EU Directive 2001/83/EC

Dr. P. V. Appaji, M.Pharm, Ph.D

Director General,PHARMACEUTICALS EXPORT PROMOTION COUNCIL OF INDIA

HyderabadEmail: dg@pharmexcil.com

Presentation by

CONTENTSWhich are EU Countries?Objectives of EU Directive 2001/83/ECDefinition of Falsified Medicinal ProductPotential targets of EU Directive 2001/83/ECCurrent Indian Pharmaceutical Industry StatusAdvantages with EU Directive to IndiaDisadvantages with EU Directive to IndiaPossible 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…

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

Objectives Of EU Directive 2001/83/EC

EU Defines Falsified Medicine AsAny medicinal product with a false representation of:

a. 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;

b. Its source, its manufacture, its country of manufacturing, its country of origin or its marketing authorisation holder;

c. 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…

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

Potential Targets Of EU Directive 2001/83/EC

Contd…

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

Potential Targets Of EU Directive 2001/83/EC

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

EU rules for import of API’s.

According to Articles 46b 2(b) i, ii & iiiWritten 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.

Directive 2001/83/EC as amended by Directive 2011/62/EU

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 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.

Written Confirmation & Equivalence Assessment (111b)

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.

Equivalence Assessment

Third countries rules for GMP implementationPending 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).

Country's Rules For GMP (111b(1)(a))

Article 111b(3)The Commission shall verify regularly whether the conditions of

the GMP equivalence are fulfilledThe first verification shall take place no later than three years

after the country has been included in the list.

Regular Verification

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.

Minimum Expectations Of 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.

Responsibility of Formulators in the new directive

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/SPharmaceutical Inspection Convention (PIC)

&Pharmaceutical Inspection Co-operation

Scheme (PICS)

• PICS Established in 1995.• Current members – 40 Participating Authorities • Partners

a) EDQM European Directorate for Quality of Medicines and Health Care, Franceb) EMA- European Medicines Agencyc) UNICEFd) 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

Brief note on PIC/S

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

• Mutual recognition of Inspections.

• Harmonisation of GMP requirements.

• Uniform inspection systems.

• Training of inspectors.

• Exchange of information.

• Mutual confidence.

Goals of PIC/S

• 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.

Financial Costs

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.

Benefits