regulatory compliance for global pharma market dr rajiv a. desai president – quality dishman...

Regulatory Compliance for Global Pharma Market

Dr Rajiv A. DesaiPresident – QualityDishman Pharmaceuticals and Chemicals LtdAhmedabad , INDIA

Workshop Organised by

Ahmedabad, Gujarat 18th December 2012

Regulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18 th Dec 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

Pharma share around the world

33% USA

30% Europe18% Japan

7% Latin America

6% China

2% 2% 1% 1%

USEuropeJapanLatin AmericaChinaMiddle EastAustraliaCanadaAfrica


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

Generic Pharmaceutical Industry


Year Patent expiry of Drugs2010 142011 82012 212013 72014 142015 62016 12017 42018 22019 12020 12021 1

Patent expiration of drugs (year wise )


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

Opportunities in the US Market


UK Germany Netherlands France Spain Italy

0

10

20

30

40

50

60

70

6155

50

3225

17

Generic Penetration in Europe

European Generics market is diverse

Regulations and Generics penetration varies across Countries

Several governments have implemented measures at reducing healthcare spending

Opportunities in the Europe 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 2012This has gone up to ~ 30% by end of 2012

Opportunities in the Japanese 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

Opportunities in the Emerging Market


Increase in DMF submissions with the US FDA

Reference : US FDA presentation on GDUFA

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 20110

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Increase in ANDA submissions with the US FDA


Year 2011 saw the highest number of submissions

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 20110

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2006 2007 2008 2009 2010 20110

500

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Backlog of ANDAs


Reference : US FDA presentation on GDUFARegulatory Compliance for Global Pharma Market - Dr Rajiv Desai , Dishman Pharmaceuticals - IPA / FDCA Workshop, Ahmedabad, Gujarat, 18 th Dec 2012

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

US FDA outside USA


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

US DMF filings from India


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


Generic Drug User Fee Act (GDUFA)

Fees for DMF (Drug Master file) $ 21,340 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

US FDA will now charge fees !


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


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

Recent European Union Directive


Format to be used for th

e Certification

as per EU

Current format as used by the FDCA, Gujarat

Initiative by the CDSCO on the EU directive


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


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

Opportunities


1 Protect Consumers ( Patients )

2 Collect evidence

Why is an audit done ?


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

Why an audit is required ?


– 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

Importance of an audit


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 !!

Audit methodologies


It’s a known fact that nobody is perfect, problems will be faced,

lets see how the problems are handled ….

1 Deviations / Non-conformance 2 Change controls3 OOS 4 Reprocess / Rework5 Rejections6 Complaints7 Preventive maintenance

New approach of auditing


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 !

Auditor’s wish list


Be on-line

Last minute preparation should be avoided

Concentrate on….

Team members

Facilities

Documents

Audit preparation


• 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 spendmore time at the shop floor talking to employees

During the audit


• 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

What do Auditors evaluate ?


• 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

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

During the audit


• 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

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)

During the audit – Unacceptable points


• 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

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

Response to the audit observations


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

Pharmaceutical

Semiconductor

Quality standard comparison


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

Setting high standards for Quality


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 guidelines


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

Expectations


Communication, Interaction and Support between Manufacturers and Regulators

Communication is important


Let us strive to develop, manufacture, comply safe sale and availability of medicines


Thank you

regulatory compliance for global pharma market dr rajiv a. desai president – quality dishman...

Documents

global pharma market

emerging market

matured market

us pharma market size

pharma share

brands generics market

world regulatory compliance

money slide