EU Directive 2001/83/EC Dr. P. V. Appaji, M.Pharm, Ph.D Presentation by Dr. P. V. Appaji, M.Pharm, Ph.D Director General, PHARMACEUTICALS EXPORT PROMOTION COUNCIL OF INDIA Hyderabad Email: dg@pharmexcil.com

CONTENTS Which are EU Countries? Objectives of EU Directive 2001/83/EC Definition of Falsified Medicinal Product Potential targets of EU Directive 2001/83/EC Current Indian Pharmaceutical Industry Status Advantages with EU Directive to India Disadvantages with EU Directive to India Possible Negotiations

Which Are EU Countries?

Objectives Of EU Directive 2001/83/EC Introduction of a New Term Falsified Medicinal Product Aims to prevent suspected medicines reaching patients Safety features to be harmonised within the Union Aims safety measures All through the supply chain (manufacturer to end user) Contd…

Objectives Of EU Directive 2001/83/EC Prevent distortions in the internal market Prevent falsified medicinal products entering the legal supply chain Aims at Ensuring Good Manufacturing Process of EU/EU Pharmacopoeia standards Aims at Pharmaceutical product quality for APIs, Generics formulations, Excipients at the manufacturing level

EU Defines Falsified Medicine As Any medicinal product with a false representation of: Its identity, inclusive of package and labeling, its name or its composition as regards to any of the ingredients inclusive of excipients and the strength of those ingredients; Its source, its manufacture, its country of manufacturing, its country of origin or its marketing authorisation holder; Its history: The records and documents relating to the distribution channels used The definition Excludes unintentional quality defects and is without prejudice to infringements of intellectual property rights

Potential Targets Of EU Directive 2001/83/EC Confirming GMP with audits (for APIs, formulations, Excipients) Confirming distribution with audits Confirming GMP practices at least equivalent to those laid down by the Union Notification to the authority for any changes that may impact on the quality or safety of the active substances that are manufactured, imported or distributed Contd…

Potential Targets Of EU Directive 2001/83/EC Implementation of anti-tampering devices Maintaining records in the form of purchase/sales at various levels of supply chain Persons brokering medicinal products are also subject to inspection by competent authorities Persons brokering must have permanent address, contact details in the Union Contd…

Potential Targets Of EU Directive 2001/83/EC Repeated inspections of Manufacturers (located in the Union or in third countries) and wholesale distributors of medicinal products Inspections of the premises of marketing authorisation holders and of brokers of medicinal products are possible Data submitted to comply with monographs of European Pharmacopoeia

Current Indian Pharmaceutical Industry Status India is a leading exporter of quality pharmaceutical products globally Indian exporters comply with ISO, GMP/WHO GMP, ICH guidelines etc., Indian Drugs & Cosmetic Act terminology - Spurious drugs - Not of standard quality or substandard drugs - Adulterated drugs - Misbranded drugs may fall under the purview with international acts

Directive 2001/83/EC as amended by Directive 2011/62/EU EU rules for import of API’s. According to Articles 46b 2(b) i, ii & iii Written confirmation from the competent authority of the exporting third country of the following: The standards of good manufacturing practice applicable to the plant manufacturing the exported active substance are at least equivalent to those laid down by the Union. The manufacturing plant concerned is subject to regular, strict and transparent controls and to the effective enforcement of good manufacturing practice, including repeated and unannounced inspections, so as to ensure a protection of public health at least equivalent to that in the Union; In the event of findings relating to non-compliance, information on such findings is supplied by the exporting third country to the Union without any delay.

Implementation Of The New Directive Concept paper submitted for public consultation. “Implementing act on the requirements for the assessment of the regulatory framework applicable to the manufacturing of Active Substances of Medicinal products for Human Use”. Consultation closed on March 23 , 2012. Implementation date : July 2013

Written Confirmation & Equivalence Assessment (111b) Written confirmation waived for countries to be listed as per Article 111b. Third country to request for “Equivalence assessment” Assessment to be done by the commission If assessment confirms equivalence , third country will be included in the list. Regular verification thereafter.

Equivalence Assessment A review of relevant documentation An on-site review of the third country's regulatory system, unless a mutual recognition agreement ('MRA') is in place that covers the manufacturing of active substances; and If necessary, an observed inspection of one or more of the third country's manufacturing sites for active substances.

Country's Rules For GMP (111b(1)(a)) Third countries rules for GMP implementation Pending the adoption of a delegated act on the principles and guidelines of good manufacturing practice for Active Substance EU rules to be taken into account are contained in Part II of the good manufacturing practice guideline of the EU (Eudralex Volume 4).

Regular Verification Article 111b(3) The Commission shall verify regularly whether the conditions of the GMP equivalence are fulfilled The first verification shall take place no later than three years after the country has been included in the list.

Minimum Expectations Of New Directive The manufacture of active substances should be subject to good manufacturing practice regardless of whether those active substances are manufactured in the Union or imported. With regard to the manufacture of active substances in third countries, it should be ensured that the legislative provisions applicable to the manufacturing of active substances intended for export to the Union, as well as inspections of facilities and enforcement of the applicable provisions, provide for a level of protection of public health equivalent to that provided for by Union law.

Responsibility of Formulators in the new directive A written confirmation that the manufacturer of the medicinal product has verified, compliance of the manufacturer of the active substance with principles and guidelines of good manufacturing practice by conducting audits, in accordance with point (f) of Article 46. The written confirmation shall contain a reference to the date of the audit and a declaration that the outcome of the audit confirms that the manufacturing complies with the principles and guidelines of good manufacturing practice.

Global Bulk Drugs Imports Region Wise (Values In US$ Mn) Sr. no  Region 2008 2009 2010 YOY % %share 1 EU 14794.04 15649.54 16673.38 6.54 50.58 2 North America 7379.52 4494.00 3866.23 -13.97 11.73 3 LAC 2180.33 3338.82 3611.87 8.18 10.96 4 Asia (Excluding Middle East) 2337.40 2445.33 2611.03 6.78 7.92 5 Other European Countries 1483.95 1045.19 1680.84 60.82 5.10 6 Asean 1211.84 1250.18 1255.68 0.44 3.81 7 South Asia 1069.94 1079.49 1082.13 0.24 3.28 8 Middle East 761.60 599.14 995.23 66.11 3.02 9 Africa 420.60 423.74 450.69 6.36 1.37 10 Oceania 392.32 368.32 378.67 2.81 1.15 11 CIS 261.88 385.31 355.17 -7.82 1.08 12 Other America 4.37 5.43 6.19 14.10 0.02   World 32297.79 31084.49 32967.11 6.06 Source : UN COMTRADE

PIC/S Pharmaceutical Inspection Convention (PIC) & Pharmaceutical Inspection Co-operation Scheme (PICS)

Brief note on PIC/S PICS Established in 1995. Current members – 40 Participating Authorities Partners a) EDQM European Directorate for Quality of Medicines and Health Care, France b) EMA- European Medicines Agency c) UNICEF d) WHO Requirements : Law on medicinal products. A GMP guide equivalent to PIC/S or EU GMP Guide. A GMP inspectorate fulfils PIC/S quality system requirements. Experienced GMP inspectors

Objective of PIC/S An active and constructive co-operation in the field of GMP. To facilitate networking between participating authorities and to increase mutual trust, to exchange information and experience, in the field of GMP and related areas, and mutual training of GMP inspectors. Attain confidence of drug regulatory authority. Avoid duplication relating to → Inspections → Licensing procedures → Expenditure → One time procedure

Goals of PIC/S Mutual recognition of Inspections. Harmonisation of GMP requirements. Uniform inspection systems. Training of inspectors. Exchange of information. Mutual confidence.

Financial Costs PIC/S Constituted fee 8,100 CHF PIC/S Committee meetings – 2 per annum Seminars - 1 per year. Expert Circle meetings 3- per annum Events duration are 1 to 3 days in other PIC/S countries. Registration fee 8100 CHF & In assessment process, annual fee is 50% of Reg. fee for expert.

Benefits PIC/S is not a trade agreement. Membership in PIC/S may facilitate the export of pharmaceuticals. Non-PIC/S Countries (e.g. Colombia) may accept accreditation of PIC/S participating Authorities. Consequently, the Pharmaceutical industry located in these countries indirectly benefits PIC/S membership.