Supplier Management and Outsourcing Falsification – new European legislation –

Transcription

Supplier Management and Outsourcing
Falsification – new European legislation –
and how to prevent counterfeit medicines
in the supply chain
FDA/Xavier PharmaLINK Conference, March 2013
Cincinnati, USA
Anne Junttonen
Senior Pharmaceutical Inspector
EU/EEA European Economic Area
• Austria
Belgium
Bulgaria
Cyprus
Czech Republic
Denmark
Estonia
Finland
France
Germany
Lääkealan turvallisuus- ja kehittämiskeskus
Greece
Hungary
Iceland
Republic of Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
March 12, 2013 Anne Junttonen
The Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
UK
EU agreements with non-EEA countries
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/documen
t_listing/document_listing_000248.jsp&mid=WC0b01ac058005f8ac
http://ec.europa.eu/enterprise/policies/single-market-goods/internationalaspects/acaa-neighbouring-countries/index_en.htm
MRA
ACAA
Mutual Recognition
Agreements
•
•
•
•
•
Switzerland
Canada
Australia
New Zealand
Japan (limited scope)
Agreement on Conformity
Assessment and Acceptance
of Industrial Products
• Israel (GMPs 19 Jan
2013)
(USA not in operation)
Supplier Management and Outsourcing - facts to
note
• Marketing Authorization MA of the Medicinal product defines
all the manufacturing sites involved in the manufacturing of the
API and the medicinal product, including the manufacturing
site of release.
• The importer into EEA and the release site must locate in
the EEA and have a Manufacturing and Importation
Authorization MIA.
• Before release for supply the Qualified Person of the site of
release must certify that the batch has been manufactured in
accordance with the MA of the destination country, with EU
GMPs, or equivalent, and any legal requiments of the
releasing and the destination member states.
Supplier Management and Outsourcing
The site of release is viewed as the actual
Contract Giver and all the other players as
Contract acceptors and subcontractors.
The Qualified Person
(Dir. 2001/83/EC)
Articles 48 - 52
• Every MIA holder must have at least one QP
• Defined Qualifications are required
• The duties to ensure and certify batch compliance with GMP
and MA, incl. safety feature, records of the certification
• Actions to be taken by Members States
Oursourcing (EU GMP Guide) (1)
http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm
Chapter 1 Pharmaceutical Quality System
The regular Product Quality Review should include the
review of contractual arrangements as defined in Chapter
7 to ensure that they are up to date.
Chapter 7 Outsourced Activities
• The Contract Giver should be responsible for reviewing and
assessing the records and the results related to the
outsourced activities. He should also ensure, either by
himself, or based on the confirmation of the Contract
Acceptor’s Qualified Person, that all products and materials
delivered to him by the Contract Acceptor have been
processed in accordance with GMP and the marketing
authorisation.
Annex 16 Certification by a Qualified Person and Batch
Release:
• Each batch of finished product* must be certified by a Q.P.
within the EEA before being released for sale or supply in
the EEA or for export.
• Manufacturing stages, including quality control QC testing,
may be conducted at different sites and by different
manufacturers. Each stage should be conducted in
accordance with the relevant MA, GMP and the laws of the
MS concerned, and should be taken into account by the
Q.P. who certifies the finished product batch.
• Certification need not be repeated on the same batch
provided the batch has remained within the EEA.
*in its final pack for release to the market.
Release:
• This Q.P. may need therefore to rely in part on the advice and
decisions of others. Before doing so he should ensure that
this reliance is well founded, either from personal
knowledge or from the confirmation by other Q.P.s within
a quality system which he has accepted.
• This confirmation by other Q.P.s should be documented
and should identify clearly the matters which have been
confirmed. The systematic arrangements to achieve this
should be defined in a written agreement.
Chapter 7 Outsourced Activities
• the Contract Giver is responsible for assessing the legality*,
suitability and the competence of the Contract Acceptor…
• The Contract Acceptor should not subcontract to a third party …
without the Contract Giver’s prior evaluation and approval….
Arrangements… should ensure that information and knowledge,
including those from assessments of the suitability of the third
party, are made available…
• outsourced activities may be subject to inspections
• Contract Giver must be permitted to audit outsourced activities,
performed by the Contract Acceptor or his mutually agreed
subcontractors.
Release:
• Unless a MRA is in operation samples from each batch
should be tested in the EEA before certification of the finished
product batch by a Q.P.
• In order to represent the batch it may be preferable to take
some samples during processing in the third country. For
example, samples for sterility testing may best be taken
throughout the filling operation. However in order to represent
the batch after storage and transportation some samples
should also be taken after receipt of the batch in the EEA.
Annex 16 is being revised to address the
complicated supply chains
Maybe something
like this?
The entire supply chain of the medicinal product, starting
from the manufacturing sites of the starting materials and
components, and including all actors involved in any
manufacturing and importation activities of the medicinal
product, is documented for each medicinal product, and
available for the QP. The document should preferably be in
the format of a comprehensive diagram, where each actor,
including subcontractors of critical steps such as e.g. the
sterilization of components and equipment for aseptic
processing, are included.
.
Suppliers (EU GMP Guide) (1)
http://ec.europa.eu/health/human-use/quality/developements/index_en.htm
Draft Chapter 5: Production – public consultation on-going until
18 July 2013
• 5.26 The selection, qualification, approval and
maintenance of suppliers of starting materials, together with
their purchase and acceptance, should be documented as
part of the pharmaceutical quality system. The level of
supervision should be proportionate to the risks posed
by the individual materials, taking account of their source,
manufacturing process, supply chain complexity and the final
use to which the material is put in the medicinal product. The
supporting evidence for each supplier / material approval
should be maintained. Staff involved in these activities should
have a current knowledge of the suppliers, the supply chain
and the associated risks involved. Where possible starting
materials should be purchased directly from the
manufacturer of the starting material.
Lääkealan turvallisuus- ja kehittämiskeskus March 12, 2013 Anne Junttonen
18 July 2013
(5.26)
• The quality requirements established by the manufacturer for
the starting materials should be discussed and agreed with
the suppliers. Appropriate aspects of the production, and
control, including handling, labelling, packaging and
distribution requirements, complaints, recalls and rejection
procedures should be documented in a quality agreement or
specification.
Chapter 4: Documentation
4.14 Specifications for starting and primary or printed
packaging materials should include or provide reference to, if
applicable:
a) A description of the materials, including:
- The designated name and the internal code reference;
- The reference, if any, to a pharmacopoeial monograph;
- The approved suppliers and, if reasonable, the original
producer of the material;
- A specimen of printed materials;
b) Directions for sampling and testing;
c) Qualitative and quantitative requirements with acceptance
limits;
18 July 2013
5.27 For the approval and maintenance of suppliers of active
substances and excipients, the following is required:
Active substances
• Supply chain traceability should be established and the
associated risks, from active substance starting materials
to the finished medicinal product, should be formally
assessed and periodically verified. Appropriate measures
should be put in place to reduce risks to the quality of the
active substance.
• The supply chain and traceability records for each active
substance (including active substance starting materials)
should be available and be retained by the EEA based
manufacturer or importer of the medicinal product.
18 July 2013
(5.27)
• Audits should be carried out at the manufacturers and
distributors of active substances… The holder of the
manufacturing authorization shall verify such compliance
either by himself or through an entity acting on his behalf
under a contract. For veterinary medicinal products, audits
should be conducted based on risk.
• Audits should be of an appropriate duration and scope…
The report should fully reflect what was done and seen on the
audit with any deficiencies clearly identified. Corrective and
preventive actions should be implemented.
18 July 2013
(5.27)
• Further audits should be undertaken at intervals defined by
the quality risk management process to ensure the
maintenance of standards and continued use of the approved
supply chain.
Excipients
• Excipients which are considered to pose a particular risk to
the quality of the medicinal product, based on formalised
quality risk management, should be given similar attention
to those for active substances.
18 July 2013
5.28 For each delivery of starting material the containers should
be checked for integrity of package, including tamper evident
seal where relevant, and for correspondence between the
delivery note, the supplier’s labels and approved supplier
information maintained by the medicinal product manufacturer.
The receiving checks on each delivery should be documented.
5.31 There should be appropriate procedures or measures to
assure the identity of the contents of each container of
starting material. Bulk containers from which samples have
been drawn should be identified.
ANNEX 8 SAMPLING OF STARTING AND PACKAGING MATERIALS
• The identity of a complete batch of starting materials can
normally only be ensured if individual samples are taken
from all the containers and an identity test performed on
each sample. It is permissible to sample only a proportion of
the containers where a validated procedure has been
established to ensure that no single container of starting
material has been incorrectly labelled. ...
• It is improbable that a procedure could be satisfactorily
validated for:
— starting materials supplied by intermediaries such as
brokers where the source of manufacture is unknown or not
audited;
— starting materials for use in parenteral products.
Draft Chapter 5: Production – public consultation on-going
5.33
Manufacturers of finished products are responsible for
any testing of starting materials as described in the marketing
authorisation dossier. They can utilise partial or full test results
from the approved starting material manufacturer but must, as a
minimum, perform identification testing of each batch themselves
according to annex 8.
… the following requirements should be fulfilled:
• a) A formal agreement should be signed, according to chapter
7,… special attention should be paid to those related to the
distribution conditions (transport, wholesaling, storage and
delivery) in order to maintain the quality characteristics of the
starting materials and to ensure that test results remain
applicable to the delivered material
(5.33)
• b) The finished product manufacturer should perform audits at
appropriate intervals at the site(s) carrying out the testing
(including sampling) of the starting materials in order to assure
compliance with Good Manufacturing Practice and with the
specifications and testing methods described in the Marketing
Authorisation dossier.
• c) The certificate of analysis provided by the starting material
manufacturer should be signed by a designated person with
appropriate qualifications and experience. This person should
ensure that each batch has been manufactured and checked for
compliance with the requirements of the formal agreement.
(5.33)
• d) The finished product manufacturer should have a significant
experience in dealing with the starting material manufacturer
including assessment of batches previously received and the
history of compliance before reducing in-house testing. Any
significant change in the manufacturing or testing processes should
be considered.
• e) The finished product manufacturer should also perform a full
analysis at appropriate intervals and compare the results with the
supplier’s certificate of analysis in order to check the reliability of
the latter. Should this testing identify any discrepancy then an
investigation should be performed and appropriate measures taken.
The acceptance of certificate of analysis from the supplier
should be discontinued until these measures are completed.
18 July 2013
(5.33)
Notes:
• 1. A similar approach should apply to packaging
materials as stated in GMP part I,…
• 2. Identity testing of starting materials should be performed
according to the methods and the specifications of the
relevant Marketing Authorisation dossier.
Draft Chapter 5: Production – public consultation on-going:
5.42 The purchase, handling and control of primary and
printed packaging materials shall be accorded attention
similar to that given to starting materials.
5.43 Particular attention should be paid to printed materials. ..
stored in adequately secure conditions … avoid mix-ups.
Packaging materials should be issued for use only by
authorised personnel following an approved and documented
procedure.
…braille…
Falsified Medicines Directive FMD
2007 cases of falsified medicinal products in the legal supply chain in
some Member States
2008 heparin adulteration
Dec 2008 Proposal published to amend the Medicines directive
(2001/83/EC) as regards the prevention of the entry into the legal
supply chain of medicinal products which are falsified in relation to
their identity, history or source.
July 2011 Falsified Medicines Directive (2011/62/EU) published
Jan 2013 Directive entry into force in MSs with some exceptions
regarding application deadlines.
Legal Proposal: 3 Pillars + 1 added by EP
1.
Safety
Features
2.
3.
4.
Supply Chain
Active
Substances
Internet Sale
and
Good
Distribution
Practices
Lääkealan turvallisuus- ja kehittämiskeskus Anne
MarchJunttonen
12, 2013
FMD: Definition of a Falsified medicinal product
• Any medicinal product with a false representation of:
a) its identity, including its packaging and labelling, its
name or its composition as regards any of the
ingredients including excipients and the strength of
those ingredients;
b) its source, including its manufacturer, its country of
manufacturing, its country of origin or its marketing
authorisation holder; or
c) its history, including the records and documents relating
to the distribution channels used.
This definition does not include unintentional quality
defects and is without prejudice to infringements of
intellectual property rights.
Falsified Medicines Directive 2011/62/EU (1)
Applies only to commercial medicinal products for human
use.
Does not apply to Investigational Medicinal Products IMPs or
veterinary medicines.
Increased controls of APIs and excipients.
Increased obligations on wholesale distributors and
extending regulation to brokers of medicinal product.
Provisions for introduction of medicines to EU territory for
export - and not to be placed on EU market; e.g. in free trade
zones and warehouses.
Falsified Medicines Directive 2011/62/EU (2)
Requiring safety features on medicinal products at risk of
falsification.
Inspections e.g. of manufacturers, importers and distributors of
APIs – also in 3. countries, manufacturers or importers of
excipients, and of bokers.
Addressing internet supply of medicinal products to the public.
Penalties for falsification
Product recall system down to patients.
Illegal Supply Chain
• Medicines/pharmaceuticals/intermediates/
APIs/ are supplied and/or received by
persons/players/actors with no legal
entitlement
• Out of ignorance or deliberately?
• Awareness campaigns!
Players in the legal Supply Chain
• Marketing Authorization holders MAH
FDM
• API manufacturers, importers and distributors
• Excipient manufacturers and importers
• Medicinal Product manufacturers, inc. partial
manufacturing/subcontractors, EEA importers, release
testing laboratories, release site
• Brokers of Medicinal product
• Wholesale Distributors
• Authorized/qualified/entitled suppliers of medicinal products
to the public – including internet sales
Legal API supply chain (1)
FDM
Manufacturers are defined in the MA
with a ”QP Declaration”:
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,… 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
and for biological and/or sterile APIs:
• GMP certificate by EEA competent authority - or
in accordance with MRA, ACAA – entered into
EudraGMDP database.
FDM
• … manufactured in accordance with good manufacturing
practice for active substances and distributed in accordance
with good distribution practices for active substances.
• … the holder of the manufacturing authorisation shall
verify compliance…. by conducting audits at the
manufacturing and distribution sites of the manufacturer
and distributors of active substances... either by himself or,
without prejudice to his responsibility as provided for in this
Directive, through an entity acting on his behalf under a
contract.
FMD: GDP for APIs
DRAFT
• GUIDELINES ON THE PRINCIPLES OF GOOD DISTRIBUTION
PRACTICES FOR ACTIVE SUBSTANCES FOR MEDICINAL
PRODUCTS FOR HUMAN USE DRAFT SUBMITTED FOR PUBLIC
CONSULTATION
PUBLIC CONSULTATION until 30 April 2013
http://ec.europa.eu/health/files/gmp/2013-02_gdp_for_api_cons.pdf
FDM
• Manufacturers, importers and distributors in
EEA must be registered with the Competent
Authority CA of the Member State MS where
located – entry into EudraGMDP database.
• CA of the MS concerned shall have a system of supervision
including by inspections at an appropriate frequency based on risk,
at the premises of the manufacturers, importers, or distributors of
active substances, located on its territory, and effective follow-up
thereof
FDM
API shall only be imported (to EEA) if:
• API manufactured in accordance with at least EU equivalent
GMP
• API accompanied by written confirmation from the CA of
the exporting country on the GMP, supervision and prompt
information sharing of Non-compliance issues regarding the
manufacturing plant
• Waivers form the Requirement of written confirmation:
• The exporting country is included in the Commission’s list
(“white list”).
• Exceptionally to ensure the availability of medicinal
products and when the plant has been inspected by a EEA
CA – by a valid GMPc.
To be applied July 2013.
FMD: Importation of APIs
QUESTIONS AND ANSWERS ON THE IMPORTATION OF
ACTIVE SUBSTANCES FOR MEDICINAL PRODUCTS FOR
HUMAN USE
http://ec.europa.eu/health/files/gmp/2013_01_28_qa_en.pdf
Template for the 'written confirmation' for active substances
exported to the European Union for medicinal products for
human use, in accordance with Article 46b(2)(b) of Directive
2001/83/EC
http://ec.europa.eu/health/files/gmp/2013_01_28_template.pdf
Third countries which have so far requested to be listed:
Switzerland (approved), Australia, Japan, USA, Israel, Brazil,
Singapore,
FMD: GMP of Excipients (1)
• The holder of the manufacturing authorisation
shall ensure that the excipients are suitable for use in
medicinal products by ascertaining what the appropriate good
manufacturing practice is. This shall be ascertained on the
basis of a formalised risk assessment...
• … shall ensure that the appropriate good manufacturing
practice so ascertained, is applied. The holder of the
manufacturing authorisation shall document the measures
taken under this paragraph;
FMD: GMP of Excipients (2)
DRAFT
GUIDELINES ON THE FORMALISED RISK ASSESSMENT FOR
ASCERTAINING THE APPROPRIATE GOOD MANUFACTURING
PRACTICE FOR EXCIPIENTS OF MEDICINAL PRODUCTS FOR
HUMAN USE
• PUBLIC CONSULTATION until 30 April 2013
http://ec.europa.eu/health/files/gmp/2013-02_guidelines_excipients_cons.pdf
Medicinal Product manufacturing sites
• including partial manufacturing e.g. contract
manufacturers
• Located in EEA:
FDM
• valid Manufacturing and Importation
Authorization MIA entered into EudraGMDP
database
• Located outside EEA:
• valid GMP certificate issued by EEA
competent authority - or in accordance with
MRA, ACAA - entered into EudraGMDP
database
FMD: Medicinal Product Manufacturers
• …to inform the competent authority and the marketing
authorisation holder immediately if he obtains information that
medicinal products which come under the scope of his
manufacturing authorisation are, or are suspected of being,
falsified irrespective of whether those medicinal products
were distributed within the legal supply chain or by illegal
means, including illegal sale by means of information society
services;
• … to verify that the manufacturers, importers or distributors
from whom he obtains active substances are registered
with the competent authority of the Member State in which
they are established;
• …to verify the authenticity and quality of the active
substances and the excipients
FMD: Safety features (1)
• for medicinal products other than radiopharmaceuticals
• safety features enabling wholesale distributors and persons
authorised or entitled to supply medicinal products to the
public to:
— verify the authenticity of the medicinal product, and
— identify individual packs,
as well as a device allowing verification of whether the outer
packaging has been tampered with.
• …shall not be removed or covered, either fully or partially,
unless the following conditions are fulfilled:
• (a) the manufacturing authorisation holder verifies, prior to
partly or fully removing or covering those safety features, that
the medicinal product concerned is authentic and that it has
not been tampered with;
• (b) …replacing those safety features with safety features
which are equivalent as regards the possibility to verify the
authenticity, identification and to provide evidence of
tampering of the medicinal product. … without opening the
immediate packaging
•…
• Medicinal products subject to prescription shall bear the
safety features…, unless they have been listed…
• Medicinal products not subject to prescription shall not
bear the safety features…, unless… they have been listed…
after having been assessed to be at risk of falsification.
• The Commission shall … detailed rules for the safety
features...
to be applied within 3 (or 6) years after the date of publication
of the Commissions delegated acts
• DELEGATED ACT ON THE DETAILED RULES FOR A
UNIQUE IDENTIFIER FOR MEDICINAL PRODUCTS FOR
HUMAN USE, AND ITS VERIFICATION
PUBLIC CONSULTATION ON THE CONCEPT PAPER
Ended April 2012.
http://ec.europa.eu/health/files/counterf_par_trade/safety_2011-11.pdf
Responses to the public consultation has been published:
http://ec.europa.eu/health/humanuse/falsified_medicines/developments/2013-01_pc1_en.htm
Wholesale distribution of medicinal products
• All activities consisting of procuring, holding,
supplying or exporting medicinal products,
apart from supplying medicinal products to the
public. Such activities are carried out with manufacturers or
their depositories, importers, other wholesale distributors or
with pharmacists and persons authorized or entitled to supply
medicinal products to the public in the Member State
concerned (EU Medicines Directive 2001/83/EC).
Wholesale Distributors
• Wholesale Distribution authorization WDA
entered into EudraGMDP database
FDM
• whether or not they physically handle the
medicinal products; ”virtual” wholesalers
• whenever on Union territory - including in areas
such as free trade zones or free warehouses
Revised EU GDP rules for medicinal
products in the EU published March 8, 2013
introduces e.g. rules for
• Quality Management, incl. QRM
• appropriate management of suspected falsified medicinal
products;
• outsourced activities
• qualification of suppliers and customers – and brokers
• for transport in particular to protect medicinal products
against breakage, adulteration and theft, and to ensure that
temperature conditions are maintained within acceptable
limits during transport;
• for exporting
• for brokers
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2013:068:0001:0014:EN:PDF
EU GDP Guide 5.9. Export to third countries
• …person exporting medicinal products must hold a wholesale
distribution authorisation or a manufacturing authorisation.
This is also the case if the exporting wholesale
distributor is operating from a free zone.
• … they shall ensure that such supplies are only made to
persons who are authorised or entitled to receive medicinal
products for wholesale distribution or supply to the public in
accordance with the applicable legal and administrative
provisions of the country concerned.
Medicines Directive 2001/83/EG
revised Article 85a as amended by Directive 2012/26/EU
In the case of wholesale distribution of medicinal products to third
countries,… wholesale distributors shall ensure that the medicinal
products
are obtained only from persons who are authorised or entitled
to supply medicinal products in accordance with the
applicable legal and administrative provisions of the third
country concerned.
…supplies are only made to persons who are authorised or entitled
to receive medicinal products for wholesale distribution or supply to
the public in accordance with the applicable legal and
administrative provisions of the third country concerned.
…
FMD: Brokering of Medicinal Products (1)
Definition:
• All activities in relation to the sale or purchase of medicinal
products, except for wholesale distribution, that do not include
physical handling and that consist of negotiating
independently and on behalf of another legal or natural
person.
FMD: Brokering of Medicinal Products (2)
• Only medicinal products covered by a marketing authorisation
granted in EU
• Register their activity with the competent authority of the MS
where they are located; registration to be entered in a publicly
accessible register.
• Must have permanent address and contact details in EU
• Must notify authorities of changes without delay
Retail supply of Medicinal Products to the
public
• National legislation of EU Member states applies
but
• Sale of medicinal products to the public via the
Internet:
• The public should be assisted in identifying
websites which are legally offering medicinal
products for sale at a distance to the public.
• awareness campaigns to warn of the risks of
purchasing medicinal products from illegal
sources via the Internet.
Retail supply of Medicinal Products to the
public / FI National legislation
• Only Finished Medicinal products – no intermediates, APIs,
• Only by authorized pharmacies, hospital pharmacies and
dispensaries (except for nicotine gum)
• Distant sales e.g. internet sales only from authorized
pharmacies within EEA.
• There must always be a prescription when a prescription
would be required in Fi.
• No medicines from outside the EEA by mail!
March 12, 2013
Anne Junttonen

Supplier Management and Outsourcing Falsification – new European legislation –

Transcription

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