-line
 Last minute preparation should be avoided
Concentrate on….
 Team members
 Facilities
 Documents
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
During the audit
• Investigation
– Quality records and documents are reviewed
– Documents and the actual practices are cross verified
Remember ….
What was not documented, was not done
US FDA is well known to emphasise on documents
European Regulatory agencies focus more on the facilities and spend
more time at the shop floor talking to employees
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
What do Auditors evaluate ?
• Auditors observe body language
• Non-verbal and verbal behavior, looking for some mistakes
• Look out for typical style of the auditee for
–
–
–
–
–
Too anxious or polite
Defensive
Rationalizing
Apologetic
Quiet
• Posture and body position
–
–
–
–
Restless
Very Rigid
Rapid changes in posture
Avoids eye contact
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
During the audit
• Listen to the question, if it isn’t clear… ask again
• Answer all questions honestly
• Don’t answer what is not asked
• Don’t ever guess
• Don’t volunteer information
• Don’t be afraid of silence
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
During the audit
• Demonstrate a cooperative, polite and professional attitude
• Speak with confidence
• Answer with supporting facts and evidence
• Restrict the number of team members interacting with the auditor.
• Every thing that is said to the auditor will go on record and will be
part of the report
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
During the audit – Unacceptable points
• Become Defensive and start an argument
• Make blunt refusals on the requests
• Respond to questions outside your expertise
• Attempt to answer a hypothetical question
• Intentionally mislead or lie
• Start blaming others or departments for the mistakes
• Make any personal comment on the quality of the investigator
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
During the audit – Unacceptable points
• Agree or disagree if the Auditor points out a potential problem or concern
• Claim to be an expert in Good Manufacturing Practices (GMP) or other
regulations
• Generate questions by offering un-requested information or asking
questions of the Investigator
• Feel obligated to fill silence (pauses) with further clarification or talk
• Say something is impossible or could not happen
• Ask a team member additional questions in front of the Investigator
• Allow the use of audio or video recording devices by the investigator
(without first getting approval from site management)
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Response to the audit observations
• Ensure that the audit response is sent before the agreed date
• Response should include
•
•
•
•
Root cause analysis
Correction, Corrective action, Preventive action,
Proof of actions taken
Evaluation of other similar areas not seen by the auditor
• An updated response would be required , in case of a delayed
completion of the corrective action.
• Keep the language as soft as possible
• Try to get the proper understanding of the observations so that
the response is appropriate for the point made.
• Seek clarifications on the observations during the audit
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Response to the audit observations
– Respond clearly and completely to the observations and show that
the observation was properly understood and addresses the issue in
full
– Response should have the full story, because the response is read by
other members within the regulatory agency who were not part of the
audit.
– Provide a confidence that by responding to the observation , all the
applicable laws and regulations are followed
– Provide corrective actions, taking into consideration impact to
product, processes and Quality System
– Explain how corrective and preventive actions will be monitored to
ensure effectiveness
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Quality standard comparison
Defects per
Defects per
Defects per
Success
Sigma
100
10,000
1,000,000
rate
Value
69
6,910
691,000
31.00000%
1
31
3,090
309,000
69.10000%
2
7
668
66,800
93.32000%
3
1
62
6,210
99.37900%
4
2
233
99.97670%
5
3.4
99.99966%
6
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
Pharmaceutical
Semiconductor
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Setting high standards for Quality
Voluntary recall of formulations by Pharma companies in US
Year
Total recalls
Indian Companies
2012 (till 17th Dec )
42
3
2011
42
Nil
2010
35
1
US FDA database
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Regulatory guidelines
Regulatory Agencies update their websites with the latest requirements
What’s known today becomes obsolete after a few months.
Misinterpretation of guidelines
Over reacting to Regulatory guidelines
Simple problems have simple solutions
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Expectations
Members working in Research and Manufacturing
should consider a job rotation in Quality Assurance
and Regulatory Affairs
Universities and Institutes should proactively update
their post graduate syllabus to include QA and
Regulatory topics
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Communication is important
Communication, Interaction and Support between
Manufacturers and Regulators
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Let us strive to develop, manufacture, comply safe sale and
availability of medicines
Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals
- IPA / FDCA Workshop, Ahmedabad, Gujarat, 18th Dec 2012
Thank you